Glutathione S-conjugates as prodrugs to target drug-resistant tumors

PubMed Central

Ramsay, Emma E.; Dilda, Pierre J.

2014-01-01

Living organisms are continuously exposed to xenobiotics. The major phase of enzymatic detoxification in many species is the conjugation of activated xenobiotics to reduced glutathione (GSH) catalyzed by the glutathione-S-transferase (GST). It has been reported that some compounds, once transformed into glutathione S-conjugates, enter the mercapturic acid pathway whose end products are highly reactive and toxic for the cell responsible for their production. The cytotoxicity of these GSH conjugates depends essentially on GST and gamma-glutamyl transferases (γGT), the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and γGT expression were employed to selectively target tumor with GST- or γGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs. PMID:25157234

Glutathione- and pH-responsive nonporous silica prodrug nanoparticles for controlled release and cancer therapy

NASA Astrophysics Data System (ADS)

Xu, Zhigang; Liu, Shiying; Kang, Yuejun; Wang, Mingfeng

2015-03-01

A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were covalently encapsulated into silica matrices through glutathione (GSH)-responsive disulfide and pH-responsive hydrazone bonds, respectively, resulting in NPs with sizes tunable in the range of 50-200 nm. Both silica prodrug NPs showed stimuli-responsive controlled release upon exposure to a GSH-rich or acidic environment, resulting in improved anticancer efficacy. Notably, two prodrug NPs simultaneously taken up by HeLa cells showed a remarkable combinatorial efficacy compared to free drug pairs. These results suggest that the stimuli-responsive silica prodrug NPs are promising anticancer drug carriers for efficient cancer therapy.A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were

Transporter targeted gatifloxacin prodrugs: Synthesis, permeability, and topical ocular delivery

PubMed Central

Vooturi, Sunil K.; Kadam, Rajendra S.; Kompella, Uday B.

2013-01-01

Purpose To design and synthesize prodrugs of gatifloxacin targeting OCT, MCT, and ATB (0, +) transporters and to identify a prodrug with enhanced delivery to the back of the eye. Method Dimethylamino-propyl, carboxy-propyl, and amino-propyl(2-methyl) derivatives of gatifloxacin (GFX), DMAP-GFX, CP-GFX, and APM-GFX, were designed and synthesized to target OCT, MCT, and ATB (0, +) transporters, respectively. LC-MS method was developed to analyze drug and prodrug levels in various studies. Solubility and Log D (pH 7.4) were measured for prodrugs and the parent drug. Permeability of the prodrugs was determined in cornea, conjunctiva, and sclera-choroidretinal pigment epitheluim (SCRPE) and compared with gatifloxacin using Ussing chamber assembly. Permeability mechanisms were elucidated by determining the transport in the presence of transporter specific inhibitors. 1-Methyl-4-phenylpyridinium iodide (MPP+), nicotinic acid sodium salt, and α-methyl-DL-tryptophan were used to inhibit OCT, MCT, and ATB (0, +) transporters, respectively. A prodrug selected based on in vitro studies was administered as an eye drop to pigmented rabbits and the delivery to various eye tissues including vitreous humor was compared with gatifloxacin dosing. Results DMAP-GFX exhibited 12.8-fold greater solubility than GFX. All prodrugs were more lipophilic, with the measured Log D (pH 7.4) values ranging from 0.05 to 1.04, when compared to GFX (Log D: -1.15). DMAP-GFX showed 1.4-, 1.8-, and 1.9-fold improvement in permeability across cornea, conjunctiva, as well as SCRPE when compared to GFX. Moreover, it exhibited reduced permeability in the presence of MPP+ (competitive inhibitor of OCT), indicating OCT-mediated transport. CP-GFX showed 1.2-, 2.3- and 2.5-fold improvement in permeability across cornea, conjunctiva and SCRPE, respectively. In the presence of nicotinic acid (competitive inhibitor of MCT), permeability of CP-GFX was reduced across conjunctiva. However, cornea and SCRPE

Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.

PubMed

Kumar, Varun; Hong, Sam Y; Maciag, Anna E; Saavedra, Joseph E; Adamson, Douglas H; Prud'homme, Robert K; Keefer, Larry K; Chakrapani, Harinath

2010-02-01

We report the stabilization of the nitric oxide (NO) prodrugs and anticancer lead compounds, PABA/NO (O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and "Double JS-K" 1,5-bis-{1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato}-2,4-dinitrobenzene, through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO are protected from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit.

Transporter targeted gatifloxacin prodrugs: synthesis, permeability, and topical ocular delivery.

PubMed

Vooturi, Sunil K; Kadam, Rajendra S; Kompella, Uday B

2012-11-05

In this work, we aim to design and synthesize prodrugs of gatifloxacin targeting organic cation transporter (OCT), monocarboxylate transporter (MCT), and ATB (0, +) transporters and to identify a prodrug with enhanced delivery to the back of the eye. Dimethylamino-propyl, carboxy-propyl, and amino-propyl(2-methyl) derivatives of gatifloxacin (GFX), DMAP-GFX, CP-GFX, and APM-GFX, were designed and synthesized to target OCT, MCT, and ATB (0, +) transporters, respectively. An LC-MS method was developed to analyze drug and prodrug levels in various studies. Solubility and log D (pH 7.4) were measured for prodrugs and the parent drug. The permeability of the prodrugs was determined in the cornea, conjunctiva, and sclera-choroid-retinal pigment epitheluim (SCRPE) and compared with gatifloxacin using an Ussing chamber assembly. Permeability mechanisms were elucidated by determining the transport in the presence of transporter specific inhibitors. 1-Methyl-4-phenylpyridinium iodide (MPP+), nicotinic acid sodium salt, and α-methyl-DL-tryptophan were used to inhibit OCT, MCT, and ATB (0, +) transporters, respectively. A prodrug selected based on in vitro studies was administered as an eye drop to pigmented rabbits, and the delivery to various eye tissues including vitreous humor was compared with gatifloxacin dosing. DMAP-GFX exhibited 12.8-fold greater solubility than GFX. All prodrugs were more lipophilic, with the measured log D (pH 7.4) values ranging from 0.05 to 1.04, when compared to GFX (log D: -1.15). DMAP-GFX showed 1.4-, 1.8-, and 1.9-fold improvement in permeability across the cornea, conjunctiva, and SCRPE when compared to GFX. Moreover, it exhibited reduced permeability in the presence of MPP+ (competitive inhibitor of OCT), indicating OCT-mediated transport. CP-GFX showed 1.2-, 2.3-, and 2.5-fold improvement in permeability across the cornea, conjunctiva, and SCRPE, respectively. In the presence of nicotinic acid (competitive inhibitor of MCT), the

Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

PubMed Central

Mandal, Pijus K.; Gao, Fengqin; Lu, Zhen; Ren, Zhiyong; Ramesh, Rajagopal; Birtwistle, J. Sanderson; Kaluarachchi, Kumaralal K.; Chen, Xiaomin; Bast, Robert C.; Liao, Warren S.; McMurray, John S.

2011-01-01

Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure-activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the β-position of the pTyr mimic, 4-phosphocinfnamide, enhanced affinity 2–3 fold. Bis-pivaloyloxymethyl prodrugs containing β-methyl cinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5–1 µM in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3. PMID:21486047

Simvastatin Prodrug Micelles Target Fracture and Improve Healing

PubMed Central

Dusad, Anand; Yuan, Hongjiang; Ren, Ke; Li, Fei; Fehringer, Edward V.; Purdue, P. Edward; Goldring, Steven R.; Daluiski, Aaron; Wang, Dong

2014-01-01

Simvastatin (SIM), a widely used anti-lipidaemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug’s hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles’ therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing. PMID:25542644

Stabilization of the Nitric Oxide (NO) Prodrugs and Anti-Cancer Leads, PABA/NO and Double JS-K through Incorporation into PEG-Protected Nanoparticles

PubMed Central

Kumar, Varun; Hong, Sam Y.; Maciag, Anna E.; Saavedra, Joseph E.; Adamson, Douglas H.; Prud'homme, Robert K.; Keefer, Larry K.; Chakrapani, Harinath

2009-01-01

Here we report the stabilization of the nitric oxide (NO) prodrugs and anti-cancer lead compounds, PABA/NO (O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and “Double JS-K” (1,5-bis{[1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato]-2,4-dinitrobenzene), through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit. PMID:20000791

Folate Receptor-Mediated Enhanced and Specific Delivery of Far-Red Light-Activatable Prodrugs of Combretastatin A-4 to FR-Positive Tumor

PubMed Central

2015-01-01

We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1–4 (CA4-L-Pc-PEGn-FA: n = 0, 2, 18, ∼45) and one non-FA-conjugated prodrug 5 (CA4-L-Pc-PEG18-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more specific localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug. PMID:25351441

Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs.

PubMed

Eklund, Birgitta I; Gunnarsdottir, Sjofn; Elfarra, Adnan A; Mannervik, Bengt

2007-06-01

cis-6-(2-Acetylvinylthio)purine (cAVTP) and trans-6-(2-acetylvinylthio)guanine (tAVTG) are thiopurine prodrugs provisionally inactivated by an alpha,beta-unsaturated substituent on the sulfur of the parental thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). The active thiopurines are liberated intracellularly by glutathione (GSH) in reactions catalyzed by glutathione transferases (GSTs) (EC 2.5.1.18). Catalytic activities of 13 human GSTs representing seven distinct classes of soluble GSTs have been determined. The bioactivation of cAVTP and tAVTG occurs via a transient addition of GSH to the activated double bond of the S-substituent of the prodrug, followed by elimination of the thiopurine. The first of these consecutive reactions is rate-limiting for thiopurine release, but GST-activation of this first addition is shifting the rate limitation to the subsequent elimination. Highly active GSTs reveal the transient intermediate, which is detectable by UV spectroscopy and HPLC analysis. LC/MS analysis of the reaction products demonstrates that the primary GSH conjugate, 4-glutathionylbuten-2-one, can react with a second GSH molecule to form the 4-(bis-glutathionyl)butan-2-one. GST M1-1 and GST A4-4 were the most efficient enzymes with tAVTG, and GST M1-1 and GST M2-2 had highest activity with cAVTP. The highly efficient GST M1-1 is polymorphic and is absent in approximately half of the human population. GST P1-1, which is overexpressed in many cancer cells, had no detectable activity with cAVTP and only minor activity with tAVTG. Other GST-activated prodrugs have targeted GST P1-1-expressing cancer cells. Tumors expressing high levels of GST M1-1 or GST A4-4 can be predicted to be particularly vulnerable to chemotherapy with cAVTP or tAVTG.

Gene expression profiling for nitric oxide prodrug JS-K to kill HL-60 myeloid leukemia cells.

PubMed

Liu, Jie; Malavya, Swati; Wang, Xueqian; Saavedra, Joseph E; Keefer, Larry K; Tokar, Erik; Qu, Wei; Waalkes, Michael P; Shami, Paul J

2009-07-01

The nitric oxide (NO) prodrug JS-K is shown to have anticancer activity. To profile the molecular events associated with the anticancer effects of JS-K, HL-60 leukemia cells were treated with JS-K and subjected to microarray and real-time RT-PCR analysis. JS-K induced concentration- and time-dependent gene expression changes in HL-60 cells corresponding to the cytolethality effects. The apoptotic genes (caspases, Bax, and TNF-alpha) were induced, and differentiation-related genes (CD14, ITGAM, and VIM) were increased. For acute phase protein genes, some were increased (TP53, JUN) while others were suppressed (c-myc, cyclin E). The expression of anti-angiogenesis genes THBS1 and CD36 and genes involved in tumor cell migration such as tissue inhibitors of metalloproteinases, were also increased by JS-K. Confocal analysis confirmed key gene changes at the protein levels. Thus, multiple molecular events are associated with JS-K effects in killing HL-60, which could be molecular targets for this novel anticancer NO prodrug.

Troxacitabine prodrugs for pancreatic cancer.

PubMed

Adema, A D; Radi, M; Daft, J; Narayanasamy, J; Hoebe, E K; Alexander, L E; Chu, C K; Peters, G J

2007-01-01

Troxacitabine is a cytotoxic deoxycytidine analogue with an unnatural L-configuration, which is activated by deoxycytidine kinase (dCK). The configuration is responsible for differences in the uptake and metabolism of troxacitabine compared to other deoxynucleoside analogues. The main drawback in the use of most nucleoside anticancer agents originates from their hydrophilic nature, which property requires a high and frequent dosage for an intravenous administration. To overcome this problem several troxacitabine prodrugs modified in the aminogroup with a linear aliphatic chain with a higher lipophilicity were developed. To determine whether these prodrugs have an advantage over Troxacitabine pancreatic cancer cell lines were exposed to Troxacitabine and the lipophilic prodrugs. The addition of linear aliphatic chains to troxacitabine increased sensitivity of pancreatic cancer cell lines to the drug > 100-fold, possibly due to a better uptake and retention of the drug.

Targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission light-up apoptosis sensor for noninvasive early evaluation of its therapeutic responses in situ.

PubMed

Yuan, Youyong; Kwok, Ryan T K; Tang, Ben Zhong; Liu, Bin

2014-02-12

Targeted drug delivery to tumor cells with minimized side effects and real-time in situ monitoring of drug efficacy is highly desirable for personalized medicine. In this work, we report the synthesis and biological evaluation of a chemotherapeutic Pt(IV) prodrug whose two axial positions are functionalized with a cyclic arginine-glycine-aspartic acid (cRGD) tripeptide for targeting integrin αvβ3 overexpressed cancer cells and an apoptosis sensor which is composed of tetraphenylsilole (TPS) fluorophore with aggregation-induced emission (AIE) characteristics and a caspase-3 enzyme specific Asp-Glu-Val-Asp (DEVD) peptide. The targeted Pt(IV) prodrug can selectively bind to αvβ3 integrin overexpressed cancer cells to facilitate cellular uptake. In addition, the Pt(IV) prodrug can be reduced to active Pt(II) drug in cells and release the apoptosis sensor TPS-DEVD simultaneously. The reduced Pt(II) drug can induce the cell apoptosis and activate caspase-3 enzyme to cleave the DEVD peptide sequence. Due to free rotation of the phenylene rings, TPS-DEVD is nonemissive in aqueous media. The specific cleavage of DEVD by caspase-3 generates the hydrophobic TPS residue, which tends to aggregate, resulting in restriction of intramolecular rotations of the phenyl rings and ultimately leading to fluorescence enhancement. Such noninvasive and real-time imaging of drug-induced apoptosis in situ can be used as an indicator for early evaluation of the therapeutic responses of a specific anticancer drug.

Targeting Carcinoma-Associated Fibroblasts Within the Tumor Stroma With a Fibroblast Activation Protein-Activated Prodrug

PubMed Central

2012-01-01

Background Fibroblasts undergo a morphological transformation to a reactive phenotype in the tumor microenvironment characterized by the expression of proteins such as fibroblast activation protein (FAP), a post-prolyl endopeptidase with expression largely restricted to carcinoma-associated fibroblasts. Thapsigargin (TG) is a highly toxic natural plant product that triggers a rise in intracellular calcium levels and apoptosis. FAP is therefore a provocative target for the activation of prodrugs consisting of a FAP-specific peptide coupled to a potent cytotoxic analog of TG. Methods The efficacy of FAP-activated peptidyl-TG prodrugs was tested in vitro in cell proliferation assays and effects on intracellular calcium in human cancer cell lines. The effects of FAP-activated prodrugs on tumor growth and host toxicity were tested in Balb-C nude MCF-7 and LNCaP xenograft mice (n = 9–11 per group). P values were calculated using permutation tests based on 50 000 permutations. Mixed effects models were used to account for correlations among replicate measures. All statistical tests were two-sided. Results FAP-activated prodrugs killed human cancer cells at low nanomolar concentrations (MCF-7 cells: IC50 = 3.5nM). Amino acid-12ADT analogs from FAP-cleaved prodrugs, but not uncleaved prodrugs, produced a rapid rise in intracellular calcium within minutes of exposure. Immunohistochemical analysis of xenografts exposed to FAP-prodrugs documented stromal-selective cell death of fibroblasts, pericytes, and endothelial cells of sufficient magnitude to inhibit growth of MCF-7 and LNCaP xenografts with minimal systemic toxicity, whereas non-FAP cleavable prodrugs were inactive. MCF-7 and LNCaP xenografts treated with a FAP-activated prodrug had maximal treated-to-control tumor volume ratios of 0.36 (treated: mean = 0.206mm3, 95% CI = 0.068 to 0.344mm3; control: mean = 0.580mm3, 95% CI = 0.267 to 0.893mm3) and 0.24 (treated: mean = 0.131mm3, 95% CI = 0.09 to 0.180mm3; control

Suppression of inflammation in a mouse model of rheumatoid arthritis using targeted lipase-labile fumagillin prodrug nanoparticles.

PubMed

Zhou, Hui-Fang; Yan, Huimin; Senpan, Angana; Wickline, Samuel A; Pan, Dipanjan; Lanza, Gregory M; Pham, Christine T N

2012-11-01

Nanoparticle-based therapeutics are emerging technologies that have the potential to greatly impact the treatment of many human diseases. However, drug instability and premature release from the nanoparticles during circulation currently preclude clinical translation. Herein, we use a lipase-labile (Sn 2) fumagillin prodrug platform coupled with a unique lipid surface-to-surface targeted delivery mechanism, termed contact-facilitated drug delivery, to counter the premature drug release and overcome the inherent photo-instability of fumagillin, an established anti-angiogenic agent. We show that α(v)β(3)-integrin targeted fumagillin prodrug nanoparticles, administered at 0.3 mg of fumagillin prodrug/kg of body weight suppress the clinical disease indices of KRN serum-mediated arthritis in a dose-dependent manner when compared to treatment with the control nanoparticles with no drug. This study demonstrates the effectiveness of this lipase-labile prodrug nanocarrier in a relevant preclinical model that approximates human rheumatoid arthritis. The lipase-labile prodrug paradigm offers a translatable approach that is broadly applicable to many targeted nanosystems and increases the translational potential of this platform for many diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

Redox activation of metal-based prodrugs as a strategy for drug delivery

PubMed Central

Graf, Nora

2012-01-01

This review provides an overview of metal-based anticancer drugs and drug candidates. In particular, we focus on metal complexes that can be activated in the reducing environment of cancer cells, thus serving as prodrugs. There are many reports of Pt and Ru complexes as redox-activatable drug candidates, but other d-block elements with variable oxidation states have a similar potential to serve as prodrugs in this manner. In this context are compounds based on Fe, Co, or Cu chemistry, which are also covered. A trend in the field of medicinal inorganic chemistry has been toward molecularly targeted, metal-based drugs obtained by functionalizing complexes with biologically active ligands. Another recent activity is the use of nanomaterials for drug delivery, exploiting passive targeting of tumors with nanosized constructs made from Au, Fe, carbon, or organic polymers. Although complexes of all of the above mentioned metals will be described, this review focuses primarily on Pt compounds, including constructs containing nanomaterials. PMID:22289471

Synthesis and anti-cancer efficacy of rapid hydrolysed water-soluble paclitaxel pro-drugs.

PubMed

Ryu, Beom-Young; Sohn, Jeong-Sun; Hess, Michael; Choi, Soo-Kyung; Choi, Jae-Kon; Jo, Byung-Wook

2008-01-01

A new series of poly(ethylene glycol)(PEG)-paclitaxel conjugates that increases water solubility of paclitaxel was synthesized. We developed well-designed self-immolating linkers between a drug and a water-soluble polymer moiety which gave an extremely rapid hydrolysis rate to convert a pro-drug into a parent drug without any reduction in drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of paclitaxel in order to control the rate of enzymatic hydrolysis. All these pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-tumor efficacy of the pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-tumor activity and the anti-metastatic potential of the pro-drug were examined. The pro-drug was potent to inhibit the growth of various cancer cell lines, such as human lung, ovarian, colon and melanoma cancer cells. On the development of melanoma lung colonies in C57B/6 mice following intravenous administration of metastatic murine B16/F10 melanoma cells, the pro-drug seems to be more efficacious than paclitaxel. The reduction of the number of melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure paclitaxel, and 24.5%, and 40.0% with the pro-drug in the dose of 0.71 mg paclitaxel equivalent/kg and 1.42 mg paclitaxel equivalent/kg, respectively.

Biotin-Pt (IV)-indomethacin hybrid: A targeting anticancer prodrug providing enhanced cancer cellular uptake and reversing cisplatin resistance.

PubMed

Hu, Weiwei; Fang, Lei; Hua, Wuyang; Gou, Shaohua

2017-10-01

A Pt(IV) prodrug (2) composed of cancer-targeting biotin and nonsteroidal anti-inflammatory drug indomethacin in the axial positions of the six-coordinated octahedral geometry derived from cisplatin was developed, which could be highly accumulated in cancer cells more than normal ones and activated by endogenous reducing molecules to release cisplatin and indomethacin moieties simultaneously to inhibit tumor progression synergistically. In vitro assays revealed that 2 exhibited significantly selective inhibition to the tested cancer cell lines and sensitivity to cisplatin resistant cancer cells. Moreover, 2 presented cyclooxygenases inhibition properties to reduce tumor-associated inflammation, reduced the invasiveness of the highly aggressive PC-3 cells, and disrupted capillary-like tube formation in EA.hy926 cells. In all, this study offers a new strategy to enhance sensitivity and reduce toxicity of cisplatin. Copyright © 2017 Elsevier Inc. All rights reserved.

Re-engineering Cytochrome P450 2B11dH for Enhanced Metabolism of Several Substrates Including the Anti-cancer Prodrugs Cyclophosphamide and Ifosfamide

PubMed Central

Sun, Ling; Chen, Chong S.; Waxman, David J.; Liu, Hong; Halpert, James R.; Kumar, Santosh

2007-01-01

Based on recent directed evolution of P450 2B1, six P450 2B11 mutants at three positions were created in an N-terminal modified construct termed P450 2B11dH and characterized for enzyme catalysis using five substrates. Mutant I209A demonstrated a 3.2-fold enhanced kcat/Km for 7-ethoxy-4-trifluoromethylcourmarin O-deethylation, largely due to a dramatic decrease in Km (0.72 vs. 18 μM). I209A also demonstrated enhanced selectivity for testosterone 16β-hydroxylation over 16α-hydroxylation. In contrast, V183L showed a 4-fold increased kcat for 7-benzyloxyresorufin debenzylation and a 4.7-fold increased kcat/Km for testosterone 16α-hydroxylation. V183L also displayed a 1.7-fold higher kcat/Km than P450 2B11dH with the anti-cancer prodrugs cyclophosphamide and ifosfamide, resulting from a ~4-fold decrease in Km. Introduction of the V183L mutation into full-length P450 2B11 did not enhance the kcat/Km. Overall, the re-engineered P450 2B11dH enzymes exhibited enhanced catalytic efficiency with several substrates including the anti-cancer prodrugs. PMID:17254539

Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes.

PubMed

Biessen, Erik A L; Sliedregt-Bol, Karen; 'T Hoen, Peter A Chr; Prince, Perry; Van der Bilt, Erica; Valentijn, A Rob P M; Meeuwenoord, Nico J; Princen, Hans; Bijsterbosch, Martin K; Van der Marel, Gijs A; Van Boom, Jacques H; Van Berkel, Theo J C

2002-01-01

In this study, we present the design and synthesis of an antisense peptide nucleic acid (asPNA) prodrug, which displays an improved biodistribution profile and an equally improved capacity to reduce the levels of target mRNA. The prodrug, K(GalNAc)(2)-asPNA, comprised of a 14-mer sequence complementary to the human microsomal triglyceride transfer protein (huMTP) gene, conjugated to a high-affinity tag for the hepatic asialoglycoprotein receptor (K(GalNAc)(2)). The prodrug was avidly bound and rapidly internalized by HepG2s. After iv injection into mice, K(GalNAc)(2)-asPNA accumulated in the parenchymal liver cells to a much greater extent than nonconjugated PNA (46% +/- 1% vs 3.1% +/- 0.5% of the injected dose, respectively). The prodrug was able to reduce MTP mRNA levels in HepG2 cells by 35-40% (P < 0.02) at 100 nM in an asialoglycoprotein receptor- and sequence-dependent fashion. In conclusion, hepatocyte-targeted PNA prodrugs combine a greatly improved tropism with an enhanced local intracellular availability and activity, making them attractive therapeutics to lower the expression level of hepatic target genes such as MTP.

Targeted anticancer therapy: overexpressed receptors and nanotechnology.

PubMed

Akhtar, Mohd Javed; Ahamed, Maqusood; Alhadlaq, Hisham A; Alrokayan, Salman A; Kumar, Sudhir

2014-09-25

Targeted delivery of anticancer drugs to cancer cells and tissues is a promising field due to its potential to spare unaffected cells and tissues, but it has been a major challenge to achieve success in these therapeutic approaches. Several innovative approaches to targeted drug delivery have been devised based on available knowledge in cancer biology and on technological advancements. To achieve the desired selectivity of drug delivery, nanotechnology has enabled researchers to design nanoparticles (NPs) to incorporate anticancer drugs and act as nanocarriers. Recently, many receptor molecules known to be overexpressed in cancer have been explored as docking sites for the targeting of anticancer drugs. In principle, anticancer drugs can be concentrated specifically in cancer cells and tissues by conjugating drug-containing nanocarriers with ligands against these receptors. Several mechanisms can be employed to induce triggered drug release in response to either endogenous trigger or exogenous trigger so that the anticancer drug is only released upon reaching and preferentially accumulating in the tumor tissue. This review focuses on overexpressed receptors exploited in targeting drugs to cancerous tissues and the tumor microenvironment. We briefly evaluate the structure and function of these receptor molecules, emphasizing the elegant mechanisms by which certain characteristics of cancer can be exploited in cancer treatment. After this discussion of receptors, we review their respective ligands and then the anticancer drugs delivered by nanotechnology in preclinical models of cancer. Ligand-functionalized nanocarriers have delivered significantly higher amounts of anticancer drugs in many in vitro and in vivo models of cancer compared to cancer models lacking such receptors or drug carrying nanocarriers devoid of ligand. This increased concentration of anticancer drug in the tumor site enabled by nanotechnology could have a major impact on the efficiency of cancer

Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain.

PubMed

Gou, Yi; Qi, Jinxu; Ajayi, Joshua-Paul; Zhang, Yao; Zhou, Zuping; Wu, Xiaoyang; Yang, Feng; Liang, Hong

2015-10-05

To synergistically enhance the selectivity and efficiency of anticancer copper drugs, we proposed and built a model to develop anticancer copper pro-drugs based on the nature of human serum albumin (HSA) IIA subdomain and cancer cells. Three copper(II) compounds of a 2-hydroxy-1-naphthaldehyde benzoyl hydrazone Schiff-base ligand in the presence pyridine, imidazole, or indazole ligands were synthesized (C1-C3). The structures of three HSA complexes revealed that the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. Among them, the pyridine and imidazole ligands of C1 and C2 are replaced by Lys199, and His242 directly coordinates with Cu(II). The indazole and Br ligands of C3 are replaced by Lys199 and His242, respectively. Compared with the Cu(II) compounds alone, the HSA complexes enhance cytotoxicity in MCF-7 cells approximately 3-5-fold, but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent. We find that the HSA complex has a stronger capacity for cell cycle arrest in the G2/M phase of MCF-7 by targeting cyclin-dependent kinase 1 (CDK1) and down-regulating the expression of CDK1 and cyclin B1. Moreover, the HSA complex promotes MCF-7 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.

Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery.

PubMed

Pan, Dipanjan; Pham, Christine T N; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

2016-01-01

Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a 'magic bullet' to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a 'Grail Quest' by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made 'made the turn' toward meaningful translational success. © 2015 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.

Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

PubMed Central

Pan, Dipanjan; Pham, Christine TN; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

2016-01-01

Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success. PMID:26296541

In Vivo Anticancer Efficacy and Toxicity Studies of a Novel Polymer Conjugate N-Acetyl Glucosamine (NAG)-PEG-Doxorubicin for Targeted Cancer Therapy.

PubMed

Pawar, Smita; Mahajan, Ketan; Vavia, Pradeep

2017-11-01

A novel polymer-drug conjugate, polyethylene glycol-N-(acetyl)-glucosamine-doxorubicin (PEG-NAG-DOX) was evaluated in this study for its in vivo potential for treatment of tumours demonstrating improved efficacy and reduced toxicity. The proposed polymer-drug conjugate comprised of polyethylene glycol-maleimide (mPEG-MAL, 30000 Da) as a carrier, doxorubicin (DOX) as an anticancer drug and N-acetyl glucosamine (NAG) as a targeting moiety as well as penetration enhancer. Doxorubicin has a potent and promising anticancer activity; however, severe cardiotoxicity limits its application in cancer treatment. By modifying DOX in PEG-NAG-DOX prodrug conjugate, we aimed to eliminate this limitation. In vivo anticancer efficacy of the conjugate was evaluated using BDF mice-induced skin melanoma model by i.v. administration of DOX conjugates. Anticancer efficacy studies were done by comparing tumour volume, body weight, organ index and percent survival rate of the animals. Tumour suppression achieved by PEG-NAG-DOX at the cumulative dose of 7.5 mg/kg was two-fold better than that achieved by DOX solution. Also, the survival rate for PEG-NAG-DOX conjugate was >70% as compared to <50% survival rate for DOX solution. In addition, toxicity studies and histopathological studies revealed that while maintaining its cytotoxicity towards tumour cells, PEG-NAG-DOX conjugate showed no toxicities to major organs. Therefore, PEG-NAG-DOX conjugate can be suggested as a desirable candidate for targeted cancer therapy.

Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives.

PubMed

Akinboye, Emmanuel S; Rosen, Marc D; Bakare, Oladapo; Denmeade, Samuel R

2017-12-15

Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2' secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser-Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala-Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC 50 of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transdermal delivery and cutaneous targeting of antivirals using a penetration enhancer and lysolipid prodrugs.

PubMed

Diblíková, Denisa; Kopečná, Monika; Školová, Barbora; Krečmerová, Marcela; Roh, Jaroslav; Hrabálek, Alexandr; Vávrová, Kateřina

2014-04-01

In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin. The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. The ability of ANPs to cross the human skin barrier was very low (0.5-1.4 nmol/cm(2)/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm(2)/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.

Utilization of peptide carrier system to improve intestinal absorption: targeting prolidase as a prodrug-converting enzyme

NASA Technical Reports Server (NTRS)

Bai, J. P.; Hu, M.; Subramanian, P.; Mosberg, H. I.; Amidon, G. L.

1992-01-01

The feasibility of targeting prolidase as a peptide prodrug-converting enzyme has been examined. The enzymatic hydrolysis by prolidase of substrates for the peptide transporter L-alpha-methyldopa-pro and several dipeptide analogues without an N-terminal alpha-amino group (phenylpropionylproline, phenylacetylproline, N-benzoylproline, and N-acetylproline) was investigated. The Michaelis-Menten parameters Km and Vmax for L-alpha-methyldopa-pro are 0.09 +/- 0.02 mM and 3.98 +/- 0.25 mumol/min/mg protein, respectively. However, no hydrolysis of the dipeptide analogues without an N-terminal alpha-amino group is observed, suggesting that an N-terminal alpha-amino group is required for prolidase activity. These results demonstrate that prolidase may serve as a prodrug-converting enzyme for the dipeptide-type prodrugs, utilizing the peptide carrier for transport of prodrugs into the mucosal cells and prolidase, a cytosolic enzyme, to release the drug. However, a free alpha-amino group appears to be necessary for prolidase hydrolysis.

Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT.

PubMed

Zheng, Xiaowan; Polli, James E

2010-08-30

The objective was to synthesize prodrugs of niacin and ketoprofen that target the human apical sodium-dependent bile acid transporter (ASBT) and potentially allow for prolonged drug release. Each drug was conjugated to the naturally occurring bile acid chenodeoxycholic acid (CDCA) using lysine as a linker. Their inhibitory binding and transport properties were evaluated in stably transfected ASBT-MDCK monolayers, and the kinetic parameters K(i), K(t), normJ(max), and P(p) were characterized. Enzymatic stability of the conjugates was evaluated in Caco-2 and liver homogenate. Both conjugates were potent inhibitors of ASBT. For the niacin prodrug, substrate kinetic parameter K(t) was 8.22microM and normJ(max) was 0.0917. In 4h, 69.4% and 26.9% of niacin was released from 1microM and 5microM of the conjugate in Caco-2 homogenate, respectively. For the ketoprofen prodrug, K(t) was 50.8microM and normJ(max) was 1.58. In 4h, 5.94% and 3.73% of ketoprofen was released from 1microM and 5microM of the conjugate in Caco-2 homogenate, and 24.5% and 12.2% of ketoprofen was released in liver homogenate, respectively. In vitro results showed that these bile acid conjugates are potential prolonged release prodrugs with binding affinity for ASBT. Copyright 2010 Elsevier B.V. All rights reserved.

Promising Targets in Anti-cancer Drug Development: Recent Updates.

PubMed

Kumar, Bhupinder; Singh, Sandeep; Skvortsova, Ira; Kumar, Vinod

2017-01-01

Cancer is a multifactorial disease and its genesis and progression are extremely complex. The biggest problem in the anticancer drug development is acquiring of multidrug resistance and relapse. Classical chemotherapeutics directly target the DNA of the cell, while the contemporary anticancer drugs involve molecular-targeted therapy such as targeting the proteins possessing abnormal expression inside the cancer cells. Conventional strategies for the complete eradication of the cancer cells proved ineffective. Targeted chemotherapy was successful in certain malignancies however, the effectiveness has often been limited by drug resistance and side effects on normal tissues and cells. Since last few years, many promising drug targets have been identified for the effective treatment of cancer. The current review article describes some of these promising anticancer targets that include kinases, tubulin, cancer stem cells, monoclonal antibodies and vascular targeting agents. In addition, promising drug candidates under various phases of clinical trials are also described. Multi-acting drugs that simultaneously target different cancer cell signaling pathways may facilitate the process of effective anti-cancer drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer.

PubMed

Levy, Oren; Brennen, W Nathaniel; Han, Edward; Rosen, David Marc; Musabeyezu, Juliet; Safaee, Helia; Ranganath, Sudhir; Ngai, Jessica; Heinelt, Martina; Milton, Yuka; Wang, Hao; Bhagchandani, Sachin H; Joshi, Nitin; Bhowmick, Neil; Denmeade, Samuel R; Isaacs, John T; Karp, Jeffrey M

2016-06-01

Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug. G114-particles (∼950 nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic 'Trojan Horse' therapy for targeted delivery of therapeutic agents to sites of metastatic PCa. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs

PubMed Central

van Rijt, Sabine H.; Sadler, Peter J.

2010-01-01

This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry with many new approaches to the design of innovative metal-based anticancer drugs emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action, and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. PMID:19782150

New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

PubMed

Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

2016-01-01

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their

Anticancer Pyrroloquinazoline LBL1 Targets Nuclear Lamins.

PubMed

Li, Bingbing X; Chen, Jingjin; Chao, Bo; David, Larry L; Xiao, Xiangshu

2018-05-18

Target identification of bioactive compounds is critical for understanding their mechanism of action. We previously discovered a novel pyrroloquinazoline compound LBL1 with significant anticancer activity. However, its molecular targets remain to be established. Herein, we developed a clickable photoaffinity probe based on LBL1. Using extensive chemical, biochemical, and cellular studies with this probe and LBL1, we found that LBL1 targets nuclear lamins, which are type V intermediate filament (IF) proteins. Further studies showed that LBL1 binds to the coiled-coil domain of lamin A. These results revealed that IF proteins can also be targeted with appropriate small molecules besides two other cytoskeletal proteins actin filaments and microtubules, providing a novel avenue to investigate lamin biology and a novel strategy to develop distinct anticancer therapies.

[Cellular uptake of TPS-L-carnitine synthesised as transporter-based renal targeting prodrug].

PubMed

Li, Li; Zhu, Di; Sun, Xun

2012-11-01

To synthesize transporter-based renal targeting prodrug TPS-L-Carnitine and to determine its cellular uptake in vitro. Triptolide (TP) was conjugated with L-carnitine using succinate as the linker to form TPS-L-Carnitine, which could be specifically recognized by OCTN2, a cationic transporter with high affinity to L-Carnitine and is highly expressed on the apical membrane of renal proximal tubule cells. Cellular uptake assays of the prodrug and its parent drug were performed on HK-2 cells, a human proximal tubule cell line, in different temperature, concentration and in the presence of competitive inhibitors. TPS-L-Carnitine was taken up into HK-2 cells in a saturable and temperature- and concentration-dependent manner. The uptake process could be inhibited by the competitive inhibitors. The uptake of TPS-L-Carnitine was significantly higher than that of TP at 37 degrees C in the same drug concentration. TPS-L-Carnitine was taken through endocytosis mediated by transporter. TPS-L-Carnitine provides a good renal targeting property and lays the foundation for further studies in vivo.

Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.

PubMed

Phillips, Roger M

2016-03-01

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.

In vitro optimization of non-small cell lung cancer activity with troxacitabine, L-1,3-dioxolane-cytidine, prodrugs.

PubMed

Radi, Marco; Adema, Auke D; Daft, Jonathan R; Cho, Jong H; Hoebe, Eveline K; Alexander, Lou-Ella M M; Peters, Godefridus J; Chu, Chung K

2007-05-03

l-1,3-Dioxolane-cytidine, a potent anticancer agent against leukemia, has limited efficacy against solid tumors, perhaps due to its hydrophilicity. Herein, a library of prodrugs were synthesized to optimize in vitro antitumor activity against non-small cell lung cancer. N4-Substituted fatty acid amide prodrugs of 10-16 carbon chain length demonstrated significantly improved antitumor activity over l-1,3-dioxolane-cytidine. These in vitro results suggest that the in vivo therapeutic efficacy of l-1,3-dioxolane-cytidine against solid tumors may be improved with prodrug strategies.

Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease

NASA Astrophysics Data System (ADS)

Dahan, Arik; Markovic, Milica; Keinan, Shahar; Kurnikov, Igor; Aponick, Aaron; Zimmermann, Ellen M.; Ben-Shabat, Shimon

2017-11-01

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA2, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA2 to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA2, and the optimal linker will enable maximal PLA2-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA2 transition state binding free energy of the prodrug molecule (ΔΔGtr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA2-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.

Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

NASA Astrophysics Data System (ADS)

Yang, Yang; Zhang, Ying-Ming; Chen, Yong; Chen, Jia-Tong; Liu, Yu

2016-01-01

The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

Design and Synthesis of Phosphotyrosine Peptidomimetic Prodrugs

PubMed Central

Garrido-Hernandez, Hugo; Moon, Kyung D.; Geahlen, Robert L.; Borch, Richard F.

2008-01-01

A novel approach to the intracellular delivery of aryl phosphates has been developed that utilizes a phosphoramidate-based prodrug approach. The prodrugs contain an ester group that undergoes reductive activation intracellularly with concomitant expulsion of a phosphoramidate anion. This anion undergoes intramolecular cyclization and hydrolysis to generate aryl phosphate exclusively with a t1/2 = ∼ 20 min. Phosphoramidate prodrugs (8-10) of phosphate-containing peptidomimetics that target the SH2 domain were synthesized. Evaluation of these peptidomimetic prodrugs in a growth inhibition assay and, in a cell-based transcriptional assay, demonstrated that the prodrugs had IC50 values in the low micromolar range. Synthesis of phosphorodiamidate analogs containing a P-NH-Ar linker (16 – 18) was also carried out in the hope that the phosphoramidates released might be phosphatase-resistant. Comparable activation rates and cell-based activities were observed for these prodrugs, but the intermediate phosphoramidate dianion underwent spontaneous hydrolysis with a t1/2 = ∼ 30 min. PMID:16722656

Anticancer substances of mushroom origin.

PubMed

Ivanova, T S; Krupodorova, T A; Barshteyn, V Y; Artamonova, A B; Shlyakhovenko, V A

2014-06-01

The present status of investigations about the anticancer activity which is inherent to medicinal mushrooms, as well as their biomedical potential and future prospects are discussed. Mushroom products and extracts possess promising immunomodulating and anticancer effects, so the main biologically active substances of mushrooms responsible for immunomodulation and direct cytoto-xicity toward cancer cell lines (including rarely mentioned groups of anticancer mushroom proteins), and the mechanisms of their antitumor action were analyzed. The existing to date clinical trials of mushroom substances are mentioned. Mushroom anticancer extracts, obtained by the different solvents, are outlined. Modern approaches of cancer treatment with implication of mushroom products, including DNA vaccinotherapy with mushroom immunomodulatory adjuvants, creation of prodrugs with mushroom lectins that can recognize glycoconjugates on the cancer cell surface, development of nanovectors etc. are discussed. The future prospects of mushroom anticancer substances application, including chemical modification of polysaccharides and terpenoids, gene engineering of proteins, and implementation of vaccines are reviewed.

Amino acids as promoieties in prodrug design and development.

PubMed

Vig, Balvinder S; Huttunen, Kristiina M; Laine, Krista; Rautio, Jarkko

2013-10-01

Prodrugs are biologically inactive agents that upon biotransformation in vivo result in active drug molecules. Since prodrugs might alter the tissue distribution, efficacy and the toxicity of the parent drug, prodrug design should be considered at the early stages of preclinical development. In this regard, natural and synthetic amino acids offer wide structural diversity and physicochemical properties. This review covers the use of amino acid prodrugs to improve poor solubility, poor permeability, sustained release, intravenous delivery, drug targeting, and metabolic stability of the parent drug. In addition, practical considerations and challenges associated with the development of amino acid prodrugs are also covered. Copyright © 2012 Elsevier B.V. All rights reserved.

Amphipathic dextran-doxorubicin prodrug micelles for solid tumor therapy.

PubMed

Jin, Rong; Guo, Xuelian; Dong, Lingli; Xie, Enyuan; Cao, Aoneng

2017-10-01

A group of micelles self-assembled from deoxycholic acid-doxorubicin-conjugated dextran (denoted as Dex-DCA-DOX) prodrugs were designed and prepared for pH-triggered drug release and cancer chemotherapy. These prodrugs could be successfully produced by chemically coupling hydrophobic deoxycholic acid (DCA) to dextran hydrazine (denoted as Dex-NHNH 2 ) and hydrazone linker formation between doxorubicin (DOX) and Dex-NHNH 2 . These Dex-DCA-DOX prodrugs self-assembled to form micelles under physiological conditions with varied particle sizes depending on molecular weight of dextran, degree of substitution (DS) of DCA and DOX. After optimization, Dex10k-DCA9-DOX5.5 conjugate comprising dextran of 10kDa, DCA of DS 9 and DOX loading content of 5.5wt%, formed the micelles with the smallest size (110nm). These prodrug micelles could slowly liberate DOX under physiological conditions but efficiently released the drug at an acidified endosomal pH by the hydrolysis of acid-labile hydrazone linker. In vitro cytotoxicity experiment indicated that Dex10k-DCA9-DOX5.5 micelles exerted marked antitumor activity against MCF-7 and SKOV-3 cancer cells. Besides, intravenous administration of the micelles afforded growth inhibition of SKOV-3 tumor bearing in nude mice at a dosage of 2.5mg per kg with anti-cancer efficacy comparable to free DOX-chemotherapy but low systemic toxicity. This study highlights the feasibility of bio-safe and efficient dextran-based prodrug micelles designed for cancer chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Modulating lipophilicity of rohitukine via prodrug approach: Preparation, characterization, and in vitro enzymatic hydrolysis in biorelevant media.

PubMed

Kumar, Vikas; Bharate, Sonali S; Vishwakarma, Ram A

2016-09-20

Rohitukine is a medicinally important natural product which has inspired the discovery of two anticancer clinical candidates. Rohitukine is highly hydrophilic in nature which hampers its oral bioavailability. Thus, herein our objective was to improve the drug-like properties of rohitukine via prodrug-strategy. Various ester prodrugs were synthesized and studied for solubility, lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. All prodrugs displayed lower aqueous solubility and improved lipophilicity compared with rohitukine, which was in accordance with the criteria of compounds in drug-discovery. The stability of synthesized prodrugs was evaluated in buffers at different pH, SGF, SIF, rat plasma and in esterase enzyme. The rate of hydrolysis in all incubation media was dependent primarily on the acyl promoieties. Hexanoyl ester prodrug of rohitukine, 3d, was stable under chemical conditions; however it was completely hydrolyzed to rohitukine, in plasma and in esterase in 4h. Hexanoate ester 3d appeared to be the most promising prodrug as it remained intact at gastric/intestinal pH and was completely transformed to the parent compound in plasma as desired for an ideal prodrug. The data presented herein, will help in designing prodrugs with desired physicochemical properties in future in structurally similar chemotypes. Copyright © 2016 Elsevier B.V. All rights reserved.

Lymphatic Transport and Lymphocyte Targeting of a Triglyceride Mimetic Prodrug Is Enhanced in a Large Animal Model: Studies in Greyhound Dogs.

PubMed

Han, Sifei; Hu, Luojuan; Gracia; Quach, Tim; Simpson, Jamie S; Edwards, Glenn A; Trevaskis, Natalie L; Porter, Christopher J H

2016-10-03

In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans. The bioavailability and lymphatic transport of free MPA and total MPA related materials were examined following oral administration of the parent drug (MPA) and the prodrug (2-MPA-TG) to both thoracic lymph duct cannulated and intact (noncannulated) greyhound dogs. The enrichment of free MPA in lymph nodes and lymph-derived lymphocytes was also determined to examine the efficiency of drug targeting to potential sites of action within the lymph. Via biochemical integration into a series of site-specific metabolic processes, the prodrug markedly increased (288-fold) lymphatic transport of total MPA related material (present as re-esterified 2-MPA-TG) when compared to the parent MPA and the extent of lymphatic transport was significantly greater in the dog (36.4% of the dose recovered in lymph) when compared to the previous data in the rat (13.4% of the dose). Conversion from 2-MPA-TG derivatives to parent MPA occurred in vivo, resulting in a marked increase in MPA concentrations in lymph nodes (5-6-fold) and lymph lymphocytes (21-fold), when compared to animals administered the parent drug. In conclusion, the data demonstrate that the TG prodrug of MPA facilitates efficient delivery of MPA to the lymphatic system in dogs and suggest that the TG prodrug strategy may more effectively facilitate targeted delivery in large animals than in rats.

Lipid prodrug nanocarriers in cancer therapy.

PubMed

Mura, Simona; Bui, Duc Trung; Couvreur, Patrick; Nicolas, Julien

2015-06-28

Application of nanotechnology in the medical field (i.e., nanomedicine) plays an important role in the development of novel drug delivery methods. Nanoscale drug delivery systems can indeed be customized with specific functionalities in order to improve the efficacy of the treatments. However, despite the progresses of the last decades, nanomedicines still face important obstacles related to: (i) the physico-chemical properties of the drug moieties which may reduce the total amount of loaded drug; (ii) the rapid and uncontrolled release (i.e., burst release) of the encapsulated drug after administration and (iii) the instability of the drug in biological media where a fast transformation into inactive metabolites can occur. As an alternative strategy to alleviate these drawbacks, the prodrug approach has found wide application. The covalent modification of a drug molecule into an inactive precursor from which the drug will be freed after administration offers several benefits such as: (i) a sustained drug release (mediated by chemical or enzymatic hydrolysis of the linkage between the drug-moiety and its promoiety); (ii) an increase of the drug chemical stability and solubility and, (iii) a reduced toxicity before the metabolization occurs. Lipids have been widely used as building blocks for the design of various prodrugs. Interestingly enough, these lipid-derivatized drugs can be delivered through a nanoparticulate form due to their ability to self-assemble and/or to be incorporated into lipid/polymer matrices. Among the several prodrugs developed so far, this review will focus on the main achievements in the field of lipid-based prodrug nanocarriers designed to improve the efficacy of anticancer drugs. Gemcitabine (Pubchem CID: 60750); 5-fluorouracil (Pubchem CID: 3385); Doxorubicin (Pubchem CID: 31703); Docetaxel (Pubchem CID: 148124); Methotrexate (Pubchem CID: 126941); Paclitaxel (Pubchem CID: 36314). Copyright © 2015 Elsevier B.V. All rights reserved.

Recent Development of Anticancer Therapeutics Targeting Akt

PubMed Central

Morrow, John K.; Du-Cuny, Lei; Chen, Lu; Meuillet, Emmanuelle J.; Mash, Eugene A.; Powis, Garth; Zhang, Shuxing

2013-01-01

The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches. PMID:21110830

Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases

PubMed Central

Jain, Chetan Kumar; Majumder, Hemanta Kumar; Roychoudhury, Susanta

2017-01-01

DNA topoisomerases are important cellular enzymes found in almost all types of living cells (eukaryotic and prokaryotic). These enzymes are essential for various DNA metabolic processes e.g. replication, transcription, recombination, chromosomal decatenation etc. These enzymes are important molecular drug targets and inhibitors of these enzymes are widely used as effective anticancer and antibacterial drugs. However, topoisomerase inhibitors have some therapeutic limitations and they exert serious side effects during cancer chemotherapy. Thus, development of novel anticancer topoisomerase inhibitors is necessary for improving cancer chemotherapy. Nature serves as a repertoire of structurally and chemically diverse molecules and in the recent years many DNA topoisomerase inhibitors have been identified from natural sources. The present review discusses anticancer properties and therapeutic importance of eighteen recently identified natural topoisomerase inhibitors (from the year 2009 to 2015). Structural characteristics of these novel inhibitors provide backbones for designing and developing new anticancer drugs. PMID:28503091

Smart activatable and traceable dual-prodrug for image-guided combination photodynamic and chemo-therapy.

PubMed

Hu, Fang; Yuan, Youyong; Mao, Duo; Wu, Wenbo; Liu, Bin

2017-11-01

Activatable photosensitizers (PSs) and chemo-prodrugs are highly desirable for anti-cancer therapy to reduce systemic toxicity. However, it is difficult to integrate both together into a molecular probe for combination therapy due to the complexity of introducing PS, singlet oxygen quencher, chemo-drug, chemo-drug inhibitor and active linker at the same time. To realize activatable PS and chemo-prodrug combination therapy, we develop a smart therapeutic platform in which the chemo-prodrug serves as the singlet oxygen quencher for the PS. Specifically, the photosensitizing activity and fluorescence of the PS (TPEPY-SH) are blocked by the chemo-prodrug (Mitomycin C, MMC) in the probe. Meanwhile, the cytotoxicity of MMC is also inhibited by the electron-withdrawing acyl at the nitrogen position next to the linker. Upon glutathione activation, TPEPY-S-MMC can simultaneously release active PS and MMC for combination therapy. The restored fluorescence of TPEPY-SH is also used to report the activation for both PS and MMC as well as to guide the photodynamic therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antitumor Synergism and Enhanced Survival with a Tumor Vasculature-Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide.

PubMed

Krais, John J; Virani, Needa; McKernan, Patrick H; Nguyen, Quang; Fung, Kar-Ming; Sikavitsas, Vassilios I; Kurkjian, Carla; Harrison, Roger G

2017-09-01

Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with Annexin A1 or Annexin A5. Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart nonnative methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of nontoxic selenomethionine. The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of nonnative proteins and/or DNA required with other enzyme prodrug systems. The enzyme fusion exhibits strong and stable in vitro binding with dissociation constants in the nanomolar range for both human and mouse breast cancer cells and in a cell model of tumor vascular endothelium. Daily administration of the therapy suppressed growth of highly aggressive triple-negative murine 4T1 mammary tumors in immunocompetent BALB/cJ mice and MDA-MB-231 tumors in SCID mice. Treatment did not result in the occurrence of negative side effects or the elicitation of neutralizing antibodies. On the basis of the vasculature-targeted nature of the therapy, combinations with rapamycin and cyclophosphamide were evaluated. Rapamycin, an mTOR inhibitor, reduces the prosurvival signaling of cells in a hypoxic environment potentially exacerbated by a vasculature-targeted therapy. IHC revealed, unsurprisingly, a significant hypoxic response (increase in hypoxia-inducible factor 1 α subunit, HIF1A) in the enzyme prodrug-treated tumors and a dramatic reduction of HIF1A upon rapamycin treatment. Cyclophosphamide, an immunomodulator at low doses, was combined with the enzyme prodrug therapy and rapamycin; this combination synergistically reduced tumor volumes, inhibited metastatic progression, and enhanced survival. Mol Cancer Ther; 16(9); 1855-65. ©2017 AACR . ©2017 American Association for Cancer Research.

Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis.

PubMed

Xie, Haibo; Chen, Gang; Young, Robert N

2017-08-24

A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.

Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy.

PubMed

Yang, Yuhui; Karakhanova, Svetlana; Hartwig, Werner; D'Haese, Jan G; Philippov, Pavel P; Werner, Jens; Bazhin, Alexandr V

2016-12-01

Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy.

PubMed

Yoo, Wooyoung; Yoo, Donghyuck; Hong, Eunmi; Jung, Eunkyeong; Go, Yebin; Singh, S V Berwin; Khang, Gilson; Lee, Dongwon

2018-01-10

Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy.

PubMed

Akinboye, Emmanuel S; Brennen, W Nathaniel; Rosen, D Marc; Bakare, Oladapo; Denmeade, Samuel R

2016-06-01

There is an urgent need to develop new agents for treating metastatic prostate cancer to overcome multiple drug resistance to the current standard targeted cancer therapy. Emetine is a highly cytotoxic natural product protein synthesis inhibitor, which is toxic to all cell types. Its cytotoxicity can be blocked by derivatizing its N-2' position. Thus emetine can be selectively delivered to cancer cells in the region of metastatic cancer as a prodrug that will be activated by an enzyme selectively overexpressed within the metastatic tumor microenvironment. In this work, we convert emetine to a prodrug activatable by the fibroblast activation protein (FAP), a serine protease overexpressed by the carcinoma associated fibroblasts. By using an iterative structure-activity relationship strategy, several peptidyl emetine prodrug analogs (1-11) were synthesized by chemical derivatization of emetine at its N-2' position and tested for in-vitro activation by FAP. The lead prodrug 11 is made up of a DPPIV activatable prodrug precursor 10 (Ala-Pro-PABC-Emetine) coupled to FAP substrate (Ala-Ser-Gly-Pro-Ala-Gly-Pro). Activation assays of the prodrugs were performed in purified FAP, DPPIV, FBS, and human serum and were analyzed by LCMS. In vitro cytotoxicity assays of these prodrugs are carried out in prostate (LNCaP, PC3) and breast (MCF7 and MDA-MB-231) cancer cell lines. The prodrugs are also tested in normal immortalized human prostatic epithelial cell line (PrEC). The lead FAP activated emetine prodrug 11 is activated to emetine in tandem by FAP and DPPIV in about 70% conversion within 24 hr. In prostate and breast cancer cell lines treated with prodrug 11, it is found to be equipotent with emetine in the presence of FAP and DPPIV. However, in the PrEC cell line grown in serum free media, prodrug 11 is more than 200-fold less cytotoxic than emetine in the absence of FAP and DPPIV. This FAP activated prodrug of cytotoxic agent emetine further shows the crucial role of the

Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy.

PubMed

Mistry, Ishna N; Thomas, Matthew; Calder, Ewen D D; Conway, Stuart J; Hammond, Ester M

2017-08-01

With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Mono- and di-bromo platinum(IV) prodrugs via oxidative bromination: synthesis, characterization, and cytotoxicity.

PubMed

Xu, Zoufeng; Wang, Zhigang; Yiu, Shek-Man; Zhu, Guangyu

2015-12-14

Platinum(IV)-based anticancer prodrugs have attracted much attention due to their relative inertness under physiological conditions, being activated inside cells, and their capacity for functionalization with a variety of small-molecule or macromolecule moieties. Novel asymmetric platinum(IV) compounds synthesized through expedient and unique methods are desired. Here we utilize N-bromosuccinimide (NBS) and carry out oxidative bromination on platinum(II) drugs, namely cisplatin, carboplatin, and oxaliplatin, to obtain asymmetric and mono-bromo platinum(IV) prodrugs. Different solvents are used to obtain various compounds, and the compounds are further functionalized. Di-bromo compounds are also obtained through NBS-directed oxidative bromination in ethanol. The crystal structures of representative compounds are discussed, and the reduction potentials of some compounds are examined. A cytotoxicity test shows that the mono- and di-bromo platinum(IV) compounds are active against human ovarian cancer cells. Our study enriches the family of asymmetric platinum(IV) prodrugs and provides with a convenient strategy to obtain brominated platinum(IV) complexes.

Strategy for Imidazotetrazine Prodrugs with Anticancer Activity Independent of MGMT and MMR

PubMed Central

2012-01-01

The imidazotetrazine ring is an acid-stable precursor and prodrug of highly reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and have antitumor activity independent of the O6-methylguanine-DNA methyltransferase and DNA mismatch repair constraints that limit the use of Temozolomide. PMID:24900418

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38.

PubMed

Bala, Vaskor; Rao, Shasha; Boyd, Ben J; Prestidge, Clive A

2013-11-28

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. © 2013 Elsevier B.V. All rights reserved.

PARP Inhibitor and NO-Donor Dual Prodrugs as Anticancer Agents | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute’s Chemical Biology Laboratory seeks partners interested in collaborative research to co-develop PARP inhibitor and NO-donor hybrid prodrugs for the treatment of cancer.

Development of macromolecular prodrug for rheumatoid arthritis☆

PubMed Central

Yuan, Fang; Quan, Ling-dong; Cui, Liao; Goldring, Steven R.; Wang, Dong

2012-01-01

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases. PMID:22433784

Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy.

PubMed

Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc; Brennen, W Nathaniel; Dalrymple, Susan; Dach, Ingrid; Olesen, Claus; Gurel, Bora; Demarzo, Angelo M; Wilding, George; Carducci, Michael A; Dionne, Craig A; Møller, Jesper V; Nissen, Poul; Christensen, S Brøgger; Isaacs, John T

2012-06-27

Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

The antiproliferative cytostatic effects of a self-activating viridin prodrug

PubMed Central

Smith, Adam; Blois, Joseph; Yuan, Hushan; Aikawa, Elena; Ellson, Christian; Figueiredo, Jose-Luiz; Weissleder, Ralph; Kohler, Rainer; Yaffe, Michael B.; Cantley, Lewis C.; Josephson, Lee

2009-01-01

Although viridins like wortmannin (Wm) have long been examined as anticancer agents, their ability to self-activate has only recently been recognized. Here, we describe the cytostatic effects of a self-activating viridin (SAV), which is an inactive, polymeric prodrug. SAV self-activates to generate a bioactive, fluorescent viridin NBD-Wm with a half-time of 9.2 hours. With cultured A549 cells, 10 µmol/L SAV caused growth arrest without inducing apoptosis or cell death, a cytostatic action markedly different from other chemotherapeutic agents (vinblastine, camptothecin, and paclitaxel). In vivo, a SAV dosing of 1 mg/kg once in 48 hours (i.p.) resulted in growth arrest of an A549 tumor xenograft, with growth resuming when dosing ceased. With a peak serum concentration of SAV of 2.36 µmol/L (at 2 hours post i.p. injection), the concentration of bioactive NBD-Wm was 41 nmol/L based on the partial inhibition of neutrophil respiratory burst. Therefore, SAV was present as an inactive prodrug in serum (peak = 2.36 µmol/L), which generated low concentrations of active viridin (41 nmol/L). SAV is a prodrug, the slowrelease and cytostatic activities of which suggest that it might be useful as a component of metronomic-based chemotherapeutic strategies. PMID:19509266

Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy)

PubMed Central

2003-01-01

This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D7 for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy. PMID:12686722

Nanoassemblies from amphiphilic cytarabine prodrug for leukemia targeted therapy.

PubMed

Liu, Jing; Zhao, Dujuan; He, Wenxiu; Zhang, Huiyuan; Li, Zhonghao; Luan, Yuxia

2017-02-01

The anti-leukemia effect of cytarabine (Ara-C) is severely restricted by its high hydrophilic properties and rapid plasma degradation. Herein, a novel amphiphilic small molecular prodrug of Ara-C was developed by coupling a short aliphatic chain, hexanoic acid (HA) to 4-NH 2 of the parent drug. Based on the amphiphilic nature, the resulting bioconjugate (HA-Ara) could spontaneously self-assemble into stable spherical nanoassemblies (NAs) with an extremely high drug loading (∼71wt%). Moreover, folate receptor (FR)-targeting NAs with high grafting efficient folic acid - bovine serum albumin (FA-BSA) conjugate immobilized on the surface (NAs/FA-BSA) was prepared. The results of MTT assays on FR-positive K562 cells and FR-negative A549 cells demonstrated higher cytotoxicity of HA-Ara NAs than the native drug. Especially, the IC 50 values revealed that NAs/FA-BSA was 3 and 2-fold effective than non-targeted NAs after 24 and 48h treatment with K562 cells, respectively indicating FR-mediated enhanced anti-tumor efficacy. In vitro cellular uptake, larger accumulation of HA-Ara NAs were observed in comparative with the free FITC and the results further confirmed the selective uptake of NAs/FA-BSA in folate receptor enriched cancer cells. Above all, self-assembled HA-Ara NAs exhibited potential superiority for Ara-C delivery and FA-modified NAs would be an excellent candidate for targeting leukemia therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Photolabile ruthenium complexes to cage and release a highly cytotoxic anticancer agent.

PubMed

Wei, Jianhua; Renfrew, Anna K

2018-02-01

CHS-828 (N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N″-4-pyridyl guanidine) is an anticancer agent with low bioavailability and high systemic toxicity. Here we present an approach to improve the therapeutic profile of the drug using photolabile ruthenium complexes to generate light-activated prodrugs of CHS-828. Both prodrug complexes are stable in the dark but release CHS-828 when irradiated with visible light. The complexes are water-soluble and accumulate in tumour cells in very high concentrations, predominantly in the mitochondria. Both prodrug complexes are significantly less cyototoxic than free CHS-828 in the dark but their toxicity increases up to 10-fold in combination with visible light. The cellular responses to light treatment are consistent with release of the cytotoxic CHS-828 ligand. Copyright © 2017 Elsevier Inc. All rights reserved.

Electrospun poly-l-lactide scaffold for the controlled and targeted delivery of a synthetically obtained Diclofenac prodrug to treat actinic keratosis.

PubMed

Piccirillo, Germano; Bochicchio, Brigida; Pepe, Antonietta; Schenke-Layland, Katja; Hinderer, Svenja

2017-04-01

Actinic Keratosis' (AKs) are small skin lesions that are related to a prolonged sun-damage, which can develop into invasive squamous cell carcinoma (SCC) when left untreated. Effective, specific and well tolerable therapies to cure AKs are still of great interest. Diclofenac (DCF) is the current gold standard for the local treatment of AKs in terms of costs, effectiveness, side effects and tolerability. In this work, an electrospun polylactic acid (PLA) scaffold loaded with a synthetic DCF prodrug was developed and characterized. Specifically, the prodrug was successfully synthetized by binding DCF to a glycine residue via solid phase peptide synthesis (SPPS) and then incorporated in an electrospun PLA scaffold. The drug encapsulation was verified using multiphoton microscopy (MPM) and its scaffold release was spectrophotometrically monitored and confirmed with MPM. The scaffold was further characterized with scanning electron microscopy (SEM), tensile testing and contact angle measurements. Its biocompatibility was verified by performing a cell proliferation assay and compared to PLA scaffolds containing the same amount of DCF sodium salt (DCFONa). Finally, the effect of the electrospun scaffolds on human dermal fibroblasts (HDFs) morphology and metabolism was investigated by combining MPM with fluorescence lifetime imaging microscopy (FLIM). The obtained results suggest that the obtained scaffold could be suitable for the controlled and targeted delivery of the synthesized prodrug for the treatment of AKs. Electrospun scaffolds are of growing interest as materials for a controlled drug delivery. In this work, an electrospun polylactic acid scaffold containing a synthetically obtained Diclofenac prodrug is proposed as a novel substrate for the topical treatment of actinic keratosis. A controlled drug delivery targeted to the area of interest could enhance the efficacy of the therapy and favor the healing process. The prodrug was synthesized via solid phase

PET imaging of β-glucuronidase activity by an activity-based 124I-trapping probe for the personalized glucuronide prodrug targeted therapy.

PubMed

Su, Yu-Cheng; Cheng, Ta-Chun; Leu, Yu-Ling; Roffler, Steve R; Wang, Jaw-Yuan; Chuang, Chih-Hung; Kao, Chien-Han; Chen, Kai-Chuan; Wang, Hsin-Ell; Cheng, Tian-Lu

2014-12-01

Beta-glucuronidase (βG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image βG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of βG activity for medical usage is not yet available. Here, we developed a radioactive βG activity-based trapping probe for positron emission tomography (PET). We generated a (124)I-tyramine-conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form (124)I-TrapG that could be selectively activated by βG for subsequent attachment of (124)I-tyramine to nucleophilic moieties near βG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half-life of (124)I-TrapG. βG targeting of (124)I-TrapG in vivo was examined by micro-PET. The biodistribution of (131)I-TrapG was investigated in different organs. Finally, we imaged the endogenous βG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at βG-expressing CT26 (CT26/mβG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. (124)I-TrapG preferentially accumulated in CT26/mβG but not CT26 cells. Meanwhile, micro-PET and whole-body autoradiography results demonstrated that (124)I-TrapG signals in CT26/mβG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous βG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. (124)I-TrapG exhibited low cytotoxicity allowing long-term monitoring of βG activity in vivo to aid in the optimization of prodrug targeted therapy. ©2014 American Association for Cancer Research.

Effects of histone deacetylase inhibitory prodrugs on epigenetic changes and DNA damage response in tumor and heart of glioblastoma xenograft.

PubMed

Tarasenko, Nataly; Nudelman, Abraham; Rozic, Gabriela; Cutts, Suzanne M; Rephaeli, Ada

2017-08-01

The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity. In order to determine the processes underlying these opposing effects, the changes induced by these treatments on the epigenetic landscape, the DDR, and fibrosis were compared in tumors and hearts of glioblastoma xenografts. The potency of AN7 and AN446 as HDAC inhibitors was correlated with their effects on the viability of the cancer and non-cancer cells. The prodrugs affected the epigenetic landscape and the DDR in a tissue-specific and context-dependent manner. Findings suggest that the selectivity of the prodrugs could be attributed to their different effects on histone modification patterns in normal vs. transformed tissues. Further studies are warranted to substantiate the potential of AN446 as a new anticancer drug for glioblastoma patients.

Acid-activatable prodrug nanogels for efficient intracellular doxorubicin release.

PubMed

Zhan, Fuxing; Chen, Wei; Wang, Zhongjuan; Lu, Wentao; Cheng, Ru; Deng, Chao; Meng, Fenghua; Liu, Haiyan; Zhong, Zhiyuan

2011-10-10

Endosomal pH-activatable doxorubicin (DOX) prodrug nanogels were designed, prepared, and investigated for triggered intracellular drug release in cancer cells. DOX prodrugs with drug grafting contents of 3.9, 5.7, and 11.7 wt % (denoted as prodrugs 1, 2, and 3, respectively) were conveniently obtained by sequential treatment of poly(ethylene glycol)-b-poly(2-hydroxyethyl methacrylate-co-ethyl glycinate methacrylamide) (PEG-b-P(HEMA-co-EGMA)) copolymers with hydrazine and doxorubicin hydrochloride. Notably, prodrugs 1, 2, and 3 formed monodispersed nanogels with average sizes of 114.4, 75.3, and 66.3 nm, respectively, in phosphate buffer (PB, 10 mM, pH 7.4). The in vitro release results showed that DOX was released rapidly and nearly quantitatively from DOX prodrug nanogels at endosomal pH and 37 °C in 48 h, whereas only a minor amount (ca. 20% or less) of drug was released at pH 7.4 under otherwise the same conditions. Confocal laser scanning microscope (CLSM) observations revealed that DOX prodrug nanogels delivered and released DOX into the cytosols as well as cell nuclei of RAW 264.7 cells following 24 h incubation. MTT assays demonstrated that prodrug 3 had pronounced cytotoxic effects to tumor cells following 72 h incubation with IC(50) data determined to be 2.0 and 3.4 μg DOX equiv/mL for RAW 264.7 and MCF-7 tumor cells, respectively. The corresponding polymer carrier, PEG-b-P(HEMA-co-GMA-hydrazide), was shown to be nontoxic up to a tested concentration of 1.32 mg/mL. These endosomal pH-activatable DOX prodrug nanogels uniquely combining features of water-soluble macromolecular prodrugs and nanogels offer a promising platform for targeted cancer therapy.

Application of Nanotechnology in the Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment

DTIC Science & Technology

2007-12-01

used in detection, diagnosis, and treatment of cancer . When loaded with chemotherapeutic agents, nanoparticle delivery to cancerous tissues...Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment PRINCIPAL INVESTIGATOR: Colleen Feltmate, M.D. CONTRACTING ORGANIZATION...5a. CONTRACT NUMBER Application of Nanotechnology in the Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment 5b. GRANT NUMBER

Rational Design of Multifunctional Gold Nanoparticles via Host-Guest Interaction for Cancer-Targeted Therapy.

PubMed

Chen, Wei-Hai; Lei, Qi; Luo, Guo-Feng; Jia, Hui-Zhen; Hong, Sheng; Liu, Yu-Xin; Cheng, Yin-Jia; Zhang, Xian-Zheng

2015-08-12

A versatile gold nanoparticle-based multifunctional nanocomposite AuNP@CD-AD-DOX/RGD was constructed flexibly via host-guest interaction for targeted cancer chemotherapy. The pH-sensitive anticancer prodrug AD-Hyd-DOX and the cancer-targeted peptide AD-PEG8-GRGDS were modified on the surface of AuNP@CD simultaneously, which endowed the resultant nanocomposite with the capability to selectively eliminate cancer cells. In vitro studies indicated that the AuNP@CD-AD-DOX/RGD nanocomposite was preferentially uptaken by cancer cells via receptor-mediated endocytosis. Subsequently, anticancer drug DOX was released rapidly upon the intracellular trigger of the acid microenvirenment of endo/lysosomes, inducing apoptosis in cancer cells. As the ideal drug nanocarrier, the multifunctional gold nanoparticles with the active targeting and controllable intracellular release ability hold the great potential in cancer therapy.

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

PubMed

Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

2017-08-18

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury.

PubMed

Lee, Dongwon; Park, Seunggyu; Bae, Soochan; Jeong, Dahee; Park, Minhyung; Kang, Changsun; Yoo, Wooyoung; Samad, Mohammed A; Ke, Qingen; Khang, Gilson; Kang, Peter M

2015-11-13

Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries.

Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury

PubMed Central

Lee, Dongwon; Park, Seunggyu; Bae, Soochan; Jeong, Dahee; Park, Minhyung; Kang, Changsun; Yoo, Wooyoung; Samad, Mohammed A.; Ke, Qingen; Khang, Gilson; Kang, Peter M.

2015-01-01

Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries. PMID:26563741

Photo-triggered fluorescent theranostic prodrugs as DNA alkylating agents for mechlorethamine release and spatiotemporal monitoring.

PubMed

Cao, Yanting; Pan, Rong; Xuan, Weimin; Wei, Yongyi; Liu, Kejian; Zhou, Jiahong; Wang, Wei

2015-06-28

We describe a new theranostic strategy for selective delivery and spatiotemporal monitoring of mechlorethamine, a DNA alkylating agent. A photo-responsive prodrug is designed and composed of a photolabile o-nitrophenylethyl group, a DNA alkylating mechlorethamine drug and a coumarin fluorophore. Masking of the "N" in mechlorethamine in a positively charged state in the prodrug renders it inactive, non-toxic, selective and non-fluorescent. Indeed, the stable prodrug shows negligible cytotoxicity towards normal cells with and without UV activation and is completely non-fluorescent. However, upon photo-irradiation, the active mechlorethamine is released and induces efficient DNA cross-links, accompanied by a strong fluorescence enhancement (152 fold). Furthermore, DNA cross-linking activity from the release can be transformed into anticancer activity observed in in vitro studies of tumor cells. Importantly, the drug release progress and the movement can be conveniently monitored by fluorescence spectroscopy. The mechanistic study proves that the DNA cross-linking activity is mainly due to the release of DNA alkylating mechlorethamine. Altogether, the studies show the power of the theranostic strategy for efficient therapy in cancer treatment.

Mitochondrial chaperones may be targets for anti-cancer drugs

Cancer.gov

Scientists at NCI have found that a mitochondrial chaperone protein, TRAP1, may act indirectly as a tumor suppressor as well as a novel target for developing anti-cancer drugs. Chaperone proteins, such as TRAP1, help other proteins adapt to stress, but sc

Analgesic Prodrugs for Combating their Side-Effects: Rational Approach.

PubMed

Ruchita; Sucheta; Nanda, Sanju; Pathak, Dharampal

2017-01-01

Analgesics are the drugs which bring insensibility to pain without loosing consciousness. Treatment strategy is generally based on the type of pain. Most of the analgesics are associated with serious side effects, such as NSAIDS can cause severe GI disturbance and opioids can cause addiction. There are various ways to reduce their side effects The analgesic prodrug approach is one of the several strategies used to attain the required pharmacological response with a considerable decrease in side effects. The aim of this paper is to introduce in depth the rational behind the use of the analgesic prodrug approach from past to present. Data is collected from online as well as from extensive literature survey which have appeared on this subject during the last decades. This review will map the origins and development of the most important of the analgesic prodrugs to date. This review indicates that, designing analgesic prodrugs represent successful strategy to gain the required pharmacological activity with a considerable decrease in side effects. However thorough knowledge of diverse biological phenomena is needed which enables scientists to invent and design superior, nontoxic and better-targeted prodrugs. The newly synthesized chemical entity or prodrugs may or may not have intrinsic pharmacological activity and also synthesizing novel molecules consume a lot of time and money than developing prodrugs of existing clinically used analgesic drugs which is surely an attractive and promising area of research now a days. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy.

PubMed

Joubert, Nicolas; Denevault-Sabourin, Caroline; Bryden, Francesca; Viaud-Massuard, Marie-Claude

2017-12-15

The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris ® and Kadcyla ® made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's "magic bullet". However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms. In this context, alternative non-internalizing ADCs and prodrugs have been developed to circumvent these limitations, in which the drug can be selectively released by an extracellular stimulus in the tumor microenvironment. Each strategy and method of activation will be discussed as potential alternatives to internalizing ADCs for cancer therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

PubMed Central

Zhao, Yunqi; Duan, Shaofeng; Zeng, Xing; Liu, Chunjing; Davies, Neal M.; Li, Benyi; Forrest, M. Laird

2013-01-01

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment. PMID:22494444

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies

PubMed Central

Chen, Chun-Bing; Wu, Ming-Ying; Ng, Chau Yee; Lu, Chun-Wei; Wu, Jennifer; Kao, Pei-Han; Yang, Chan-Keng; Peng, Meng-Ting; Huang, Chen-Yang; Chang, Wen-Cheng; Hui, Rosaline Chung-Yee; Yang, Chih-Hsun; Yang, Shun-Fa; Chung, Wen-Hung; Su, Shih-Chi

2018-01-01

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate

Clickable prodrugs bearing potent and hydrolytically cleavable nicotinamide phosphoribosyltransferase inhibitors.

PubMed

Sadrerafi, Keivan; Mason, Emilia O; Lee, Mark W

2018-01-01

Our previous study indicated that carborane containing small-molecule 1-(hydroxymethyl)-7-(4'-( trans -3″-(3'″-pyridyl)acrylamido)butyl)-1,7-dicarbadodecaborane (hm-MC4-PPEA), was a potent inhibitor of nicotinamide phosphoribosyltransferase (Nampt). Nampt has been shown to be upregulated in most cancers and is a promising target for the treatment of many different types of cancers, including breast cancers. To increase the selectivity of hm-MC4-PPEA toward cancer cells, three prodrugs were synthesized with different hydrolyzable linkers: ester, carbonate, and carbamate. Using click chemistry a fluorophore was attached to these prodrugs to act as a model for our conjugation strategy and to serve as an aid for prodrug stability studies. The stabilities of these drug conjugates were tested in phosphate-buffered saline (PBS) at normothermia (37°C) using three different pH levels, 5.5, 7.5, and 9.5, as well as in horse serum at physiological pH. The stability of each was monitored using reversed-phase HPLC equipped with both diode array and fluorescence detection. The inhibitory activity of hm-MC4-PPEA was also measured using a commercially available colorimetric assay. The biological activities of the drug conjugates as well as those of the free drug (hm-MC4-PPEA), were evaluated using the MTT assay against the human breast cancer cell lines T47D and MCF7, as well as the noncancerous, transformed, Nampt-dependent human breast epithelium cell line 184A1. hm-MC4-PPEA showed to be a potent inhibitor of recombinant Nampt activity, exhibiting an IC50 concentration of 6.8 nM. The prodrugs showed great stability towards hydrolytic degradation under neutral, mildly acidic and mildly basic conditions. The carbamate prodrug also showed to be stable in rat serum. However, the carbonate and the ester prodrug release at various rates in serum presumably owing to the presence of several different classes of esterase. The biological activities of the drug conjugates correlate

Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature

PubMed Central

Chen, Yingzhi; Zhang, Meng; Jin, Hongyue; Tang, Yisi; Wang, Huiyuan; Xu, Qin; Li, Yaping; Li, Feng; Huang, Yongzhuo

2017-01-01

Poor tumor-targeted and cytoplasmic delivery is a bottleneck for protein toxin-based cancer therapy. Ideally, a protein toxin drug should remain stealthy in circulation for prolonged half-life and reduced side toxicity, but turn activated at tumor. PEGylation is a solution to achieve the first goal, but creates a hurdle for the second because PEG rejects interaction between the drugs and tumor cells therein. Such PEG dilemma is an unsolved problem in protein delivery. Herein proposed is a concept of turning PEG dilemma into prodrug-like feature. A site-selectively PEGylated, gelatinase-triggered cell-penetrating trichosanthin protein delivery system is developed with three specific aims. The first is to develop an intein-based ligation method for achieving site-specific modification of protein toxins. The second is to develop a prodrug feature that renders protein toxins remaining stealthy in blood for reduced side toxicity and improved EPR effect. The third is to develop a gelatinase activatable cell-penetration strategy for enhanced tumor targeting and cytoplasmic delivery. Of note, site-specific modification is a big challenge in protein drug research, especially for such a complicated, multifunctional protein delivery system. We successfully develop a protocol for constructing a macromolecular prodrug system with intein-mediated ligation synthesis. With an on-column process of purification and intein-mediated cleavage, the site-specific PEGylation then can be readily achieved by conjugation with the activated C-terminus, thus constructing a PEG-capped, cell-penetrating trichosanthin system with a gelatinase-cleavable linker that enables tumor-specific activation of cytoplasmic delivery. It provides a promising method to address the PEG dilemma for enhanced protein drug delivery, and importantly, a facile protocol for site-specific modification of such a class of protein drugs for improving their druggability and industrial translation. PMID:27914267

Management of pulmonary toxicity associated with targeted anticancer therapies.

PubMed

Teuwen, Laure-Anne; Van den Mooter, Tom; Dirix, Luc

2015-01-01

Targeted anticancer therapies act by interfering with defined molecular entities and/or biologic pathways. Because of their more specific mechanism of action, adverse events (AEs) on healthy tissues are intended to be minimal, resulting in a different toxicity profile from that observed with conventional cytotoxic chemotherapy. Pulmonary AEs are rare but potentially life-threatening and it is, therefore, critical to recognize early on and manage appropriately. In this review, we aim to offer an overview of both more frequent and rare pulmonary AEs caused by targeted anticancer therapies and discuss possible treatment algorithms. Anti-vascular endothelial growth factor, anti-human epidermal growth factor receptor and anti-CD20 therapy will be reviewed, as well as immune checkpoint inhibitors, anaplastic lymphoma kinase inhibitors and mammalian target of rapamycin inhibitors. Novel agents used in the treatment of cancer have specific side-effects, the result of allergic reactions, on-target and off-target effects. Clinical syndromes associated with pulmonary toxicity vary from bronchospasms, hypersensitivity reactions, pneumonitis, acute respiratory distress, lung bleeding, pleural effusion to pneumothorax. Knowledge of risk factors, a high index of suspicion and a complete diagnostic work-up are essential for limiting the risk of these events becoming life threatening. The development of treatment algorithms is extremely helpful in managing these events. It is probable that these toxicities will be even more frequent with the introduction of combination therapies with the obvious challenge of discerning the responsible agent.

Pharmacokinetics and Toxicology of a Fibroblast Activation Protein (FAP)-activated Prodrug in Murine Xenograft Models of Human Cancer

PubMed Central

Brennen, W. Nathaniel; Rosen, D. Marc; Chaux, Alcides; Netto, George J.; Isaacs, John T.; Denmeade, Samuel R.

2014-01-01

Background As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. Methods Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. Results These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (~12 vs. ~4.5 hrs). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. Conclusion FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. PMID:25053236

Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer.

PubMed

Brennen, W Nathaniel; Rosen, D Marc; Chaux, Alcides; Netto, George J; Isaacs, John T; Denmeade, Samuel R

2014-09-01

As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (∼12 vs. ∼4.5 hr). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. © 2014 Wiley Periodicals, Inc.

Prodrugs of phosphonates and phosphates: crossing the membrane barrier

PubMed Central

Wiemer, Andrew J.; Wiemer, David F.

2016-01-01

A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs. PMID:25391982

DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics

NASA Astrophysics Data System (ADS)

Latorre, Alfonso; Posch, Christian; Garcimartín, Yolanda; Celli, Anna; Sanlorenzo, Martina; Vujic, Igor; Ma, Jeffrey; Zekhtser, Mitchell; Rappersberger, Klemens; Ortiz-Urda, Susana; Somoza, Álvaro

2014-06-01

Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells.Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further

Expression of β-glucuronidase on the surface of bacteria enhances activation of glucuronide prodrugs.

PubMed

Cheng, C-M; Chen, F M; Lu, Y-L; Tzou, S-C; Wang, J-Y; Kao, C-H; Liao, K-W; Cheng, T-C; Chuang, C-H; Chen, B-M; Roffler, S; Cheng, T-L

2013-05-01

Extracellular activation of hydrophilic glucuronide prodrugs by β-glucuronidase (βG) was examined to increase the therapeutic efficacy of bacteria-directed enzyme prodrug therapy (BDEPT). βG was expressed on the surface of Escherichia coli by fusion to either the bacterial autotransporter protein Adhesin (membrane βG (mβG)/AIDA) or the lipoprotein (lpp) outermembrane protein A (mβG/lpp). Both mβG/AIDA and mβG/lpp were expressed on the bacterial surface, but only mβG/AIDA displayed enzymatic activity. The rate of substrate hydrolysis by mβG/AIDA-BL21cells was 2.6-fold greater than by pβG-BL21 cells, which express periplasmic βG. Human colon cancer HCT116 cells that were incubated with mβG/AIDA-BL21 bacteria were sensitive to a glucuronide prodrug (p-hydroxy aniline mustard β-D-glucuronide, HAMG) with an half maximal inhibitory concentration (IC50) value of 226.53±45.4 μM, similar to the IC50 value of the active drug (p-hydroxy aniline mustard, pHAM; 70.6±6.75 μM), indicating that mβG/AIDA on BL21 bacteria could rapidly and efficiently convert HAMG to an active anticancer agent. These results suggest that surface display of functional βG on bacteria can enhance the hydrolysis of glucuronide prodrugs and may increase the effectiveness of BDEPT.

Metronidazole prodrugs: synthesis, physicochemical properties, stability, and ex vivo release studies.

PubMed

Mura, Carla; Valenti, Donatella; Floris, Costantino; Sanna, Roberta; De Luca, Maria Antonietta; Fadda, Anna Maria; Loy, Giuseppe

2011-09-01

The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole-succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning ((13)C NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 °C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): An updated review.

PubMed

Gan, Ren-You; Li, Hua-Bin; Sui, Zhong-Quan; Corke, Harold

2018-04-13

Green tea is one of the most popular beverages in the world, especially in Asian countries. Consumption of green tea has been demonstrated to possess many health benefits, which mainly attributed to the main bioactive compound epigallocatechin gallate (EGCG), a flavone-3-ol polyphenol, in green tea. EGCG is mainly absorbed in the intestine, and gut microbiota play a critical role in its metabolism prior to absorption. EGCG exhibits versatile bioactivities, with its anti-cancer effect most attracting due to the cancer preventive effect of green tea consumption, and a great number of studies intensively investigated its anti-cancer effect. In this review, we therefore, first stated the absorption and metabolism process of EGCG, and then summarized its anti-cancer effect in vitro and in vivo, including its manifold anti-cancer actions and mechanisms, especially its anti-cancer stem cell effect, and next highlighted its various molecular targets involved in cancer inhibition. Finally, the anti-cancer effect of EGCG analogs and nanoparticles, as well as the potential cancer promoting effect of EGCG were also discussed. Understanding of the absorption, metabolism, anti-cancer effect and molecular targets of EGCG can be of importance to better utilize it as a chemopreventive and chemotherapeutic agent.

Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy.

PubMed

Shi, Yunli; Liu, Shengnan; Ahmad, Shabir; Gao, Qingzhi

2018-05-22

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hyaluronic acid-coated, prodrug-based nanostructured lipid carriers for enhanced pancreatic cancer therapy.

PubMed

Lu, Zhihe; Su, Jingrong; Li, Zhengrong; Zhan, Yuzhu; Ye, Decai

2017-01-01

Gemcitabine (GEM) and Baicalein (BCL) are reported to have anti-tumor effects including pancreatic cancer. Hyaluronic acid (HA) can bind to over-expressed receptors in various kinds of cancer cells. The aim of this study is to develop prodrugs containing HA, BCL and GEM, and construct nanomedicine incorporate GEM and BCL in the core and HA on the surface. This system could target the cancer cells and co-deliver the drugs. GEM-stearic acid lipid prodrug (GEM-SA) and hyaluronic acid-amino acid-baicalein prodrug (HA-AA-BCL) were synthesized. Then, GEM and BCL prodrug-based targeted nanostructured lipid carriers (HA-GEM-BCL NLCs) were prepared by the nanoprecipitation technique. The in vitro cytotoxicity studies of the NLCs were evaluated on AsPC1 pancreatic cancer cell line. In vivo anti-tumor effects were observed on the murine-bearing pancreatic cancer model. HA-GEM-BCL NLCs were effective in entering pancreatic cancer cells over-expressing HA receptors, and showed cytotoxicity of tumor cells in vitro. In vivo study revealed significant tumor growth inhibition ability of HA-GEM-BCL NLCs in murine pancreatic cancer model. It could be concluded that HA-GEM-BCL NLCs could be featured as promising co-delivery, tumor-targeted nanomedicine for the treatment of cancers.

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents.

PubMed

Sagnella, Sharon M; Gong, Xiaojuan; Moghaddam, Minoo J; Conn, Charlotte E; Kimpton, Kathleen; Waddington, Lynne J; Krodkiewska, Irena; Drummond, Calum J

2011-03-01

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery.

PubMed

Chen, Rui; Xu, Liu; Fan, Qin; Li, Man; Wang, Jingjing; Wu, Li; Li, Weidong; Duan, Jinao; Chen, Zhipeng

2017-11-01

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC-MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.

Nanoscale coordination polymers for anticancer drug delivery

NASA Astrophysics Data System (ADS)

Phillips, Rachel Huxford

This dissertation reports the synthesis and characterization of nanoscale coordination polymers (NCPs) for anticancer drug delivery. Nanoparticles have been explored in order to address the limitations of small molecule chemotherapeutics. NCPs have been investigated as drug delivery vehicles as they can exhibit the same beneficial properties as the bulk metal-organic frameworks as well as interesting characteristics that are unique to nanomaterials. Gd-MTX (MTX = methotrexate) NCPs with a MTX loading of 71.6 wt% were synthesized and stabilized by encapsulation within a lipid bilayer containing anisamide (AA), a small molecule that targets sigma receptors which are overexpressed in many cancer tissues. Functionalization with AA allows for targeted delivery and controlled release to cancer cells, as shown by enhanced efficacy against leukemia cells. The NCPs were doped with Ru(bpy)32+ (bpy = 2,2'-bipyridine), and this formulation was utilized as an optical imaging agent by confocal microscopy. NCPs containing the chemotherapeutic pemetrexed (PMX) were synthesized using different binding metals. Zr-based materials could not be stabilized by encapsulation with a lipid bilayer, and Gd-based materials showed that PMX had degraded during synthesis. However, Hf-based NCPs containing 19.7 wt% PMX were stabilized by a lipid coating and showed in vitro efficacy against non-small cell lung cancer (NSCLC) cell lines. Enhanced efficacy was observed for formulations containing AA. Additionally, NCP formulations containing the cisplatin prodrug disuccinatocisplatin were prepared; one of these formulations could be stabilized by encapsulation within a lipid layer. Coating with a lipid layer doped with AA rendered this formulation an active targeting agent. The resulting formulation proved more potent than free cisplatin in NSCLC cell lines. Improved NCP uptake was demonstrated by confocal microscopy and competitive binding assays. Finally, a Pt(IV) oxaliplatin prodrug was

Renal toxicity of anticancer agents targeting HER2 and EGFR.

PubMed

Cosmai, Laura; Gallieni, Maurizio; Porta, Camillo

2015-12-01

EGFR and HER2 are found overexpressed and/or activated in many different human malignancies (e.g. breast and colon cancer), and a number of drugs specifically targeting these two tyrosine kinases have been developed over the years as anticancer agents. In the present review, the renal safety profile of presently available agents targeting either HER2 or EGFR will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, even though renal toxicity is not so common with these agents, it may nevertheless happen, especially when these agents are combined with traditional chemotherapeutic agents. As a whole, kidney impairment or dialysis should not be regarded per se as reasons not to administer or to stop an active anti-HER or anti-EGFR anticancer treatment, especially given the possibility of significantly improving the life expectancy of many cancer patients with the use of these agents.

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.

2014-09-24

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipidmore » prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.« less

Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products.

PubMed

Grossman, Elizabeth A; Ward, Carl C; Spradlin, Jessica N; Bateman, Leslie A; Huffman, Tucker R; Miyamoto, David K; Kleinman, Jordan I; Nomura, Daniel K

2017-11-16

Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, and in vivo tumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prodrug Strategies for Paclitaxel.

PubMed

Meng, Ziyuan; Lv, Quanxia; Lu, Jun; Yao, Houzong; Lv, Xiaoqing; Jiang, Feng; Lu, Aiping; Zhang, Ge

2016-05-23

Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.

Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302

PubMed Central

Lohse, Ines; Rasowski, Joanna; Cao, Pinjiang; Pintilie, Melania; Do, Trevor; Tsao, Ming-Sound; Hill, Richard P.; Hedley, David W.

2016-01-01

Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX). The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche. PMID:27248663

Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302.

PubMed

Lohse, Ines; Rasowski, Joanna; Cao, Pinjiang; Pintilie, Melania; Do, Trevor; Tsao, Ming-Sound; Hill, Richard P; Hedley, David W

2016-06-07

Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.

Helicases as Prospective Targets for Anti-Cancer Therapy

PubMed Central

Gupta, Rigu; Brosh, Robert M.

2008-01-01

It has been proposed that selective inactivation of a DNA repair pathway may enhance anti-cancer therapies that eliminate cancerous cells through the cytotoxic effects of DNA damaging agents or radiation. Given the unique and critically important roles of DNA helicases in the DNA damage response, DNA repair, and maintenance of genomic stability, a number of strategies currently being explored or in use to combat cancer may be either mediated or enhanced through the modulation of helicase function. The focus of this review will be to examine the roles of helicases in DNA repair that might be suitably targeted by cancer therapeutic approaches. Treatment of cancers with anti-cancer drugs such as small molecule compounds that modulate helicase expression or function is a viable approach to selectively kill cancer cells through the inactivation of helicase-dependent DNA repair pathways, particularly those associated with DNA recombination, replication restart, and cell cycle checkpoint. PMID:18473724

Dual-targeted and pH-sensitive Doxorubicin Prodrug-Microbubble Complex with Ultrasound for Tumor Treatment

PubMed Central

Luo, Wanxian; Wen, Ge; Yang, Li; Tang, Jiao; Wang, Jianguo; Wang, Jihui; Zhang, Shiyu; Zhang, Li; Ma, Fei; Xiao, Liling; Wang, Ying; Li, Yingjia

2017-01-01

In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their

Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting.

PubMed

Ganapathy-Kanniappan, Shanmugasundaram; Kunjithapatham, Rani; Geschwind, Jean-Francois

2013-01-01

The anticancer efficacy of the pyruvate analog 3-bromopyruvate has been demonstrated in multiple tumor models. The chief principle underlying the antitumor effects of 3-bromopyruvate is its ability to effectively target the energy metabolism of cancer cells. Biochemically, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as the primary target of 3-bromopyruvate. Its inhibition results in the depletion of intracellular ATP, causing cell death. Several reports have also demonstrated that in addition to GAPDH inhibition, the induction of cellular stress also contributes to 3-bromopyruvate treatment-dependent apoptosis. Furthermore, recent evidence shows that 3-bromopyruvate is taken up selectively by tumor cells via the monocarboxylate transporters (MCTs) that are frequently overexpressed in cancer cells (for the export of lactate produced during aerobic glycolysis). The preferential uptake of 3-bromopyruvate via MCTs facilitates selective targeting of tumor cells while leaving healthy and non-malignant tissue untouched. Taken together, the specificity of molecular (GAPDH) targeting and selective uptake by tumor cells, underscore the potential of 3-bromopyruvate as a potent and promising anticancer agent. In this review, we highlight the mechanistic characteristics of 3-bromopyruvate and discuss its potential for translation into the clinic.

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.

PubMed

O'Dowd, Hardwin; Shannon, Dean E; Chandupatla, Kishan R; Dixit, Vaishali; Engtrakul, Juntyma J; Ye, Zhengqi; Jones, Steven M; O'Brien, Colleen F; Nicolau, David P; Tessier, Pamela R; Crandon, Jared L; Song, Bin; Macikenas, Dainius; Hanzelka, Brian L; Le Tiran, Arnaud; Bennani, Youssef L; Charifson, Paul S; Grillot, Anne-Laure

2015-07-09

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs.

PubMed

Marks, Paul A

2010-09-01

Histone deacetylase (HDAC) inhibitors are being developed as a new, targeted class of anticancer drugs. This review focuses on the mechanisms of action of the HDAC inhibitors, which selectively induce cancer cell death. There are 11 zinc-dependent HDACs in humans and the biological roles of these lysine deacetylases are not completely understood. It is clear that these different HDACs are not redundant in their activity. This review focuses on the mechanisms by which HDAC inhibitors can induce transformed cell growth arrest and cell death, inhibit cell mobility and have antiangiogenesis activity. There are more than a dozen HDAC inhibitors, including hydroxamates, cyclic peptides, benzamides and fatty acids, in various stages of clinical trials and many more compounds in preclinical development. The chemically different HDAC inhibitors may target different HDACs. There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents.

Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release.

PubMed

Zheng, Luping; Wang, Yunfei; Zhang, Xianshuo; Ma, Liwei; Wang, Baoyan; Ji, Xiangling; Wei, Hua

2018-01-17

Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition-fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H + for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of He

Small mitochondria-targeting molecules as anti-cancer agents

PubMed Central

Wang, Feng; Ogasawara, Marcia A.; Huang, Peng

2009-01-01

Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anticancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed. PMID:19995573

Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.

PubMed

Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias; Velez, Juliana; Harutyunyan, Karine G; Lu, Hongbo; Shi, Yue-Xi; Matre, Polina; Jacamo, Rodrigo; Ma, Helen; Konoplev, Sergej; McQueen, Teresa; Volgin, Andrei; Protopopova, Marina; Mu, Hong; Lee, Jaehyuk; Bhattacharya, Pratip K; Marszalek, Joseph R; Davis, R Eric; Bankson, James A; Cortes, Jorge E; Hart, Charles P; Andreeff, Michael; Konopleva, Marina

2016-04-01

To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. ©2015 American Association for Cancer Research.

Repurposing anticancer drugs for targeting necroptosis.

PubMed

Fulda, Simone

2018-04-25

Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases. Thus, targeted interference with necroptosis signaling may offer new opportunities for the treatment of human diseases. Besides structure-based drug design, in recent years drug repositioning has emerged as a promising alternative to develop drug-like compounds. There is accumulating evidence showing that multi-targeting kinase inhibitors, for example Dabrafenib, Vemurafenib, Sorafenib, Pazopanib and Ponatinib, used for the treatment of cancer also display anti-necroptotic activity. This review summarizes recent evidence indicating that some anticancer kinase inhibitors also negatively affect necroptosis signaling. This implies that some cancer therapeutics may be repurposed for other pathologies, e.g. ischemic or inflammatory diseases.

Application of Nanotechnology in the Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment

DTIC Science & Technology

2007-12-01

diagnosis, and treatment of cancer . When loaded with chemotherapeutic agents, nanoparticle delivery to cancerous tissues relative to healthy tissues may be...Targeted Release of Anticancer Drugs in Ovarian Cancer Treatment PRINCIPAL INVESTIGATOR: Colleen Feltmate, M.D...Anticancer Drugs in Ovarian Cancer Treatment 5b. GRANT NUMBER W81XWH-06-1-0177 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Colleen

Polysaccharides based nanomaterials for targeted anti-cancer drug delivery.

PubMed

Dheer, Divya; Arora, Divya; Jaglan, Sundeep; Rawal, Ravindra K; Shankar, Ravi

2017-01-01

Polysaccharides, an important class of biological polymers, are effectively bioactive, nontoxic, hydrophilic, biodegradable and offer a wide diversity in structure and properties. These can be easily modified chemically and biochemically to enhance the bioadhesion with biological tissues, better stability and can improve bioavailability of drugs. Most of the chemotherapeutic drugs have a narrow therapeutic index, slow drug delivery systems and poor water solubility that usually proves toxic to human bodies. The inherent biocompatibility of these biopolymers have shown enhancement of solubility of some chemotherapeutic drugs which also leads to the preparation of nanomaterials for the delivery of antibiotics, anticancer, proteins, peptides and nucleic acids using several routes of administration. Recently, synthesis and research on polysaccharides based nanomaterials have gained enormous attention as one of the most applicable resources in nanomedicine area. This review article will provide a specific emphasis on polysaccharides as natural biomaterials for targeted anticancer drug delivery system.

A prodrug micellar carrier assembled from polymers with pendant farnesyl thiosalicylic acid moieties for improved delivery of paclitaxel.

PubMed

Sun, Jingjing; Chen, Yichao; Li, Ke; Huang, Yixian; Fu, Xiaofeng; Zhang, Xiaolan; Zhao, Wenchen; Wei, Yuan; Xu, Liang; Zhang, Peijun; Venkataramanan, Raman; Li, Song

2016-10-01

In order to achieve enhanced and synergistic delivery of paclitaxel (PTX), a hydrophobic anticancer agent, two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks, were synthesized. Both POEG-b-PFTS polymers were able to form micelles with intrinsic antitumor activity in vitro and in vivo. Employing these micelles as a carrier to load PTX, their drug loading capacity, stability, in vivo biodistribution and tumor inhibition effect were evaluated. PTX/POEG15-b-PFTS16 mixed micelles exhibited an excellent stability of 9days at 4°C with a PTX loading capacity of 8.2%, which was more effective than PTX/POEG15-b-PFTS6 mixed micelles. In vivo biodistribution data showed that DiR-loaded POEG-b-PFTS micelles were more effectively localized in the tumor than in other organs. Moreover, both PTX/POEG-b-PFTS micelles showed significantly higher antitumor activity than Taxol in a 4T1.2 murine breast tumor model, and the tumor inhibition and animal survival followed the order of PTX/POEG15-b-PFTS16>PTX/POEG15-b-PFTS6>POEG15-b-PFTS16>Taxol≈POEG15-b-PFTS6. Our data suggest that POEG-b-PFTS micelles are a promising anticancer drug carrier that warrants more studies in the future. Polymerization of drug-based monomer represents a facile and precise method to obtain well-defined polymeric prodrug amphiphiles. Currently, most reports largely focus on the synthesis methods and the biophysical properties. There is limited information about their anti-tumor activity and delivery function as prodrug carriers in vitro and in vivo. In this manuscript, we report the development of two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks. Both POEG-b-PFTS polymers were able

Deorphaning the Macromolecular Targets of the Natural Anticancer Compound Doliculide.

PubMed

Schneider, Gisbert; Reker, Daniel; Chen, Tao; Hauenstein, Kurt; Schneider, Petra; Altmann, Karl-Heinz

2016-09-26

The cyclodepsipeptide doliculide is a marine natural product with strong actin-polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype-selective antagonist of prostanoid E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate in vitro validation. This proof-of-concept study demonstrates the in silico deorphanization of phenotypic screening hits as a viable concept for future natural-product-inspired chemical biology and drug discovery efforts. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: bisacyloxymethyl-6-mercaptopurine prodrugs.

PubMed

Waranis, R P; Sloan, K B

1987-08-01

A series of S6,9-bisacyloxymethyl-6-mercaptopurine (6,9-bis-6-MP) prodrug derivatives was synthesized and characterized. The solubilities of the derivatives in solvents (vehicles), which exhibited a wide range of polarities from water to oleic acid, were measured. The abilities of the prodrugs to deliver 6-mercaptopurine (6-MP) from the vehicles have also been determined, and experimental fluxes and permeability coefficients (Kp) have been calculated for a large number of prodrug: vehicle combinations. Generally the best prodrugs of the series in terms of delivering 6-MP, regardless of the vehicle, were the first two members--the bisacetyl- and the bispropionyloxymethyl-6-mercaptopurine prodrugs. This result has been attributed mainly to the increased water solubility of these two prodrugs compared with that of 6-MP and the other prodrugs, since all of the prodrugs are much more lipid soluble than 6-MP. For three vehicles--isopropyl myristate, propylene glycol, and water--there was a good correlation between log experimental Kp for the delivery of 6-MP by the prodrugs from those vehicles and the theoretical solubility parameters of the prodrugs. The stabilities of the bisacetyl-(2), bisproprionyl-(3), and bisbutyryloxymethyl-6-mercaptopurine (4) derivatives were determined in buffer and in buffer containing enzymes leached from the dermis. Prodrug 2 was more stable than 3 or 4 in the buffer containing the enzymes, while 4 was more stable than 2 or 3 in the plain buffer.

Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives.

PubMed

Lazarević, Tatjana; Rilak, Ana; Bugarčić, Živadin D

2017-12-15

Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compounds and chelating agents currently in clinical use, clinical trials or preclinical development are highlighted. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system.

PubMed

Li, Mengjie; Thapa, Pritam; Rajaputra, Pallavi; Bio, Moses; Peer, Cody J; Figg, William D; You, Youngjae; Woo, Sukyung

2017-12-01

The combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX. Using PS-conjugated PTX as a model system, we developed a quantitative mathematical model describing the intracellular trafficking. Dynamics of the prodrug and the model predictions were verified with experimental data using human cancer cells in vitro. The sensitivity analysis suggested that parameters related to extracellular concentration of released PTX, prodrug uptake, target engagement, and target abundance are critical in determining the combined killing efficacy of the prodrug. We found that released PTX cytotoxicity was most sensitive to the retention time of the drug in extracellular space. Modulating drug internalization and conjugating the agents targeted to abundant receptors may provide a new strategy for maximizing the killing capacity of the far-red light-activatable prodrug system. These results provide guidance for the design of the PDT combination study in vivo and have implications for other stimuli-responsive drug delivery systems.

A polymeric prodrug of 5-fluorouracil-1-acetic acid using a multi-hydroxyl polyethylene glycol derivative as the drug carrier.

PubMed

Li, Man; Liang, Zhen; Sun, Xun; Gong, Tao; Zhang, Zhirong

2014-01-01

Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo. PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively. The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors. This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives.

Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.

PubMed

Galluzzi, Lorenzo; Buqué, Aitziber; Kepp, Oliver; Zitvogel, Laurence; Kroemer, Guido

2015-12-14

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

A New Method Without Organic Solvent to Targeted Nanodrug for Enhanced Anticancer Efficacy

NASA Astrophysics Data System (ADS)

Wu, Shichao; Yang, Xiangrui; Zou, Mingyuan; Hou, Zhenqing; Yan, Jianghua

2017-06-01

Since the hydrophobic group is always essential to the synthesis of the drug-loaded nanoparticles, a majority of the methods rely heavily on organic solvent, which may not be completely removed and might be a potential threat to the patients. In this study, we completely "green" synthesized 10-hydroxycamptothecine (HCPT) loaded, folate (FA)-modified nanoneedles (HFNDs) for highly efficient cancer therapy with high drug loading, targeting property, and imaging capability. It should be noted that no organic solvent was used in the preparation process. In vitro cell uptake study and the in vivo distribution study showed that the HFNDs, with FA on the surface, revealed an obviously targeting property and entered the HeLa cells easier than the chitosan-HCPT nanoneedles without FA modified (NDs). The cytotoxicity tests illustrated that the HFNDs possessed better killing ability to HeLa cells than the individual drug or the NDs in the same dose, indicating its good anticancer effect. The in vivo anticancer experiment further revealed the pronounced anticancer effects and the lower side effects of the HFNDs. This new method without organic solvent will lead to a promising sustained drug delivery system for cancer diagnosis and treatment.

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

PubMed Central

Luo, Shuanghui; Wang, Zhiying; Patel, Mitesh; Khurana, Varun; Zhu, Xiaodong; Pal, Dhananjay; Mitra, Ashim. K.

2015-01-01

In order to improve oral absorption, a novel prodrug of saquinavir (Saq), ascorbyl-succinic-saquinavir (AA-Su-Saq) targeting sodium dependent vitamin C transporter (SVCT) was synthesized and evaluated. Aqueous solubility, stability and cytotoxicity were determined. Affinity of AA-Su-Saq towards effluxpump P-glycoprotein (P-gp) and recognition of AA-Su-Saq by SVCT were studied. Transepithelial permeability across polarized MDCK-MDR1 and Caco-2 cells were determined. Metabolic stability of AA-Su-Saq in rat liver microsomes was investigated. AA-Su-Saq appears to be fairly stable in both DPBS and Caco-2 cells with half lives of 9.65 and 5.73 h, respectively. Uptake of [3H]Saquinavir accelerated by 2.7 and 1.9 fold in the presence of 50 μM Saq and AA-Su-Saq in MDCK-MDR1 cells. Cellular accumulation of [14C]AA diminished by about 50–70% relative to control in the presence of 200 μM AA-Su-Saq in MDCK-MDR1 and Caco-2 cells. Uptake of AA-Su-Saq was lowered by 27% and 34% in the presence of 5 mM AA in MDCK-MDR1 and Caco-2 cells, respectively. Absorptive permeability of AA-Su-Saq was elevated about 4-5 fold and efflux index reduced by about 13-15 fold across the polarized MDCK-MDR1 and Caco-2 cells. Absorptive permeability of AA-Su-Saq decreased 44% in the presence of 5 mM AA across MDCK-MDR1 cells. AA-Su-Saq was devoid of cytotoxicity over the concentration range studied. AA-Su-Saq significantly enhanced the metabolic stability but lowered the affinity towards CYP3A4. In conclusion, prodrug modification of Saq through conjugation to AA via a linker significantly raised the absorptive permeability and metabolic stability. Such modification also caused significant evading of P-gp mediated efflux and CYP3A4 mediated metabolism. SVCT targeted prodrug approach can be an attractive strategy to enhance the oral absorption and systemic bioavailability of anti-HIV protease inhibitors. PMID:21571053

Unimolecular Micelles of Amphiphilic Cyclodextrin-Core Star-Like Copolymers with Covalent pH-Responsive Linkage of Anticancer Prodrugs.

PubMed

Jia, Tao; Huang, Shuo; Yang, Cangjie; Wang, Mingfeng

2017-08-07

Multifunctional stable and stimuli-responsive drug delivery systems are important for efficient cancer treatment due to their advantages such as enhanced cancer-targeting efficiency, improved pharmacokinetics, minimized drug leaching, and reduced undesirable side effects. Here we report a robust and pH-responsive anticancer drug delivery system based on unimolecular micelles of star-like amphiphilic copolymers. The polymers (denoted as CPOFs) were facilely synthesized via one-step atom transfer radical polymerization of functionalizable benzoaldehyde and hydrophilic poly[(oligo ethylene glycol) methyl ether methacrylate] as comonomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl]-β-cyclodextrin as the initiator. Doxorubicin (DOX) as an anticancer drug was covalently linked to the benzoaldehyde groups of CPOFs through pH-sensitive Schiff-base bonds. The DOX-conjugated polymers, denoted as CPOF-DOX, formed robust unimolecular micelles with an average diameter of 18 nm in aqueous media. More importantly, these unimolecular micelles showed higher drug loading capacity and more controllable drug release characteristics, compared to our previous unimolecular micelles of β-cyclodextrin-poly(lactic acid)-b-poly[(oligo ethylene glycol) methyl ether methacrylates] that physically encapsulated DOX via hydrophobic interaction. Moreover, the CPOF-DOX unimolecular micelles could be internalized by human cervical cancer HeLa cells in a stepwise way and showed less cytotoxicity compared to carrier-free DOX. We foresee that CPOF-DOX would provide a promising robust and controllable anticancer drug delivery system for future animal study and clinical trials for cancer treatment.

Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drugs.

PubMed

Feng, Shini; Zhang, Huijie; Yan, Ting; Huang, Dandi; Zhi, Chunyi; Nakanishi, Hideki; Gao, Xiao-Dong

With its unique physical and chemical properties and structural similarity to carbon, boron nitride (BN) has attracted considerable attention and found many applications. Biomedical applications of BN have recently started to emerge, raising great hopes in drug and gene delivery. Here, we developed a targeted anticancer drug delivery system based on folate-conjugated BN nanospheres (BNNS) with receptor-mediated targeting. Folic acid (FA) was successfully grafted onto BNNS via esterification reaction. In vitro cytotoxicity assay showed that BNNS-FA complexes were non-toxic to HeLa cells up to a concentration of 100 μg/mL. Then, doxorubicin hydrochloride (DOX), a commonly used anticancer drug, was loaded onto BNNS-FA complexes. BNNS-FA/DOX complexes were stable at pH 7.4 but effectively released DOX at pH 5.0, which exhibited a pH sensitive and sustained release pattern. BNNS-FA/DOX complexes could be recognized and specifically internalized by HeLa cells via FA receptor-mediated endocytosis. BNNS-FA/DOX complexes exhibited greater cytotoxicity to HeLa cells than free DOX and BNNS/DOX complexes due to the increased cellular uptake of DOX mediated by the FA receptor. Therefore, BNNS-FA complexes had strong potential for targeted cancer therapy.

Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drugs

PubMed Central

Feng, Shini; Zhang, Huijie; Yan, Ting; Huang, Dandi; Zhi, Chunyi; Nakanishi, Hideki; Gao, Xiao-Dong

2016-01-01

With its unique physical and chemical properties and structural similarity to carbon, boron nitride (BN) has attracted considerable attention and found many applications. Biomedical applications of BN have recently started to emerge, raising great hopes in drug and gene delivery. Here, we developed a targeted anticancer drug delivery system based on folate-conjugated BN nanospheres (BNNS) with receptor-mediated targeting. Folic acid (FA) was successfully grafted onto BNNS via esterification reaction. In vitro cytotoxicity assay showed that BNNS-FA complexes were non-toxic to HeLa cells up to a concentration of 100 μg/mL. Then, doxorubicin hydrochloride (DOX), a commonly used anticancer drug, was loaded onto BNNS-FA complexes. BNNS-FA/DOX complexes were stable at pH 7.4 but effectively released DOX at pH 5.0, which exhibited a pH sensitive and sustained release pattern. BNNS-FA/DOX complexes could be recognized and specifically internalized by HeLa cells via FA receptor-mediated endocytosis. BNNS-FA/DOX complexes exhibited greater cytotoxicity to HeLa cells than free DOX and BNNS/DOX complexes due to the increased cellular uptake of DOX mediated by the FA receptor. Therefore, BNNS-FA complexes had strong potential for targeted cancer therapy. PMID:27695318

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

PubMed Central

2016-01-01

Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics. PMID:27936709

Human transport protein carrier for controlled photoactivation of antitumor prodrug and real-time intracellular tumor imaging.

PubMed

Li, Xi; Mu, Jing; Liu, Fang; Tan, Eddy Wei Ping; Khezri, Bahareh; Webster, Richard D; Yeow, Edwin Kok Lee; Xing, Bengang

2015-05-20

Current anticancer chemotherapy often suffers from poor tumor selectivity and serious drug resistance. Proper vectors for targeted delivery and controlled drug release play crucial roles in improving the therapeutic selectivity to tumor areas and also overcoming the resistance of cancer cells. In this work, we developed a novel human serum albumin (HSA) protein-based nanocarrier system, which combines the photoactivatable Pt(IV) antitumor prodrug for realizing the controlled release and fluorescent light-up probe for evaluations of drug action and efficacy. The constructed Pt(IV)-probe@HSA platform can be locally activated by light irradiation to release the active Pt species, which results in enhanced cell death at both drug-sensitive A2780 and cisplatin-resistant A2780cis cell lines when compared to the free prodrug molecules. Simultaneously, the cytotoxicity caused by light controlled drug release would further lead to the cellular apoptosis and trigger the activation of caspases 3, one crucial protease enzyme in apoptotic process, which could cleave the recognition peptide moiety (DEVD) with a flanking fluorescent resonance energy transfer (FRET) pair containing near-infrared (NIR) fluorophore Cy5 and quencher Qsy21 on the HSA nanocarrier surface. The turn-on fluorescence in response to caspase-3 could be assessed by fluorescence microscopy and flow cytometry analysis. Our results supported the hypothesis that such a unique design may present a successful platform for multiple roles: (i) a biocompatible protein-based nanocarrier for drug delivery, (ii) the controlled drug release with strengthened therapeutic effects, (iii) real-time monitoring of antitumor drug efficacy at the earlier stage.

Copper-free click-chemistry platform to functionalize cisplatin prodrugs.

PubMed

Pathak, Rakesh K; McNitt, Christopher D; Popik, Vladimir V; Dhar, Shanta

2014-06-02

The ability to rationally design and construct a platform technology to develop new platinum(IV) [Pt(IV)] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of Pt(IV) centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single Pt(IV) precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biodegradable polymers for targeted delivery of anti-cancer drugs.

PubMed

Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

2016-06-01

Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

Gastroprotective [6]-Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin for Colon Cancer

PubMed Central

Zhu, Yingdong; Wang, Fang; Zhao, Yantao; Wang, Pei; Sang, Shengmin

2017-01-01

A growing body of research suggests daily low-dose aspirin (ASA) reduces heart diseases and colorectal cancers. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. Preclinical studies have shown that ginger constituents ameliorate ASA-induced gastric ulceration. We here report the design and synthesis of a novel prodrug of aspirin, [6]-gingerol aspirinate (GAS). Our data show that GAS exerts enhanced anti-cancer properties in vitro and superior gastroprotective effects in mice. GAS was also able to survive stomach acid and decomposed in intestinal linings or after absorption to simultaneously release ASA and [6]-gingerol. We further present that GAS inactivates both COX-1 and COX-2 equally. Our results demonstrate the enhanced anticancer properties along with gastroprotective effects of GAS, suggesting that GAS can be a therapeutic equivalent for ASA in inflammatory and proliferative diseases without the deleterious effects on stomach mucosa. PMID:28067282

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

PubMed Central

Bult, Wouter; Bos, Mariska; Storm, Gert; Nijsen, J. Frank W.; Hennink, Wim E.

2010-01-01

ABSTRACT Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward. PMID:20725771

Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: S6-acyloxymethyl-6-mercaptopurine prodrugs.

PubMed

Waranis, R P; Sloan, K B

1988-03-01

A homologous series of S6-acyloxymethyl-6-mercaptopurine (6-mono-6-MP) and two 9-acyloxymethyl-6-mercaptopurine (9-mono-6-MP) prodrugs have been synthesized and characterized. The ability of the 6-mono-6-MP prodrugs to deliver 6-mercaptopurine (6-MP) through hairless mouse skin from isopropyl myristate (IPM) and propylene glycol (PG) has been evaluated. There was a good correlation between the log experimental permeability coefficients from the diffusion data and calculated solubility parameters of the prodrugs. Although there was no statistical difference between the rates of delivery of 6-MP by the acetyl through valeryl 6-mono-6-MP prodrugs from IPM, the butyryl and valeryl prodrugs were significantly better at delivering 6-MP from PG. For a given solubility parameter value, the 6-mono-6-MP prodrugs were less soluble in water and IPM, and more soluble in PG than the previously studied S6,9-bisacyloxymethyl-6-MP (6,9-bis-6-MP) prodrugs. On the other hand, for a given solubility parameter, the 6,9-bis-6-MP prodrugs were generally more effective at delivering 6-MP from IPM and PG. The single 9-mono-6-MP prodrug that was evaluated was much less effective at delivering 6-MP than either the 6-mono- or 6,9-bis-6-MP prodrugs. Thus, it is much less important to mask the imidazole than the thionamide functional group in 6-MP to enhance the topical delivery of 6-MP using a prodrug approach.

A Polymeric Prodrug of 5-Fluorouracil-1-Acetic Acid Using a Multi-Hydroxyl Polyethylene Glycol Derivative as the Drug Carrier

PubMed Central

Sun, Xun; Gong, Tao; Zhang, Zhirong

2014-01-01

Purpose Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo. Methods PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively. Results The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors. Conclusion This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives. PMID:25389968

Macrophage mediated PCI enhanced gene-directed enzyme prodrug therapy

NASA Astrophysics Data System (ADS)

Christie, Catherine E.; Zamora, Genesis; Kwon, Young J.; Berg, Kristian; Madsen, Steen J.; Hirschberg, Henry

2015-03-01

Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. Prodrug activating gene therapy (suicide gene therapy) employing the transduction of the E. coli cytosine deaminase (CD) gene into tumor cells, is a promising method. Expression of this gene within the target cell produces an enzyme that converts the nontoxic prodrug, 5-FC, to the toxic metabolite, 5-fluorouracil (5-FU). 5-FC may be particularly suitable for brain tumors, because it can readily cross the bloodbrain barrier (BBB). In addition the bystander effect, where activated drug is exported from the transfected cancer cells into the tumor microenvironment, plays an important role by inhibiting growth of adjacent tumor cells. Tumor-associated macrophages (TAMs) are frequently found in and around glioblastomas. Monocytes or macrophages (Ma) loaded with drugs, nanoparticles or photosensitizers could therefore be used to target tumors by local synthesis of chemo attractive factors. The basic concept is to combine PCI, to enhance the ex vivo transfection of a suicide gene into Ma, employing specially designed core/shell NP as gene carrier.

Gelatin-encapsulated iron oxide nanoparticles for platinum (IV) prodrug delivery, enzyme-stimulated release and MRI.

PubMed

Cheng, Ziyong; Dai, Yunlu; Kang, Xiaojiao; Li, Chunxia; Huang, Shanshan; Lian, Hongzhou; Hou, Zhiyao; Ma, Pingan; Lin, Jun

2014-08-01

A facile method for transferring hydrophobic iron oxide nanoparticles (IONPs) from chloroform to aqueous solution via encapsulation of FITC-modified gelatin based on the hydrophobic-hydrophobic interaction is described in this report. Due to the existence of large amount of active groups such as amine groups in gelatin, the fluorescent labeling molecules of fluorescein isothiocyanate (FITC) and platinum (IV) prodrug functionalized with carboxylic groups can be conveniently conjugated on the IONPs. The nanoparticles carrying Pt(IV) prodrug exhibit good anticancer activities when the Pt(IV) complexes are reduced to Pt(II) in the intracellular environment, while the pure Pt(IV) prodrug only presents lower cytotoxicity on cancer cells. Meanwhile, fluorescence of FITC on the surface of nanoparticles was completely quenched due to the possible Förster Resonance Energy Transfer (FRET) mechanism and showed a fluorescence recovery after gelatin release and detachment from IONPs. Therefore FITC as a fluorescence probe can be used for identification, tracking and monitoring the drug release. In addition, adding pancreatic enzyme can effectively promote the gelatin release from IONPs owing to the degradation of gelatin. Noticeable darkening in magnetic resonance image (MRI) was observed at the tumor site after in situ injection of nanoparticles, indicating the IONPs-enhanced T2-weighted imaging. Our results suggest that the gelatin encapsulated Fe3O4 nanoparticles have potential applications in multi-functional drug delivery system for disease therapy, MR imaging and fluorescence sensor. Copyright © 2014 Elsevier Ltd. All rights reserved.

Explorative study on the anticancer activity, selectivity and metabolic stability of related analogs of aminosteroid RM-133.

PubMed

Perreault, Martin; Maltais, René; Dutour, Raphaël; Poirier, Donald

2016-11-01

RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-activity relationship study was conducted by synthesizing eleven RM-133-related compounds and addressing their antiproliferative activity on 3 human cancer cells (HL-60, OVCAR-3 and PANC-1) and 3 human normal cell lines (primary ovary, pancreas and renal proximal tubule) as well as their metabolic stability in human liver microsomes. When the 2β-tertiary amine of RM-133 was transformed into a salt or moved to position 3β, the anticancer activity was lost. Modifying the orientation of the side chain of RM-133 increased anticancer activity and selectivity, but led to a drastic loss of stability. The protection of the 3α-hydroxyl of RM-133 by the formation of an ester or a carbamate stabilized the molecule against the phase I metabolic enzymes without affecting its anticancer activity. In comparison to RM-133, the 3-dimethylcarbamate derivative 3 is more selective for cancer cells over normal cells and is much more stable in liver microsomes. Those results support the use of a pro-drug strategy targeting the 3α-hydroxyl of RM-133 as an approach to improve its drug properties. The work presented will enable the development of an optimized anticancer drug of the aminosteroid family that is suitable for a future phase I clinical trial. Copyright © 2016 Elsevier Inc. All rights reserved.

Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs

PubMed Central

2013-01-01

A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP–NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy. PMID:23663277

Targeting SVCT for enhanced drug absorption: synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir.

PubMed

Luo, Shuanghui; Wang, Zhiying; Patel, Mitesh; Khurana, Varun; Zhu, Xiaodong; Pal, Dhananjay; Mitra, Ashim K

2011-07-29

In order to improve oral absorption, a novel prodrug of saquinavir (Saq), ascorbyl-succinic-saquinavir (AA-Su-Saq) targeting sodium dependent vitamin C transporter (SVCT) was synthesized and evaluated. Aqueous solubility, stability and cytotoxicity were determined. Affinity of AA-Su-Saq towards efflux pump P-glycoprotein (P-gp) and recognition of AA-Su-Saq by SVCT were studied. Transepithelial permeability across polarized MDCK-MDR1 and Caco-2 cells were determined. Metabolic stability of AA-Su-Saq in rat liver microsomes was investigated. AA-Su-Saq appears to be fairly stable in both DPBS and Caco-2 cells with half lives of 9.65 and 5.73 h, respectively. Uptake of [(3)H]Saquinavir accelerated by 2.7 and 1.9 fold in the presence of 50 μM Saq and AA-Su-Saq in MDCK-MDR1 cells. Cellular accumulation of [(14)C]AA diminished by about 50-70% relative to control in the presence of 200 μM AA-Su-Saq in MDCK-MDR1 and Caco-2 cells. Uptake of AA-Su-Saq was lowered by 27% and 34% in the presence of 5mM AA in MDCK-MDR1 and Caco-2 cells, respectively. Absorptive permeability of AA-Su-Saq was elevated about 4-5 fold and efflux index reduced by about 13-15 fold across the polarized MDCK-MDR1 and Caco-2 cells. Absorptive permeability of AA-Su-Saq decreased 44% in the presence of 5mM AA across MDCK-MDR1 cells. AA-Su-Saq was devoid of cytotoxicity over the concentration range studied. AA-Su-Saq significantly enhanced the metabolic stability but lowered the affinity towards CYP3A4. In conclusion, prodrug modification of Saq through conjugation to AA via a linker significantly raised the absorptive permeability and metabolic stability. Such modification also caused significant evading of P-gp mediated efflux and CYP3A4 mediated metabolism. SVCT targeted prodrug approach can be an attractive strategy to enhance the oral absorption and systemic bioavailability of anti-HIV protease inhibitors. Copyright © 2011 Elsevier B.V. All rights reserved.

Polysaccharide-gold nanocluster supramolecular conjugates as a versatile platform for the targeted delivery of anticancer drugs.

PubMed

Li, Nan; Chen, Yong; Zhang, Ying-Ming; Yang, Yang; Su, Yue; Chen, Jia-Tong; Liu, Yu

2014-02-25

Through the high affinity of the β-cyclodextrin (β-CD) cavity for adamantane moieties, novel polysaccharide-gold nanocluster supramolecular conjugates (HACD-AuNPs) were successfully constructed from gold nanoparticles (AuNPs) bearing adamantane moieties and cyclodextrin-grafted hyaluronic acid (HACD). Due to their porous structure, the supramolecular conjugates could serve as a versatile and biocompatible platform for the loading and delivery of various anticancer drugs, such as doxorubicin hydrochloride (DOX), paclitaxel (PTX), camptothecin (CPT), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT), by taking advantage of the controlled association/dissociation of drug molecules from the cavities formed by the HACD skeletons and AuNPs cores as well as by harnessing the efficient targeting of cancer cells by hyaluronic acid. Significantly, the release of anticancer drugs from the drug@HACD-AuNPs system was pH-responsive, with more efficient release occurring under a mildly acidic environment, such as that in a cancer cell. Taking the anticancer drug DOX as an example, cell viability experiments revealed that the DOX@HACD-AuNPs system exhibited similar tumor cell inhibition abilities but lower toxicity than free DOX due to the hyaluronic acid reporter-mediated endocytosis. Therefore, the HACD-AuNPs supramolecular conjugates may possess great potential for the targeted delivery of anticancer drugs.

Polysaccharide-Gold Nanocluster Supramolecular Conjugates as a Versatile Platform for the Targeted Delivery of Anticancer Drugs

NASA Astrophysics Data System (ADS)

Li, Nan; Chen, Yong; Zhang, Ying-Ming; Yang, Yang; Su, Yue; Chen, Jia-Tong; Liu, Yu

2014-02-01

Through the high affinity of the β-cyclodextrin (β-CD) cavity for adamantane moieties, novel polysaccharide-gold nanocluster supramolecular conjugates (HACD-AuNPs) were successfully constructed from gold nanoparticles (AuNPs) bearing adamantane moieties and cyclodextrin-grafted hyaluronic acid (HACD). Due to their porous structure, the supramolecular conjugates could serve as a versatile and biocompatible platform for the loading and delivery of various anticancer drugs, such as doxorubicin hydrochloride (DOX), paclitaxel (PTX), camptothecin (CPT), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT), by taking advantage of the controlled association/dissociation of drug molecules from the cavities formed by the HACD skeletons and AuNPs cores as well as by harnessing the efficient targeting of cancer cells by hyaluronic acid. Significantly, the release of anticancer drugs from the drug@HACD-AuNPs system was pH-responsive, with more efficient release occurring under a mildly acidic environment, such as that in a cancer cell. Taking the anticancer drug DOX as an example, cell viability experiments revealed that the DOX@HACD-AuNPs system exhibited similar tumor cell inhibition abilities but lower toxicity than free DOX due to the hyaluronic acid reporter-mediated endocytosis. Therefore, the HACD-AuNPs supramolecular conjugates may possess great potential for the targeted delivery of anticancer drugs.

Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.

PubMed

Layek, Buddhadev; Sadhukha, Tanmoy; Panyam, Jayanth; Prabha, Swayam

2018-06-01

Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUC lung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196-206. ©2018 AACR . ©2018 American Association for Cancer Research.

Platinum(iv) prodrug conjugated Pd@Au nanoplates for chemotherapy and photothermal therapy

NASA Astrophysics Data System (ADS)

Shi, Saige; Chen, Xiaolan; Wei, Jingping; Huang, Yizhuan; Weng, Jian; Zheng, Nanfeng

2016-03-01

Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(iv) prodrug loading. Once injected into biological tissue, the Pt(iv) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(ii) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(ii) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The

Stepwise-activable multifunctional peptide-guided prodrug micelles for cancerous cells intracellular drug release

NASA Astrophysics Data System (ADS)

Zhang, Jing; Li, Mengfei; Yuan, Zhefan; Wu, Dan; Chen, Jia-da; Feng, Jie

2016-10-01

A novel type of stepwise-activable multifunctional peptide-guided prodrug micelles (MPPM) was fabricated for cancerous cells intracellular drug release. Deca-lysine sequence (K10), a type of cell-penetrating peptide, was synthesized and terminated with azido-glycine. Then a new kind of molecule, alkyne modified doxorubicin (DOX) connecting through disulfide bond (DOX-SS-alkyne), was synthesized. After coupling via Cu-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reaction, reduction-sensitive peptide-guided prodrug was obtained. Due to the amphiphilic property of the prodrug, it can assemble to form micelles. To prevent the nanocarriers from unspecific cellular uptake, the prodrug micelles were subsequently modified with 2,3-dimethyl maleic anhydride to obtain MPPM with a negatively charged outer shell. In vitro studies showed that MPPM could be shielded from cells under psychological environment. However, when arriving at mild acidic tumor site, the cell-penetrating capacity of MPPM would be activated by charge reversal of the micelles via hydrolysis of acid-labile β-carboxylic amides and regeneration of K10, which enabled efficient internalization of MPPM by tumor cells as well as following glutathione- and protease-induced drug release inside the cancerous cells. Furthermore, since the guide peptide sequences can be accurately designed and synthesized, it can be easily changed for various functions, such as targeting peptide, apoptotic peptide, even aptamers, only need to be terminated with azido-glycine. This method can be used as a template for reduction-sensitive peptide-guided prodrug for cancer therapy.

Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A.

PubMed

Erzinger, Melanie M; Bovet, Cédric; Hecht, Katrin M; Senger, Sabine; Winiker, Pascale; Sobotzki, Nadine; Cristea, Simona; Beerenwinkel, Niko; Shay, Jerry W; Marra, Giancarlo; Wollscheid, Bernd; Sturla, Shana J

2016-01-01

The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify proteins modulated by a low concentration of SF, we treated HT29 colon cancer cells with 2.5 μM SF. Protein abundance changes were detected by stable isotope labeling of amino acids in cell culture. Among 18 proteins found to be significantly up-regulated, aldo-keto reductase 1C3 (AKR1C3), bioactivating the DNA cross-linking prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of PR-104A 3.6-fold. The increase in PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second colon cancer cell line, SW620, but not in other colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of cancers may be susceptible to combined food-derived component and prodrug treatments with no harm to normal tissues.

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

PubMed Central

Shuvalov, Oleg; Petukhov, Alexey; Daks, Alexandra; Fedorova, Olga; Vasileva, Elena; Barlev, Nickolai A.

2017-01-01

Cancer-related metabolism has recently emerged as one of the “hallmarks of cancer”. It has several important features, including altered metabolism of glucose and glutamine. Importantly, altered cancer metabolism connects different biochemical pathways into the one fine-tuned metabolic network, which stimulates high proliferation rates and plasticity to malignant cells. Among the keystones of cancer metabolism are one-carbon metabolism and nucleotide biosynthesis, which provide building blocks to anabolic reactions. Accordingly, the importance of these metabolic pathways for anticancer therapy has well been documented by more than fifty years of clinical use of specific metabolic inhibitors – methotrexate and nucleotides analogs. In this review we discuss one-carbon metabolism and nucleotide biosynthesis as common and specific features of many, if not all, tumors. The key enzymes involved in these pathways also represent promising anti-cancer therapeutic targets. We review different aspects of these metabolic pathways including their biochemistry, compartmentalization and expression of the key enzymes and their regulation at different levels. We also discuss the effects of known inhibitors of these pathways as well as the recent data on other enzymes of the same pathways as perspective pharmacological targets. PMID:28177894

para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis.

PubMed

Zheng, Jun; Rubin, Eric J; Bifani, Pablo; Mathys, Vanessa; Lim, Vivian; Au, Melvin; Jang, Jichan; Nam, Jiyoun; Dick, Thomas; Walker, John R; Pethe, Kevin; Camacho, Luis R

2013-08-09

para-Aminosalicylic acid (PAS) is one of the antimycobacterial drugs currently used for multidrug-resistant tuberculosis. Although it has been in clinical use for over 60 years, its mechanism(s) of action remains elusive. Here we report that PAS is a prodrug targeting dihydrofolate reductase (DHFR) through an unusual and novel mechanism of action. We provide evidences that PAS is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity. Interestingly, PAS is recognized by DHPS as efficiently as its natural substrate para-amino benzoic acid. Chemical inhibition of DHPS or mutation in DHFS prevents the formation of the antimetabolite, thereby conferring resistance to PAS. In addition, we identified a bifunctional enzyme (riboflavin biosynthesis protein (RibD)), a putative functional analog of DHFR in a knock-out strain. This finding is further supported by the identification of PAS-resistant clinical isolates encoding a RibD overexpression mutation displaying cross-resistance to genuine DHFR inhibitors. Our findings reveal that a metabolite of PAS inhibits DHFR in the folate pathway. RibD was shown to act as a functional analog of DHFR, and as for DHFS, both were shown to be associated in PAS resistance in laboratory strains and clinical isolates.

Prodrugs for transdermal drug delivery - trends and challenges.

PubMed

Ita, Kevin B

2016-09-01

Prodrugs continue to attract significant interest in the transdermal drug delivery field. These moieties can confer favorable physicochemical properties on transdermal drug delivery candidates. Alkyl chain lengthening, pegylation are some of the strategies used for prodrug synthesis. It is usually important to optimize partition coefficient, water and oil solubilities of drugs. In this review, progress made in the field of prodrugs for percutaneous penetration is highlighted and the challenges discussed.

Targeting Anti-Cancer Active Compounds: Affinity-Based Chromatographic Assays

PubMed Central

de Moraes, Marcela Cristina; Cardoso, Carmen Lucia; Seidl, Claudia; Moaddel, Ruin; Cass, Quezia Bezerra

2016-01-01

Affinity-based chromatography assays encompass the use of solid supports containing immobilized biological targets to monitor binding events in the isolation , identification and/or characterization of bioactive compounds. This powerful bioanalytical technique allows the screening of potential binders through fast analyses that can be directly performed using isolated substances or complex matrices. An overview of the recent researches in frontal and zonal affinity-based chromatography screening assays, which has been used as a tool in the identification and characterization of new anti-cancer agents, is discussed. In addition, a critical evaluation of the recently emerged ligands fishing assays in complex mixtures is also discussed. PMID:27306095

Current situation and future usage of anticancer drug databases.

PubMed

Wang, Hongzhi; Yin, Yuanyuan; Wang, Peiqi; Xiong, Chenyu; Huang, Lingyu; Li, Sijia; Li, Xinyi; Fu, Leilei

2016-07-01

Cancer is a deadly disease with increasing incidence and mortality rates and affects the life quality of millions of people per year. The past 15 years have witnessed the rapid development of targeted therapy for cancer treatment, with numerous anticancer drugs, drug targets and related gene mutations been identified. The demand for better anticancer drugs and the advances in database technologies have propelled the development of databases related to anticancer drugs. These databases provide systematic collections of integrative information either directly on anticancer drugs or on a specific type of anticancer drugs with their own emphases on different aspects, such as drug-target interactions, the relationship between mutations in drug targets and drug resistance/sensitivity, drug-drug interactions, natural products with anticancer activity, anticancer peptides, synthetic lethality pairs and histone deacetylase inhibitors. We focus on a holistic view of the current situation and future usage of databases related to anticancer drugs and further discuss their strengths and weaknesses, in the hope of facilitating the discovery of new anticancer drugs with better clinical outcomes.

Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11

PubMed Central

Hatfield, M. Jason; Tsurkan, Lyudmila; Garrett, Michael; Shaver, Timothy M.; Hyatt, Janice L.; Edwards, Carol C.; Hicks, Latorya D.; Potter, Philip M.

2010-01-01

The activation of the anticancer prodrug CPT-11, to its active metabolite SN-38, is primarily mediated by carboxylesterases (CE). In humans, three CEs have been identified, of which human liver CE (hCE1; CES1) and human intestinal CE (hiCE; CES2) demonstrate significant ability to hydrolyze the drug. However, while the kinetic parameters of CPT-11 hydrolysis have been measured, the actual contribution of each enzyme to activate the drug in biological samples has not been addressed. Hence, we have used a combination of specific CE inhibition and conventional chromatographic techniques to determine the amounts, and hydrolytic activity, of CEs present within human liver, kidney, intestinal and lung specimens. These studies confirm that hiCE demonstrates the most efficient kinetic parameters for CPT-11 activation, however, due to the high levels of hCE1 that are expressed in liver, the latter enzyme can contribute up to 50% of the total of drug hydrolysis in this tissue. Conversely, in human duodenum, jejunum, ileum and kidney, where hCE1 expression is very low, greater than 99% of the conversion of CPT-11 to SN-38 was mediated by hiCE. Furthermore, analysis of lung microsomal extracts indicated that CPT-11 activation was more proficient in samples obtained from smokers. Overall, our studies demonstrate that hCE1 plays a significant role in CPT-11 hydrolysis even though it is up to 100-fold less efficient at drug activation than hiCE, and that drug activation in the intestine and kidney are likely major contributors to SN-38 production in vivo. PMID:20833148

Direct Real-Time Monitoring of Prodrug Activation by Chemiluminescence.

PubMed

Gnaim, Samer; Scomparin, Anna; Das, Sayantan; Blau, Rachel; Satchi-Fainaro, Ronit; Shabat, Doron

2018-05-22

The majority of theranostic prodrugs reported so far relay information through a fluorogenic response generated upon release of the active chemotherapeutic agent. A chemiluminescence detection mode offers significant advantages over fluorescence, mainly due to the superior signal-to-noise ratio of chemiluminescence. Here we report the design and synthesis of the first theranostic prodrug monitored by a chemiluminescence diagnostic mode. As a representative model, we prepared a prodrug from the chemotherapeutic monomethyl auristatin E, which was modified for activation by β-galactosidase. The activation of the prodrug in the presence of β-galactosidase is accompanied by emission of a green photon. Light emission intensities, which increase with increasing concentration of the prodrug, were linearly correlated with a decrease in the viability of a human cell line that stably expresses β-galactosidase. We obtained sharp intravital chemiluminescent images of endogenous enzymatic activity in β-galactosidase-overexpressing tumor-bearing mice. The exceptional sensitivity achieved with the chemiluminescence diagnostic mode should allow the exploitation of theranostic prodrugs for personalized cancer treatment. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

PubMed Central

Liu, Yi; Piao, Hongyu; Gao, Ying; Xu, Caihong; Tian, Ye; Wang, Lihong; Liu, Jinwen; Tang, Bo; Zou, Meijuan; Cheng, Gang

2015-01-01

7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0–24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery. PMID:25848251

Prodrugs of herpes simplex thymidine kinase inhibitors.

PubMed

Yanachkova, Milka; Xu, Wei-Chu; Dvoskin, Sofya; Dix, Edward J; Yanachkov, Ivan B; Focher, Federico; Savi, Lida; Sanchez, M Dulfary; Foster, Timothy P; Wright, George E

2015-04-01

Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model. Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug. Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N(2)-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication. Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo. © The Author(s) 2015.

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action.

PubMed

Wong, Yin Kwan; Xu, Chengchao; Kalesh, Karunakaran A; He, Yingke; Lin, Qingsong; Wong, W S Fred; Shen, Han-Ming; Wang, Jigang

2017-11-01

Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents. © 2017 Wiley Periodicals, Inc.

Dual function of tributyrin emulsion: solubilization and enhancement of anticancer effect of celecoxib.

PubMed

Kang, Sung Nam; Hong, Soon-Seok; Lee, Mi-Kyung; Lim, Soo-Jeong

2012-05-30

Tributyrin, a triglyceride analogue of butyrate, can act as a prodrug of an anticancer agent butyrate after being cleaved by intracellular enzymes. We recently demonstrated that the emulsion containing tributyrin as an inner oil phase possesses a potent anticancer activity. Herein we sought to develop tributyrin emulsion as a carrier of celecoxib, a poorly-water soluble drug with anticancer activity. Combined treatment of human HCT116 colon cancer cells with free celecoxib plus tributyrin emulsion inhibited the cellular proliferation more effectively than that of each drug alone, suggesting the possibility of tributyrin emulsion as a potential celecoxib carrier. The mean droplet size of emulsions tended to increase as the tributyrin content in emulsion increases and the concentration of celecoxib loaded in emulsions was affected by tributyrin content and the initial amount of celecoxib, but not by the total amount of surfactant mixture. The concentration of celecoxib required to inhibit the growth of HCT116 and B16-F10 cancer cells by 50% was 2.6- and 3.1-fold lowered by loading celecoxib in tributyrin emulsions, compared with free celecoxib. These data suggest that the anticancer activity of celecoxib was enhanced by loading in tributyrin emulsions, probably due to the solubilization capacity and anticancer activity of tributyrin emulsion. Copyright © 2012 Elsevier B.V. All rights reserved.

PEGylated anticancer-carbon nanotubes complex targeting mitochondria of lung cancer cells

NASA Astrophysics Data System (ADS)

Kim, Sang-Woo; Lee, Yeon Kyung; Lee, Jong Yeon; Hong, Jeong Hee; Khang, Dongwoo

2017-11-01

Although activating apoptosis in cancer cells by targeting the mitochondria is an effective strategy for cancer therapy, insufficient targeting of the mitochondria in cancer cells restricts the availability in clinical treatment. Here, we report on a polyethylene glycol-coated carbon nanotube (CNT)-ABT737 nanodrug that improves the mitochondrial targeting of lung cancer cells. The polyethylene glycol-coated CNT-ABT737 nanodrug internalized into the early endosomes via macropinocytosis and clathrin-mediated endocytosis in advance of early endosomal escape and delivered into the mitochondria. Cytosol release of the nanodrug led to apoptosis of lung cancer cells by abruption of the mitochondrial membrane potential, inducing Bcl-2-mediated apoptosis and generating intracellular reactive oxygen species. As such, this study provides an effective strategy for increasing the anti-lung cancer efficacy by increasing mitochondria accumulation rate of cytosol released anticancer nanodrugs.

Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum complex.

PubMed

Mezencev, Roman

2015-01-01

Since the discovery of its anticancer activity in 1970s, cisplatin and its analogs have become widely used in clinical practice, being administered to 40-80% of patients undergoing chemotherapy for solid tumors. The fascinating story of this drug continues to evolve presently, which includes advances in our understanding of complexity of molecular mechanisms involved in its anticancer activity and drug toxicity. While genomic DNA has been generally recognized as the most critical pharmacological target of cisplatin, the results reported across multiple disciplines suggest that other targets and molecular interactions are likely involved in the anticancer mode of action, drug toxicity and resistance of cancer cells to this remarkable anticancer drug. This article reviews interactions of cisplatin with non-DNA targets, including RNAs, proteins, phospholipids and carbohydrates in the context of its pharmacological activity and drug toxicity. Some of these non-DNA targets and associated mechanisms likely act in a highly concerted manner towards the biological outcome in cisplatin-treated tumors; therefore, the understanding of complexity of cisplatin interactome may open new avenues for modulation of its clinical efficacy or for designing more efficient platinum-based anticancer drugs to reproduce the success of cisplatin in the treatment of highly curable testicular germ cell tumors in its therapeutic applications to other cancers.

Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor

NASA Astrophysics Data System (ADS)

Shin, Weon Sup; Han, Jiyou; Kumar, Rajesh; Lee, Gyung Gyu; Sessler, Jonathan L.; Kim, Jong-Hoon; Kim, Jong Seung

2016-07-01

We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38—a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro and in vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic (“phototheranostic”).

ALA-Butyrate prodrugs for Photo-Dynamic Therapy

NASA Astrophysics Data System (ADS)

Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

2010-05-01

The use of 5-aminolevulinic acid (ALA) administration has led to many applications of photodynamic therapy (PDT) in cancer. However, the hydrophilic nature of ALA limits its ability to penetrate the cells and tissues, and therefore the need for ALA derivatives became an urgent research target. In this study we investigated the activity of novel multifunctional acyloxyalkyl ester prodrugs of ALA that upon metabolic hydrolysis release active components such as, formaldehyde, and the histone deacetylase inhibitory moiety, butyric acid. Evaluation of these prodrugs under photo-irradiation conditions showed that butyryloxyethyl 5-amino-4-oxopentanoate (ALA-BAC) generated the most efficient photodynamic destruction compared to ALA. ALA-BAC stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells which resulted in generation of intracellular ROS, reduction of mitochondrial activity, leading to apoptotic and necrotic death of the cells. The apoptotic cell death induced by ALA / ALA-BAC followed by PDT equally activate intrinsic and extrinsic apoptotic signals and both pathways may occur simultaneously. The main advantage of ALA-BAC over ALA stems from its ability to induce photo-damage at a significantly lower dose than ALA.

Polypharmacology of Approved Anticancer Drugs.

PubMed

Amelio, Ivano; Lisitsa, Andrey; Knight, Richard A; Melino, Gerry; Antonov, Alexey V

2017-01-01

The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Versatile Bioorthogonal Copper-free Click Chemistry Platform to Functionalize Cisplatin Prodrugs

PubMed Central

Pathak, Rakesh K.; McNitt, Christopher D.; Popik, Vladimir V.; Dhar, Shanta

2015-01-01

The ability to rationally design and construct a platform technology to develop new platinum(IV) [Pt(IV)] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities by considering the sensitivity of Pt(IV) centers to reduction, thiols, etc, we used a strain promoted azide alkyne cycloaddition (SPAAC) approach to provide a novel platform where new functionalities can easily be installed on cisplatin prodrugs from a single Pt(IV) precursor. The ability of this platform to be incorporated in nano-delivery vehicle and conjugation to fluorescent reporters were also investigated. PMID:24756923

Modular adeno-associated virus (rAAV) vectors used for cellular virus-directed enzyme prodrug therapy

PubMed Central

Hagen, Sven; Baumann, Tobias; Wagner, Hanna J.; Morath, Volker; Kaufmann, Beate; Fischer, Adrian; Bergmann, Stefan; Schindler, Patrick; Arndt, Katja M.; Müller, Kristian M.

2014-01-01

The pre-clinical and clinical development of viral vehicles for gene transfer increased in recent years, and a recombinant adeno-associated virus (rAAV) drug took center stage upon approval in the European Union. However, lack of standardization, inefficient purification methods and complicated retargeting limit general usability. We address these obstacles by fusing rAAV-2 capsids with two modular targeting molecules (DARPin or Affibody) specific for a cancer cell-surface marker (EGFR) while simultaneously including an affinity tag (His-tag) in a surface-exposed loop. Equipping these particles with genes coding for prodrug converting enzymes (thymidine kinase or cytosine deaminase) we demonstrate tumor marker specific transduction and prodrug-dependent apoptosis of cancer cells. Coding terminal and loop modifications in one gene enabled specific and scalable purification. Our genetic parts for viral production adhere to a standardized cloning strategy facilitating rapid prototyping of virus directed enzyme prodrug therapy (VDEPT). PMID:24457557

International comparison of the factors influencing reimbursement of targeted anti-cancer drugs.

PubMed

Lim, Carol Sunghye; Lee, Yun-Gyoo; Koh, Youngil; Heo, Dae Seog

2014-11-29

Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost-effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (ρ = -0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs.

Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials.

PubMed

Vemula, Praveen Kumar; Wiradharma, Nikken; Ankrum, James A; Miranda, Oscar R; John, George; Karp, Jeffrey M

2013-12-01

Prodrug-based self-assembled hydrogels represent a new class of active biomaterials that can be harnessed for medical applications, in particular the design of stimuli responsive drug delivery devices. In this approach, a promoiety is chemically conjugated to a known-drug to generate an amphiphilic prodrug that is capable of forming self-assembled hydrogels. Prodrug-based self-assembled hydrogels are advantageous as they alter the solubility of the drug, enhance drug loading, and eliminate the use of harmful excipients. In addition, self-assembled prodrug hydrogels can be designed to undergo controlled drug release or tailored degradation in response to biological cues. Herein we review the development of prodrug-based self-assembled hydrogels as an emerging class of biomaterials that overcome several common limitations encountered in conventional drug delivery. Published by Elsevier Ltd.

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

PubMed Central

Johnstone, Timothy C.; Suntharalingam, Kogularamanan; Lippard, Stephen J.

2016-01-01

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive. PMID:26865551

Magnetic polymer nanospheres for anticancer drug targeting

NASA Astrophysics Data System (ADS)

Juríková, A.; Csach, K.; Koneracká, M.; Závišová, V.; Múčková, M.; Tomašovičová, N.; Lancz, G.; Kopčanský, P.; Timko, M.; Miškuf, J.

2010-01-01

Poly(D,L-lactide-co-glycolide) polymer (PLGA) nanospheres loaded with biocom-patible magnetic fluid as a magnetic carrier and anticancer drug Taxol were prepared by the modified nanoprecipitation method with size of 200-250 nm in diameter. The PLGA polymer was utilized as a capsulation material due to its biodegradability and biocompatibility. Taxol as an important anticancer drug was chosen for its significant role against a wide range of tumours. Thermal properties of the drug-polymer system were characterized using thermal analysis methods. It was determined the solubility of Taxol in PLGA nanospheres. Magnetic properties investigated using SQUID magnetometry showed superparamagnetism of the prepared magnetic polymer nanospheres.

Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.

PubMed

Cardaci, Simone; Desideri, Enrico; Ciriolo, Maria Rosa

2012-02-01

The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities. Therefore, besides reviewing the alterations of glycolysis that occur with malignant transformation, this manuscript aims at recapitulating the most effective pharmacological therapeutics of its targeting. In particular, we describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings.

A review of economic impact of targeted oral anticancer medications.

PubMed

Shen, Chan; Chien, Chun-Ru; Geynisman, Daniel M; Smieliauskas, Fabrice; Shih, Ya-Chen T

2014-02-01

There has been a rapid increase in the use of targeted oral anticancer medications (OAMs) in the past decade. As OAMs are often expensive, economic consideration play a significant role in the decision to prescribe, receive or cover them. This paper performs a systematic review of costs or budgetary impact of targeted OAMs to better understand their economic impact on the healthcare system, patients as well as payers. We present our review in a summary table that describes the method and main findings, take into account multiple factors, such as country, analytical approach, cost type, study perspective, timeframe, data sources, study population and care setting when we interpret the results from different papers, and discuss the policy and clinical implications. Our review raises a concern regarding the role of sponsorship on findings of economic analyses as the vast majority of pharmaceutical company-sponsored studies reported cost advantages toward the sponsor's drugs.

Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.

PubMed

Aboody, Karen S; Najbauer, Joseph; Metz, Marianne Z; D'Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J; Synold, Timothy W; Couture, Larry A; Blanchard, Suzette; Moats, Rex A; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V; Frank, Richard T; Barish, Michael E; Brown, Christine E; Kim, Seung U; Badie, Behnam; Portnow, Jana

2013-05-08

High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma.

[Radiation Anticarcinogenesis by Thiazolidine Pro-drug

NASA Technical Reports Server (NTRS)

Warters, Raymond L.; Roberts, Jeanette C.; Fain, Heidi

1999-01-01

The original goal of this work was to determine the capacity of selected aminothiols to modulate radiation induced cytotoxicity, mutagenesis and carcinogenesis in a human mammary epithelial cell line. The conclusions from this work are that WR-1065 is the "gold standard" for protection against radiation induced cytotoxicity, mutagenesis and carcinogenesis. While a potent radiation protector, WR-1065 is cytotoxic in vitro and in vivo. Our rationale for a study of the thiazolidine pro-drugs was that these compounds are neither toxic in vitro or in vivo. The results obtained during this funding period indicate that the thiazolidine pro-drugs are as potent as WR-1065 as protectors against radiation induced mutation induction, and thus presumably against radiation induced carcinogenesis. Our results indicate that the thiazolidine prodrugs are excellent candidates to test as non-toxic anticarcinogens for protecting astronauts from cancer induction during space travel.

Classification of current anticancer immunotherapies

PubMed Central

Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fučíková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

2014-01-01

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment.

PubMed

Zhang, Wen; Li, Changzheng; Shen, Chengwu; Liu, Yuguo; Zhao, Xiaoting; Liu, Ying; Zou, Dongna; Gao, Zhenfa; Yue, Chunwen

2016-09-01

Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers. This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues. In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. The in vitro and in vivo anti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line. PTX/CBP NPs achieved the highest cytotoxic effect among all formulations in vitro, as compared with single drug delivery NPs. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor-targeting capacity and strong anti-tumor activity. The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.

Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery.

PubMed

Wang, Ruoning; Gu, Xiaochen; Zhou, Jianping; Shen, Lingjia; Yin, Lifang; Hua, Peiying; Ding, Yang

2016-08-10

In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. Copyright © 2016 Elsevier B.V. All rights reserved.

In situ targeted activation of an anticancer agent using ultrasound-triggered release of composite droplets.

PubMed

Bezagu, Marine; Clarhaut, Jonathan; Renoux, Brigitte; Monti, Fabrice; Tanter, Mickael; Tabeling, Patrick; Cossy, Janine; Couture, Olivier; Papot, Sebastien; Arseniyadis, Stellios

2017-12-15

The efficiency of a drug is usually highly dependent on the way it is administered or delivered. As such, targeted-therapy, which requires conceiving drug-delivery vehicles that will change their state from a relatively stable structure with a very slow leak-rate to an unstable structure with a fast release, clearly improves the pharmacokinetics, the absorption, the distribution, the metabolism and the therapeutic index of a given drug. In this context, we have developed a particularly effective double stimuli-responsive drug-delivery method allowing an ultrasound-induced release of a monomethylauristatin E-glucuronide prodrug and its subsequent activation by a β-glucuronidase. This led to an increase of cytotoxicity of about 80% on cancer cells. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Ocular Sustained Release Nanoparticles Containing Stereoisomeric Dipeptide Prodrugs of Acyclovir

PubMed Central

Jwala, Jwala; Boddu, Sai H.S.; Shah, Sujay; Sirimulla, Suman; Pal, Dhananjay

2011-01-01

Abstract Purpose The objective of this study was to develop and characterize polymeric nanoparticles of appropriate stereoisomeric dipeptide prodrugs of acyclovir (L-valine-L-valine-ACV, L-valine-D-valine-ACV, D-valine-L-valine-ACV, and D-valine-D-valine-ACV) for the treatment of ocular herpes keratitis. Methods Stereoisomeric dipeptide prodrugs of acyclovir (ACV) were screened for bioreversion in various ocular tissues, cell proliferation, and uptake across the rabbit primary corneal epithelial cell line. Docking studies were carried out to examine the affinity of prodrugs to the peptide transporter protein. Prodrugs with optimum characteristics were selected for the preparation of nanoparticles using various grades of poly (lactic-co-glycolic acid) (PLGA). Nanoparticles were characterized for the entrapment efficiency, surface morphology, size distribution, and in vitro release. Further, the effect of thermosensitive gels on the release of prodrugs from nanoparticles was also studied. Results L-valine-L-valine-ACV and L-valine-D-valine-ACV were considered to be optimum in terms of enzymatic stability, uptake, and cytotoxicity. Docking results indicated that L-valine in the terminal position increases the affinity of the prodrugs to the peptide transporter protein. Entrapment efficiency values of L-valine-L-valine-ACV and L-valine-D-valine-ACV were found to be optimal with PLGA 75:25 and PLGA 65:35 polymers, respectively. In vitro release of prodrugs from nanoparticles exhibited a biphasic release behavior with initial burst phase followed by sustained release. Dispersion of nanoparticles in thermosensitive gels completely eliminated the burst release phase. Conclusion Novel nanoparticulate systems of dipeptide prodrugs of ACV suspended in thermosensitive gels may provide sustained delivery after topical administration. PMID:21500985

Ethylene glycol-linked amino acid diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability and pharmacokinetics.

PubMed

Cao, Feng; Jia, Jinghao; Yin, Zhi; Gao, Yahan; Sha, Lei; Lai, Yisheng; Ping, Qineng; Zhang, Yihua

2012-08-06

The purposes of this study were to expand the structure of parent drugs selected for peptide transporter 1 (PepT1)-targeted ester prodrug design and to improve oral bioavailability of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug. Through an ethoxy linker the carboxylic acid group of OA was conjugated with the carboxylic acid group of different amino acid promoieties to form six diester prodrugs. The effective permeability (P(eff)) of prodrugs was screened by in situ rat single-pass intestinal perfusion (SPIP) model in two buffers with different pH (6.0 and 7.4) as PepT1 employs a proton-gradient as the driving force. Compared to OA, 2.5-fold, 2.3-fold, 2.2-fold, 2.1-fold, and 1.9-fold enhancement of P(eff) in buffer with pH 6.0 was observed for L-Phe ester (5c), L-Val ester (5a), L-Lys ester (5e), D-Phe ester (5d), and D-Val ester (5b), respectively. Furthermore, P(eff) of 5a, 5c, 5d and 5e in pH 6.0 was significantly higher than that in pH 7.4 (p < 0.01), respectively. These results showed that the H(+) concentration of perfusion solution had great effect on the transport of the prodrugs across intestinal membrane. For the further evaluation of affinity to PepT1, inhibition studies were performed by coperfusing 0.1 mM prodrug with 50 mM glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1). It turned out that the P(eff) of 5a, 5b, 5c and L-Tyr ester (6f) significantly reduced in the presence of Gly-Sar (1.7-fold, 2.2-fold, 1.9-fold, and 1.4-fold, respectively). We supposed that it may be attributed to PepT1 mediated transport of these prodrugs. 5a and 6f were selected as the optimal target prodrugs for oral absorption in vivo. Following intragastric administration of 300 mg/kg (calculated as OA) 5a, 6f and OA in three groups of rats, compared with group OA, Cmax for the group of 5a and 6f was enhanced by 1.56-fold and 1.54-fold, respectively. Fapp of group 5a and 6f was 2.21- and 2.04-fold increased, respectively, indicating

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

PubMed

Sharpe, Martyn A; Livingston, Andrew D; Gist, Taylor L; Ghosh, Pardip; Han, Junyan; Baskin, David S

2015-09-01

The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

PubMed Central

Sharpe, Martyn A.; Livingston, Andrew D.; Gist, Taylor L.; Ghosh, Pardip; Han, Junyan; Baskin, David S.

2015-01-01

The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. PMID:26501110

QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIα

PubMed Central

Alam, Sarfaraz; Khan, Feroz

2014-01-01

Due to the high mortality rate in India, the identification of novel molecules is important in the development of novel and potent anticancer drugs. Xanthones are natural constituents of plants in the families Bonnetiaceae and Clusiaceae, and comprise oxygenated heterocycles with a variety of biological activities along with an anticancer effect. To explore the anticancer compounds from xanthone derivatives, a quantitative structure activity relationship (QSAR) model was developed by the multiple linear regression method. The structure–activity relationship represented by the QSAR model yielded a high activity–descriptors relationship accuracy (84%) referred by regression coefficient (r2=0.84) and a high activity prediction accuracy (82%). Five molecular descriptors – dielectric energy, group count (hydroxyl), LogP (the logarithm of the partition coefficient between n-octanol and water), shape index basic (order 3), and the solvent-accessible surface area – were significantly correlated with anticancer activity. Using this QSAR model, a set of virtually designed xanthone derivatives was screened out. A molecular docking study was also carried out to predict the molecular interaction between proposed compounds and deoxyribonucleic acid (DNA) topoisomerase IIα. The pharmacokinetics parameters, such as absorption, distribution, metabolism, excretion, and toxicity, were also calculated, and later an appraisal of synthetic accessibility of organic compounds was carried out. The strategy used in this study may provide understanding in designing novel DNA topoisomerase IIα inhibitors, as well as for other cancer targets. PMID:24516330

Mutual Amide Prodrug of Etodolac-glucosamine: Synthesis, Characterization and Pharmacological Screening

PubMed Central

Pandey, Preeti; Pandey, S.; Dubey, Shaifali

2013-01-01

Etodolac, a nonsteroidal antiinflammatory drug, widely used in arthritis is associated with gastric ulceration and irritation due to presence of free carboxylic group. The current investigation reports synthesis of mutual amide prodrug of etodolac by masking free carboxylic group with glucosamine, a nutritional supplement for treatment of arthritis. Confirmation and characterization of the structure of the synthesized prodrug done by elemental and spectroscopy analysis, melting point, determination of migration parameters (Rf, RM, and Rt) by using thin layer chromatography and high performance liquid chromatography, respectively. Partition coefficient and solubility study confirms its lipophilic character so can be suitable candidate for controlled release delivery. In vitro hydrolytic studies of prodrug confirms good rate of hydrolysis in blood plasma, fecal matter, and simulated intestinal fluid while stable in gastric simulated fluid. In vivo pharmacological screening performed on animals. Prodrug with respect to etodolac shows good analgesic, antiinflammatory, and antiarthritic activity. The prodrug was assessed for their probable damaging effects by ulcerogeniticity and histopathological analysis. The histopathological studies showed less ulceration in the gastric region when treated with prodrug, thereby proving the prodrug to be better in action as compared to etodolac and are advantageous in having less gastrointestinal side effects. PMID:24302794

Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy

NASA Astrophysics Data System (ADS)

Han, Haijie; Wang, Haibo; Chen, Yangjun; Li, Zuhong; Wang, Yin; Jin, Qiao; Ji, Jian

2015-12-01

A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which

Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin.

PubMed

Boyapelly, Kumaraswamy; Bonin, Marc-André; Traboulsi, Hussein; Cloutier, Alexandre; Phaneuf, Samuel C; Fortin, Daniel; Cantin, André M; Richter, Martin V; Marsault, Eric

2017-04-28

Isoliquiritigenin (1) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation. In order to enable the use of 1 for in vivo studies without the use of toxic carriers or cosolvents, a phosphate prodrug strategy was implemented relying on the availability of phenol groups in the molecule. In this study, a phosphate group was added to position C-4 of 1, leading to the more water-soluble prodrug 2 and its ammonium salt 3, which possesses increased stability compared to 2. Herein are reported the synthesis, characterization, solubility, and stability of phosphate prodrug 3 in biological medium in comparison to 1, as well as new results on its anti-inflammatory properties in vivo. As designed, the solubility of prodrug 3 was superior to that of the parent natural product 1 (9.6 mg/mL as opposed to 3.9 μg/mL). Prodrug 3 as an ammonium salt was also found to possess excellent stability as a solid and in aqueous solution, as opposed to its phosphoric acid precursor 2.

Newly Engineered Magnetic Erythrocytes for Sustained and Targeted Delivery of Anti-Cancer Therapeutic Compounds

PubMed Central

Taranta, Monia; Naldi, Ilaria

2011-01-01

Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy. PMID:21373641

Esterase-sensitive prodrugs with tunable release rates and direct generation of hydrogen sulfidea

PubMed Central

Zheng, Yueqin; Yu, Bingchen; Ji, Kaili; Pan, Zhixiang; Chittavong, Vayou

2016-01-01

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2S prodrugs shows great potential as both research tools and therapeutic agents. PMID:26822005

Combination cancer therapy by hapten-targeted prodrug-activating enzymes and cytokines.

PubMed

Chuang, Kuo-Hsiang; Cheng, Chiu-Min; Roffler, Steve R; Lu, Yu-Lin; Lin, Shiu-Ru; Wang, Jaw-Yuan; Tzou, Wen-Shyong; Su, Yu-Cheng; Chen, Bing-Mae; Cheng, Tian-Lu

2006-01-01

Combination therapy can help overcome limitations in the treatment of heterogeneous tumors. In the current study, we examined whether multiple therapeutic agents could be targeted to anti-dansyl single-chain antibodies (DNS scFv) that were anchored on the plasma membrane of cancer cells. Functional DNS scFv could be stably expressed on CT-26 colon cancer cells both in vitro and in vivo. Dansyl moieties were covalently attached to recombinant beta-glucuronidase (betaG) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to form DNS-PEG-betaG and DNS-PEG-IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatory activities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively bound CT-26 cells that expressed anti-DNS scFv (CT-26/DNS cells) but not CT-26 cells that expressed control scFv (CT-26/phOx cells). DNS-PEG-betaG preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxy aniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors after intravenous administration. Systemic administration of DNS-PEG-IL-2 or DNS-PEG-betaG and BHAMG significantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment with DNS-PEG-betaG and BHAMG followed by DNS-PEG-IL-2 therapy significantly suppressed the growth of CT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modified therapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combination therapy of DNS scFv-modified tumors.

[In vitro metabolism of fenbendazole prodrug].

PubMed

Wen, Ai-Dan; Duan, Li-Ping; Liu, Cong-Shan; Tao, Yi; Xue, Jian; Wu, Ning-Bo; Jiang, Bin; Zhang, Hao-Bing

2013-02-01

Synthesized fenbendazole prodrug N-methoxycarbonyl-N'-(2-nitro-4-phenylthiophenyl) thiourea (MPT) was analyzed in vitro in artificial gastric juice, intestinal juice and mouse liver homogenate model by using HPLC method, and metabolic curve was then generated. MPT was tested against Echinococcus granulosus protoscolices in vitro. The result showed that MPT could be metabolized in the three biological media, and to the active compound fenbendazole in liver homogenate, with a metabolic rate of 7.92%. Besides, the prodrug showed a weak activity against E. granulosus protoscolices with a mortality of 45.9%.

Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

PubMed Central

Qandil, Amjad M.

2012-01-01

The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action. PMID:23247285

Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

PubMed

Van Goietsenoven, Gwendoline; Mathieu, Véronique; Lefranc, Florence; Kornienko, Alexander; Evidente, Antonio; Kiss, Robert

2013-03-01

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs. © 2012 Wiley Periodicals, Inc.

Self-Immolative Polycations as Gene Delivery Vectors and Prodrugs Targeting Polyamine Metabolism in Cancer

PubMed Central

2015-01-01

Polycations are explored as carriers to deliver therapeutic nucleic acids. Polycations are conventionally pharmacological inert with the sole function of delivering therapeutic cargo. This study reports synthesis of a self-immolative polycation (DSS-BEN) based on a polyamine analogue drug N1,N11-bisethylnorspermine (BENSpm). The polycation was designed to function dually as a gene delivery carrier and a prodrug targeting dysregulated polyamine metabolism in cancer. Using a combination of NMR and HPLC, we confirm that the self-immolative polycation undergoes intracellular degradation into the parent drug BENSpm. The released BENSpm depletes cellular levels of spermidine and spermine and upregulates polyamine catabolic enzymes spermine/spermidine N1-acetyltransferase (SSAT) and spermine oxidase (SMO). The synthesized polycations form polyplexes with DNA and facilitate efficient transfection. Taking advantage of the ability of BENSpm to sensitize cancer cells to TNFα-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNFα gene therapy. The reported findings validate DSS-BEN as a dual-function delivery system that can deliver a therapeutic gene and improve the outcome of gene therapy as a result of the intracellular degradation of DSS-BEN to BENSpm and the subsequent beneficial effect of BENSpm on dysregulated polyamine metabolism in cancer. PMID:25153488

A screen to identify drug resistant variants to target-directed anti-cancer agents

PubMed Central

Azam, Mohammad; Raz, Tal; Nardi, Valentina; Opitz, Sarah L.

2003-01-01

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair. PMID:14615817

Interaction of dipeptide prodrugs of saquinavir with multidrug resistance protein-2 (MRP-2): evasion of MRP-2 mediated efflux.

PubMed

Jain, Ritesh; Agarwal, Sheetal; Mandava, Nanda Kishore; Sheng, Ye; Mitra, Ashim K

2008-10-01

Saquinavir (SQV), the first protease inhibitor approved by FDA to treat HIV-1 infection. This drug is a well-known substrate for multidrug resistance protein-2 (MRP-2). The objective of this study was to investigate whether derivatization of SQV to dipeptide prodrugs, valine-valine-saquinavir (Val-Val-SQV) and glycine-valine-saquinavir (Gly-Val-SQV), targeting peptide transporter can circumvent MRP-2 mediated efflux. Uptake and transport studies were carried out across MDCKII-MRP2 cell monolayers to investigate the interaction of SQV and its prodrugs with MRP-2. In situ single pass intestinal perfusion experiments in rat jejunum were performed to calculate intestinal absorption rate constants and permeabilities of SQV, Val-Val-SQV and Gly-Val-SQV. Uptake studies demonstrated that the prodrugs have significantly lower interaction with MRP-2 relative to SQV. Transepithelial transport of Val-Val-SQV and Gly-Val-SQV across MDCKII-MRP2 cells exhibited an enhanced absorptive flux and reduced secretory flux as compared to SQV. Intestinal perfusion studies revealed that synthesized prodrugs have higher intestinal permeabilities relative to SQV. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. In the presence of MK-571, a MRP family inhibitor, there was a significant increase in the permeabilities of SQV and Gly-Val-SQV indicating that these compounds are probably substrates for MRP-2. However, there was no change in the permeability of Val-Val-SQV with MK-571 indicating lack of any interaction of Val-Val-SQV with MRP-2. In conclusion, peptide transporter targeted prodrug modification of MRP-2 substrates may lead to shielding of these drug molecules from MRP-2 efflux pumps.

Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.

PubMed

Lehouritis, Panos; Stanton, Michael; McCarthy, Florence O; Jeavons, Matthieu; Tangney, Mark

2016-01-28

Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action. Copyright © 2015 Elsevier B.V. All rights reserved.

Peroxisome Proliferator Activated Receptor A Ligands as Anticancer Drugs Targeting Mitochondrial Metabolism

PubMed Central

Grabacka, Maja; Pierzchalska, Malgorzata; Reiss, Krzysztof

2011-01-01

Tumor cells show metabolic features distinctive from normal tissues, with characteristically enhanced aerobic glycolysis, glutaminolysis and lipid synthesis. Peroxisome proliferator activated receptor α (PPAR α) is activated by nutrients (fatty acids and their derivatives) and influences these metabolic pathways acting antagonistically to oncogenic Akt and c-Myc. Therefore PPAR α can be regarded as a candidate target molecule in supplementary anticancer pharmacotherapy as well as dietary therapeutic approach. This idea is based on hitting the cancer cell metabolic weak points through PPAR α mediated stimulation of mitochondrial fatty acid oxidation and ketogenesis with simultaneous reduction of glucose and glutamine consumption. PPAR α activity is induced by fasting and its molecular consequences overlap with the effects of calorie restriction and ketogenic diet (CRKD). CRKD induces increase of NAD+/NADH ratio and drop in ATP/AMP ratio. The first one is the main stimulus for enhanced protein deacetylase SIRT1 activity; the second one activates AMP-dependent protein kinase (AMPK). Both SIRT1 and AMPK exert their major metabolic activities such as fatty acid oxidation and block of glycolysis and protein, nucleotide and fatty acid synthesis through the effector protein peroxisome proliferator activated receptor gamma 1 α coactivator (PGC-1α). PGC-1α cooperates with PPAR α and their activities might contribute to potential anticancer effects of CRKD, which were reported for various brain tumors. Therefore, PPAR α activation can engage molecular interplay among SIRT1, AMPK, and PGC-1α that provides a new, low toxicity dietary approach supplementing traditional anticancer regimen. PMID:21133850

Use of enzyme inhibitors to evaluate the conversion pathways of ester and amide prodrugs: a case study example with the prodrug ceftobiprole medocaril.

PubMed

Eichenbaum, Gary; Skibbe, Jennifer; Parkinson, Andrew; Johnson, Mark D; Baumgardner, Dawn; Ogilvie, Brian; Usuki, Etsuko; Tonelli, Fred; Holsapple, Jeff; Schmitt-Hoffmann, Anne

2012-03-01

An approach was developed that uses enzyme inhibitors to support the assessment of the pathways that are responsible for the conversion of intravenously administered ester and amide prodrugs in different biological matrices. The methodology was applied to ceftobiprole medocaril (BAL5788), the prodrug of the cephalosporin antibiotic, ceftobiprole. The prodrug was incubated in plasma, postmitochondrial supernatant fractions from human liver (impaired and nonimpaired), kidney, and intestine as well as erythrocytes, in the presence and absence of different enzyme inhibitors (acetylcholinesterase, pseudocholinesterase, retinyl palmitoyl hydrolase, serine esterases, amidases, and cholinesterase). Hydrolysis was rapid, extensive, and not dependent on the presence of β-nicotinamide-adenine dinucleotide phosphate (reduced form) in all matrices tested, suggesting the involvement of carboxylesterases but not P450 enzymes. Hydrolysis in healthy human plasma was rapid and complete and only partially inhibited in the presence of paraoxonase inhibitors or in liver from hepatic impaired patients, suggesting involvement of nonparaoxonase pathways. The results demonstrate the utility of this approach in confirming the presence of multiple conversion pathways of intravenously administered prodrugs and in the case of BAL5788 demonstrated that this prodrug is unlikely to be affected by genetic polymorphisms, drug interactions, or other environmental factors that might inhibit or induce the enzymes involved in its conversion. Copyright © 2011 Wiley Periodicals, Inc.

Molecular targets and anti-cancer potential of escin.

PubMed

Cheong, Dorothy H J; Arfuso, Frank; Sethi, Gautam; Wang, Lingzhi; Hui, Kam Man; Kumar, Alan Prem; Tran, Thai

2018-05-28

Escin is a mixture of triterpenoid saponins extracted from the horse chestnut tree, Aesculus hippocastanum. Its potent anti-inflammatory and anti-odematous properties makes it a choice of therapy against chronic venous insufficiency and odema. More recently, escin is being actively investigated for its potential activity against diverse cancers. It exhibits anti-cancer effects in many cancer cell models including lung adenocarcinoma, hepatocellular carcinoma and leukemia. Escin also attenuates tumor growth and metastases in various in vivo models. Importantly, escin augments the effects of existing chemotherapeutic drugs, thereby supporting the role of escin as an adjunct or alternative anti-cancer therapy. The beneficial effects of escin can be attributed to its inhibition of proliferation and induction of cell cycle arrest. By regulating transcription factors/growth factors mediated oncogenic pathways, escin also potentially mitigates chronic inflammatory processes that are linked to cancer survival and resistance. This review provides a comprehensive overview of the current knowledge of escin and its potential as an anti-cancer therapy through its anti-proliferative, pro-apoptotic, and anti-inflammatory effects. Copyright © 2018 Elsevier B.V. All rights reserved.

HYPOXIA-ACTIVATED PRO-DRUG TH-302 EXHIBITS POTENT TUMOUR SUPPRESSIVE ACTIVITY AND COOPERATES WITH CHEMOTHERAPY AGAINST OSTEOSARCOMA

PubMed Central

Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J.; Findlay, David M.; Zannettino, Andrew CW.; Evdokiou, Andreas

2015-01-01

Tumour hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumour hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumours. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. PMID:25444931

Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma.

PubMed

Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J; Findlay, David M; Zannettino, Andrew C W; Evdokiou, Andreas

2015-02-01

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

PubMed Central

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications. PMID:23412554

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications.

PubMed

Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

2013-01-01

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely (131)I-hypericin ((131)I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

Lamellar crystalline self-assembly behaviour and solid lipid nanoparticles of a palmityl prodrug analogue of Capecitabine—A chemotherapy agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gong, Xiaojuan; Moghaddam, Minoo J.; Sagnella, Sharon M.

2014-09-24

An amphiphile prodrug, 5'-deoxy-5-fluoro-N 4-(palmityloxycarbonyl) cytidine or 5'-deoxy-5-fluoro-N 4-(hexadecanaloxycarbonyl) cytidine (5-FCPal), consisting of the same head group as the commercially available chemotherapeutic agent Capecitabine, linked to a palmityl hydrocarbon chain via a carbamate bond is reported. Thermal analysis of this prodrug indicates that it melts at ~115 °C followed quickly by degradation beginning at ~120 °C. The neat solid 5-FCPal amphiphile acquires a lamellar crystalline arrangement with a d-spacing of 28.6 ± 0.3 Å, indicating interdigitation of the hydrocarbon chains. Under aqueous conditions, solid 5-FCPal is non-swelling and no lyotropic liquid crystalline phase formation is observed. In order to assessmore » the in vitro toxicity and in vivo efficacy in colloidal form, solid lipid nanoparticles (SLNs) with an average size of ~700 nm were produced via high pressure homogenization. The in vitro toxicity of the 5-FCPal SLNs against several different cancer and normal cell types was assessed over a 48 h period, and IC 50 values were comparable to those observed for Capecitabine. The in vivo efficacy of the 5-FCPal SLNs was then assessed against the highly aggressive mouse 4T1 breast cancer model. To do so, the prodrug SLNs were administered orally at 3 different dosages (0.1, 0.25, 0.5 mmol/mouse/day) and compared to Capecitabine delivered at the same dosages. After 21 days of receiving the treatments, the 0.5 mmol dose of 5-FCPal exhibited the smallest average tumour volume. Since 5-FCPal is activated in a similar manner to Capecitabine via a 3 step enzymatic pathway with the final step occurring preferentially at the tumour site, formulation of the prodrug into SLNs combines the advantage of selective, localized activation with the sustained release properties of nanostructured amphiphile self-assembly and multiple payload materials thereby potentially creating a more effective anticancer agent.« less

Evaluation of diclofenac prodrugs for enhancing transdermal delivery.

PubMed

Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

2014-03-01

Abstract Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions. The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.

Anticancer Properties of Capsaicin Against Human Cancer.

PubMed

Clark, Ruth; Lee, Seong-Ho

2016-03-01

There is persuasive epidemiological and experimental evidence that dietary phytochemicals have anticancer activity. Capsaicin is a bioactive phytochemical abundant in red and chili peppers. While the preponderance of the data strongly indicates significant anticancer benefits of capsaicin, more information to highlight molecular mechanisms of its action is required to improve our knowledge to be able to propose a potential therapeutic strategy for use of capsaicin against cancer. Capsaicin has been shown to alter the expression of several genes involved in cancer cell survival, growth arrest, angiogenesis and metastasis. Recently, many research groups, including ours, found that capsaicin targets multiple signaling pathways, oncogenes and tumor-suppressor genes in various types of cancer models. In this review article, we highlight multiple molecular targets responsible for the anticancer mechanism of capsaicin. In addition, we deal with the benefits of combinational use of capsaicin with other dietary or chemotherapeutic compounds, focusing on synergistic anticancer activities. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Enhancement of Curcumin Bioavailability Via the Prodrug Approach: Challenges and Prospects.

PubMed

Ratnatilaka Na Bhuket, Pahweenvaj; El-Magboub, Asma; Haworth, Ian S; Rojsitthisak, Pornchai

2017-06-01

Curcumin is a natural product with many interesting pharmacological properties. However, these are offset by the particularly poor biopharmaceutical properties. The oral bioavailability of curcumin in humans is very low, mainly due to low solubility, poor stability, and extensive metabolism. This has led to multiple approaches to improve bioavailability, including administration of curcumin with metabolism inhibitors, formulation into nanoparticles, modification of the curcumin structure, and development of curcumin prodrugs. In this paper, we focus on the pharmacokinetic outcomes of these approaches. Pharmacokinetic parameters of curcumin after release from prodrugs are dependent on the linker between curcumin and the promoiety, and the release itself may depend on the physiological and enzymatic environment at the site of cleavage. This is an area in which more data are required for rational design of improved linkers. Cytotoxicity of curcumin prodrugs seems to correlate well with cellular uptake in vitro, but the in vivo relevance is uncertain. We conclude that improved experimental and theoretical models of absorption of curcumin prodrugs, development of accurate analytical methods for simultaneous measurement of plasma levels of prodrug and released curcumin, and acquisition of more pharmacokinetic data in animal models for dose prediction in humans are required to facilitate movement of curcumin prodrugs into clinical trials.

Enterolactone glucuronide and β-glucuronidase in antibody directed enzyme prodrug therapy for targeted prostate cancer cell treatment.

PubMed

Di, Yunyun; Ji, Shaoping; Wolf, Philipp; Krol, Ed S; Alcorn, Jane

2017-08-01

Evidence from preclinical and animal studies demonstrated an anticancer effect of flaxseed lignans, particularly enterolactone (ENL), against prostate cancer. However, extensive first-pass metabolism following oral lignan consumption results in their systemic availability primarily as glucuronic acid conjugates (ENL-Gluc) and their modest in vivo effects. To overcome the unfavorable pharmacokinetics and improve their effectiveness in prostate cancer, antibody-directed enzyme prodrug therapy (ADEPT) might offer a novel strategy to allow for restricted activation of ENL from circulating ENL-Gluc within the tumor environment. The anti-prostate-specific membrane antigen (PSMA) antibody D7 was fused with human β-glucuronidase (hβG) via a flexible linker. The binding property of the fusion construct, D7-hβG, against purified or cell surface PSMA was determined by flow cytometry and Octet Red 384 system, respectively, with a binding rate constant, K d, of 2.5 nM. The enzymatic activity of D7-hβG was first tested using the probe, 4-methylumbelliferone glucuronide. A 3.8-fold greater fluorescence intensity was observed at pH 4.5 at 2 h compared with pH 7.4. The ability of D7-hβG to activate ENL from ENL-Gluc was tested and detected using LC-MS/MS. Enhanced generation of ENL was observed with increasing ENL-Gluc concentrations and reached 3613.2 ng/mL following incubation with 100 μM ENL-Gluc at pH 4.5 for 0.5 h. D7-hβG also decreased docetaxel IC 50 value from 23 nM to 14.9 nM in C4-2 cells. These results confirmed the binding and activity of D7-hβG and additional in vitro investigation is needed to support the future possibility of introducing this ADEPT system to animal models.

1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New Proton Pump Inhibitor Prodrugs

PubMed Central

Shin, Jai Moo; Sachs, George; Cho, Young-moon; Garst, Michael

2010-01-01

New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition. PMID:20032890

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

PubMed

Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

2015-01-01

The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database

PubMed Central

Mangal, Manu; Sagar, Parul; Singh, Harinder; Raghava, Gajendra P. S.; Agarwal, Subhash M.

2013-01-01

Plant-derived molecules have been highly valued by biomedical researchers and pharmaceutical companies for developing drugs, as they are thought to be optimized during evolution. Therefore, we have collected and compiled a central resource Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) that gathers the information related to experimentally validated plant-derived natural compounds exhibiting anti-cancerous activity (in vitro and in vivo), to complement the other databases. It currently contains 1574 compound entries, and each record provides information on their structure, manually curated published data on in vitro and in vivo experiments along with reference for users referral, inhibitory values (IC50/ED50/EC50/GI50), properties (physical, elemental and topological), cancer types, cell lines, protein targets, commercial suppliers and drug likeness of compounds. NPACT can easily be browsed or queried using various options, and an online similarity tool has also been made available. Further, to facilitate retrieval of existing data, each record is hyperlinked to similar databases like SuperNatural, Herbal Ingredients’ Targets, Comparative Toxicogenomics Database, PubChem and NCI-60 GI50 data. PMID:23203877

CD44-targeted hyaluronic acid-curcumin prodrug protects renal tubular epithelial cell survival from oxidative stress damage.

PubMed

Hu, Jing-Bo; Li, Shu-Juan; Kang, Xu-Qi; Qi, Jing; Wu, Jia-Hui; Wang, Xiao-Juan; Xu, Xiao-Ling; Ying, Xiao-Ying; Jiang, Sai-Ping; You, Jian; Du, Yong-Zhong

2018-08-01

Based on the abnormally increased expression of CD44 receptors on renal tubule epithelial cells during ischemia/reperfusion-induced acute kidney injury (AKI), we developed a hyaluronic acid-curcumin (HA-CUR) polymeric prodrug targeting to epithelial cells and then relieving oxidative stress damages. The water solubility of HA-CUR was significantly enhanced and approximately 27-fold higher than that of CUR. Cellular uptake test showed HA-CUR was preferably internalized by H 2 O 2 -pretreated tubular epithelial (HK-2) cells compared with free CUR benefiting from the specific binding between HA and CD44 receptors. Biodistribution results further demonstrated the increased accumulation of HA-CUR in kidneys with 13.9-fold higher than that of free CUR. Pharmacodynamic studies indicated HA-CUR effectively ameliorated AKI, and the exact mechanism was that HA-CUR protected renal tubule epithelial cells from oxidative stress damage via inhibiting PtdIns3K-AKT-mTOR signaling pathway. Taken together, this study provides a new therapeutic strategy for the treatment of AKI based on the pathogenesis of the disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Imaging biomarkers to monitor response to the hypoxia-activated prodrug TH-302 in the MiaPaCa2 flank xenograft model.

PubMed

Cárdenas-Rodríguez, Julio; Li, Yuguo; Galons, Jean-Philippe; Cornnell, Heather; Gillies, Robert J; Pagel, Mark D; Baker, Amanda F

2012-09-01

TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (K(trans)) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in K(trans) following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

Recent Progress of Marine Polypeptides as Anticancer Agents

PubMed

Zheng, Lanhong; Xua, Yixin; Lin, Xiukun; Yuan, Zhixin; Liu, Minghua; Cao, Shousong; Zhang, Fuming; Linhardt, Robert J

2018-04-29

Marine environment constitutes an almost infinite resource for novel anticancer drugs discovery. The biodiversity of marine organisms provides a rich source for the discovery and development of novel anticancer peptides in the treatment of human cancer. Marine peptides represent a new opportunity to obtain lead compounds in biomedical field, particularly for cancer therapy. Providing an insight of the recent progress of patented marine peptides and presenting information about the structures and mechanistic mode of anticancer activities of these marine peptides. We reviewed recent progress on the patented anticancer peptides from marine organisms according to their targets on different signal pathways. This work focuses on relevant recent patents (2010-2018) that entail the anticancer activity with associated mechanism and related molecular diversity of marine peptides. The related cellular signaling pathways for novel peptides that induce apoptosis and affect tubulin-microtubule equilibrium, angiogenesis and kinase activity that are related to the anticancer and related pharmacological properties are also discussed. The recent patents (2010-2018) of marine peptides with anticancer activity were reviewed, and the anticancer activity of marine peptides with associated mechanism and related molecular diversity of marine peptides were also discussed. Marine peptides possess chemical diversity and displays potent anticancer activity via targeting different signal pathways. Some of the marine peptides are promising to be developed as novel anticancer agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Photoinduced anticancer activity studies of iridium(III) complexes targeting mitochondria and tubules.

PubMed

Zhang, Wen-Yao; Yi, Qian-Yan; Wang, Yang-Jie; Du, Fan; He, Miao; Tang, Bing; Wan, Dan; Liu, Yun-Jun; Huang, Hong-Liang

2018-05-10

Three new iridium (III) complexes [Ir (ppy) 2 (ipbc)](PF 6 ) (1), [Ir (bzq) 2 (ipbc)](PF 6 ) (2) and [Ir (piq) 2 (ipbc)](PF 6 ) (3) were designed and synthesized. All the complexes were tested for anticancer activity using 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) method. The complexes show no cytotoxic activity toward cancer BEL-7402, SGC-7901, Eca-109, A549, HeLa and HepG2 cells. However, upon irradiation with white light, the complexes display high cytotoxicity against BEL-7402 cells with an IC 50 value of 5.5 ± 0.8, 7.3 ± 1.3 and 11.5 ± 1.6 μM for 1, 2 and 3, respectively. AO/EB staining and comet assay show that the complexes can induce apoptosis in BEL-7402 cells. The complexes can increase intracellular ROS and Ca 2+ levels and cause a decrease in the mitochondrial membrane potential. Autophagic assays exhibit that the complexes can induce autophagy and regulate the expression of Beclin-1 and LC3 proteins. The cell cycle distribution in BEL-7402 cells was carried out by flow cytometry. The expression of Bcl-2 family proteins was studied by western blot. Additionally, the complexes can release cytochrome c and inhibit the polymerization of α-tubulin. Our study reveals that the complexes inhibit the cell growth in BEL-7402 cells through an ROS-mediated mitochondria dysfunction and targeting tubules pathways. These complexes are a promising new entity for the development of multi-target anticancer drugs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy.

PubMed

Dharmawardana, Pathirage G; Peruzzi, Benedetta; Giubellino, Alessio; Burke, Terrence R; Bottaro, Donald P

2006-01-01

Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.

Integrating a novel SN38 prodrug into the PEGylated liposomal system as a robust platform for efficient cancer therapy in solid tumors.

PubMed

Fang, Tao; Dong, Yuehan; Zhang, Xiaomin; Xie, Ke; Lin, Li; Wang, Hangxiang

2016-10-15

Liposomal nanoassemblies have been used extensively as carriers for the delivery of both lipophilic and hydrophilic drugs. They represent a mature, versatile technology with considerable potential for improving the pharmacokinetics of drugs. However, the formulation of many chemotherapeutics into liposome systems has posed a significant challenge due to their incompatible physicochemical properties, as was the case with camptothecin-based chemotherapeutics. Here, we present a rational paradigm of potent chemotherapeutics that were reconstructed and subsequently integrated into liposomal nanoassemblies. Using SN38 (7-ethyl-10-hydroxy camptothecin) as a model drug, a lipophilic prodrug 1 (designated as LA-SN38) was constructed by tethering the linoleic acid (LA) moiety via esterification, which was further facilitated to form liposomal nanoparticles (LipoNP) through supramolecular nanoassembly. The resulting 1-loaded LipoNP exhibited sustained drug release kinetics and decreased cellular uptake by macrophage cells. Uptake by tumor cells was enhanced relative to our previous supramolecular nanoparticles (SNP 1), which were derived from the self-assembling prodrug 1. Notably, LipoNP outperformed SNP 1 in terms of pharmacokinetics and in vivo therapeutic efficacy in both human BEL-7402 hepatocellular carcinoma (HCC) and HCT-116 colorectal cancer-derived xenograft mouse models. These results were likely due to the improved systemic circulation and preferential accumulation of nanodrugs in tumors. Hence, our results suggest that the combination of liposomal delivery platforms with rational prodrug engineering may emerge as a promising approach for the effective and safe delivery of anticancer chemotherapeutics. Copyright © 2016 Elsevier B.V. All rights reserved.

New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity.

PubMed

Krečmerová, Marcela; Dračínský, Martin; Snoeck, Robert; Balzarini, Jan; Pomeisl, Karel; Andrei, Graciela

2017-09-01

New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC 50 's of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lipophilic nalmefene prodrugs to achieve a one-month sustained release.

PubMed

Gaekens, Tim; Guillaume, Michel; Borghys, Herman; De Zwart, Loeckie L; de Vries, Ronald; Embrechts, Roger C A; Vermeulen, An; Megens, Anton A H P; Leysen, Josée E; Herdewijn, Piet; Annaert, Pieter P; Atack, John R

2016-06-28

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene

Nano anti-cancer drugs: pros and cons and future perspectives.

PubMed

Ali, Imran

2011-02-01

For last one decade, scientists are working for developing nano anti-cancer drugs with claim of ideal ones due to their targeted chemotherapic nature. These drugs have many beneficial properties such as targeted drug delivery and gene therapy modalities with minimum side effects. This article describes pros and cons and future perspectives of nano anti-cancer drugs. Efforts have been made to address importance, special features, toxicities (general, blood identities, immune system and environmental) and future perspectives of nano anti-cancer drugs. It was concluded that nano anti-cancer drugs may be magic bullet drugs for cancer treatment leading to bright future of the whole world.

Dual delivery systems based on polyamine analog BENSpm as prodrug and gene delivery vectors

NASA Astrophysics Data System (ADS)

Zhu, Yu

Combination drug and gene therapy shows promise in cancer treatment. However, the success of such strategy requires careful selection of the therapeutic agents, as well as development of efficient delivery vectors. BENSpm (N 1, N11-bisethylnorspermine), a polyamine analogue targeting the intracellular polyamine pathway, draws our special attention because of the following reasons: (1) polyamine pathway is frequently dysregulated in cancer; (2) BENSpm exhibits multiple functions to interfere with the polyamine pathway, such as to up-regulate polyamine metabolism enzymes and down-regulate polyamine biosynthesis enzymes. Therefore BENSpm depletes all natural polyamines and leads to apoptosis and cell growth inhibition in a wide range of cancers; (3) preclinical studies proved that BENSpm can act synergistically with various chemotherapy agents, making it a promising candidate in combination therapy; (4) multiple positive charges in BENSpm enable it as a suitable building block for cationic polymers, which can be further applied to gene delivery. In this dissertation, our goal was to design dual-function delivery vector based on BENSpm that can function as a gene delivery vector and, after intracellular degradation, as an active anticancer agent targeting dysregulated polyamine metabolism. We first demonstrated strong synergism between BENSpm and a potential therapeutic gene product TRAIL. Strong synergism was obtained in both estrogen-dependent MCF-7 breast cancer cells and triple-negative MDA-MB-231 breast cancer cells. Significant dose reduction of TRAIL in combination with BENSpm in MDA-MB-231 cells, together with the fact that BENSpm rendered MCF-7 cells more sensitive to TRAIL treatment verified our rationale of designing BENSpm-based delivery platform. This was expected to be beneficial for overcoming drug resistance in chemotherapy, as well as boosting the therapeutic effect of therapeutic genes. We first designed a lipid-based BENSpm dual vector (Lipo

Chinese Medicine Amygdalin and β-Glucosidase Combined with Antibody Enzymatic Prodrug System As A Feasible Antitumor Therapy.

PubMed

Li, Yun-Long; Li, Qiao-Xing; Liu, Rui-Jiang; Shen, Xiang-Qian

2018-03-01

Amarogentin is an efficacious Chinese herbal medicine and a component of the bitter apricot kernel. It is commonly used as an expectorant and supplementary anti-cancer drug. β-Glucosidase is an enzyme that hydrolyzes the glycosidic bond between aryl and saccharide groups to release glucose. Upon their interaction, β-glucosidase catalyzes amarogentin to produce considerable amounts of hydrocyanic acid, which inhibits cytochrome C oxidase, the terminal enzyme in the mitochondrial respiration chain, and suspends adenosine triphosphate synthesis, resulting in cell death. Hydrocyanic acid is a cell-cycle-stage-nonspecific agent that kills cancer cells. Thus, β-glucosidase can be coupled with a tumor-specific monoclonal antibody. β-Glucosidase can combine with cancer-cell-surface antigens and specifically convert amarogentin to an active drug that acts on cancer cells and the surrounding antibodies to achieve a killing effect. β-Glucosidase is injected intravenously and recognizes cancer-cell-surface antigens with the help of an antibody. The prodrug amarogentin is infused after β-glucosidase has reached the target position. Coupling of cell membrane peptides with β-glucosidase allows the enzyme to penetrate capillary endothelial cells and clear extracellular deep solid tumors to kill the cells therein. The Chinese medicine amarogentin and β-glucosidase will become an important treatment for various tumors when an appropriate monoclonal antibody is developed.

Renal toxicity of anticancer agents targeting vascular endothelial growth factor (VEGF) and its receptors (VEGFRs).

PubMed

Cosmai, Laura; Gallieni, Maurizio; Liguigli, Wanda; Porta, Camillo

2017-04-01

Since angiogenesis plays a key role in tumor growth, progression and metastasization, anti-vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) agents have been developed over the years as anticancer agents, and have changed, for the better, the natural history of a number of cancer types. In the present review, the renal safety profile of presently available agents targeting either VEGF or VEGFRs will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, renal toxicity (especially, but not exclusively, hypertension and proteinuria) are quite commonly observed with these agents, and may be increased by the concomitant use of cytoxic chemotherapeutics. Despite all the above, kidney impairment or dialysis must not be regarded di per se as reasons not to administer or to stop an active anticancer treatment, especially considering the possibility of a significant survival improvement in many cancer patients treated with these agents.

Synthesis of Rapamycin Derivatives Containing the Triazole Moiety Used as Potential mTOR-Targeted Anticancer Agents.

PubMed

Xie, Lijun; Huang, Jie; Chen, Xiaoming; Yu, Hui; Li, Kualiang; Yang, Dan; Chen, Xiaqin; Ying, Jiayin; Pan, Fusheng; Lv, Youbing; Cheng, Yuanrong

2016-06-01

Rapamycin, a potent antifungal antibiotic, was approved as immunosuppressant, and lately its derivatives have been developed into mTOR targeting anticancer drugs. Structure modification was performed at the C-42 position of rapamycin, and a novel series of rapamycin triazole hybrids (4a-d, 5a-e, 8a-e, and 9a-e) was facilely synthesized via Huisgen's reaction. The anticancer activity of these compounds was evaluated against the Caski, H1299, MGC-803, and H460 human cancer cell lines. Some of the derivatives (8a-e, 9a-e) appeared to have stronger activity than that of rapamycin; however, 4a-d and 5a-e failed to show potential anticancer activity. Compound 9e with a (2,4-dichlorophenylamino)methyl moiety on the triazole ring was the most active anticancer compound, which showed IC50 values of 6.05 (Caski), 7.89 (H1299), 25.88 (MGC-803), and 8.60 μM (H460). In addition, research on the mechanism showed that 9e was able to cause cell morphological changes and to induce apoptosis in the Caski cell line. Most importantly, 9e can decrease the phosphorylation of mTOR and of its downstream key proteins, S6 and P70S6K1, indicating that 9e can effectively inhibit the mTOR signaling pathway. Thus, it may have the potential to become a new mTOR inhibitor against various cancers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A selective decoy-doxorubicin complex for targeted co-delivery, STAT3 probing and synergistic anti-cancer effect.

PubMed

Wang, Shao-Jen; Hou, Yung-Te; Chen, Lin-Chi

2015-09-04

A novel selective decoy oligodeoxynucleotide (dODN)-doxorubicin (DOX) complex is reported for cancer theranostics. It eliminates the use of a ligand or carrier for targeted delivery and disassembles into therapeutic dODN and DOX upon encountering over-activated STAT3 in cancer cells. Hence, in situ STAT3 probing and synergistic anti-cancer effect are attained at the same time.

ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.

PubMed

Miley, Galen P; Pou, Sovitj; Winter, Rolf; Nilsen, Aaron; Li, Yuexin; Kelly, Jane X; Stickles, Allison M; Mather, Michael W; Forquer, Isaac P; Pershing, April M; White, Karen; Shackleford, David; Saunders, Jessica; Chen, Gong; Ting, Li-Min; Kim, Kami; Zakharov, Lev N; Donini, Cristina; Burrows, Jeremy N; Vaidya, Akhil B; Charman, Susan A; Riscoe, Michael K

2015-09-01

ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (C max) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides.

PubMed

Dissanayake, Shama; Denny, William A; Gamage, Swarna; Sarojini, Vijayalekshmi

2017-03-28

Efficient intracellular trafficking and targeted delivery to the site of action are essential to overcome the current drawbacks of cancer therapeutics. Cell Penetrating Peptides (CPPs) offer the possibility of efficient intracellular trafficking, and, therefore the development of drug delivery systems using CPPs as cargo carriers is an attractive strategy to address the current drawbacks of cancer therapeutics. Additionally, the possibility of incorporating Tumor Targeting Peptides (TTPs) into the delivery system provides the necessary drug targeting effect. Therefore the conjugation of CPPs and/or TTPs with therapeutics provides a potentially efficient method of improving intracellular drug delivery mechanisms. Peptides used as cargo carriers in DDS have been shown to enhance the cellular uptake of drugs and thereby provide an efficient therapeutic benefit over the drug on its own. After providing a brief overview of various drug targeting approaches, this review focusses on peptides as carriers and targeting moieties in drug-peptide covalent conjugates and summarizes the most recent literature examples where CPPs on their own or CPPs together with TTPs have been conjugated to anticancer drugs such as Doxorubicin, Methotrexate, Paclitaxel, Chlorambucil etc. A short section on CPPs used in multicomponent drug delivery systems is also included. Copyright © 2017 Elsevier B.V. All rights reserved.

Click polymerization for the synthesis of reduction-responsive polymeric prodrug

NASA Astrophysics Data System (ADS)

Zhang, Xiaojin; Wang, Hongquan; Dai, Yu

2018-05-01

Click polymerization is a powerful polymerization technique for the construction of new macromolecules with well-defined structures and multifaceted functionalities. Here, we synthesize reduction-responsive polymeric prodrug PEG- b-(PSS- g-MTX)- b-PEG containing disulfide bonds and pendant methotrexate (MTX) via two-step click polymerization followed by conjugating MTX to pendant hydroxyl. MTX content in polymeric prodrug is 13.5%. Polymeric prodrug is able to form polymeric micelles by self-assembly in aqueous solution. Polymeric micelles are spherical nanoparticles with tens of nanometers in size. Of note, polymeric micelles are reduction-responsive due to disulfide bonds in the backbone of PEG- b-(PSS- g-MTX)- b-PEG and could release pendant drugs in the presence of the reducing agents such as dl-dithiothreitol (DTT).

PSMA-Specific Theranostic Nanoplex for Combination of TRAIL Gene and 5-FC Prodrug Therapy of Prostate Cancer

PubMed Central

Chen, Zhihang; Penet, Marie-France; Krishnamachary, Balaji; Banerjee, Sangeeta R.; Pomper, Martin G.; Bhujwalla, Zaver M.

2015-01-01

Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive 19F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer. PMID:26706476

Pro-drugs for indirect cannabinoids as therapeutic agents.

PubMed

Ashton, John

2008-10-01

Medicinal cannabis, cannabis extracts, and other cannabinoids are currently in use or under clinical trial investigation for the control of nausea, emesis and wasting in patients undergoing chemotherapy, the control of neuropathic pain and arthritic pain, and the control of the symptoms of multiple sclerosis. The further development of medicinal cannabinoids has been challenged with problems. These include the psychoactivity of cannabinoid CB1 receptor agonists and the lack of availability of highly selective cannabinoid receptor full agonists (for the CB1 or CB2 receptor), as well as problems of pharmacokinetics. Global activation of cannabinoid receptors is usually undesirable, and so enhancement of local endocannabinoid receptor activity with indirect cannabimimetics is an attractive strategy for therapeutic modulation of the endocannabinoid system. However, existing drugs of this type tend to be metabolized by the same enzymes as their target endocannabinoids and are not yet available in a form that is clinically useful. A potential solution to these problems may now have been suggested by the discovery that paracetamol (acetaminophen) exerts its analgesic (and probably anti-pyretic) effects by its degradation into an anandamide (an endocannabinoid) reuptake inhibitor (AM404) within the body, thus classifying it as pro-drug for an indirect cannabimimetic. Given the proven efficacy and safety of paracetamol, the challenge now is to develop related drugs, or entirely different substrates, into pro-drug indirect cannabimimetics with a similar safety profile to paracetamol but at high effective dose titrations.

Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II*

PubMed Central

Dong, Lan-Feng; Jameson, Victoria J. A.; Tilly, David; Cerny, Jiri; Mahdavian, Elahe; Marín-Hernández, Alvaro; Hernández-Esquivel, Luz; Rodríguez-Enríquez, Sara; Stursa, Jan; Witting, Paul K.; Stantic, Bela; Rohlena, Jakub; Truksa, Jaroslav; Kluckova, Katarina; Dyason, Jeffrey C.; Ledvina, Miroslav; Salvatore, Brian A.; Moreno-Sánchez, Rafael; Coster, Mark J.; Ralph, Stephen J.; Smith, Robin A. J.; Neuzil, Jiri

2011-01-01

Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC50 of 80 μm, whereas the electron transfer from CII to CIII was inhibited with IC50 of 1.5 μm. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1α fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug. PMID:21059645

Examining the effects of mass media campaign exposure and interpersonal discussions on youth's drug use: the mediating role of visiting pro-drug websites.

PubMed

Kam, Jennifer A; Lee, Chul-Joo

2013-01-01

To extend past research on interpersonal communication and campaign effects, we hypothesized that anti-drug mass media campaign message exposure indirectly affects visiting anti- and pro-drug websites through targeted parent-child and friend-to-friend communication against drugs, as well as through having drug-related discussions during organized group activities. Second, we posited that engaging in anti-drug interpersonal communication indirectly affects adolescents' drug use through two intervening variables: visiting anti-drug websites and visiting pro-drug websites. Using self-reported longitudinal data from 2,749 youth, we found that as youth reported higher levels of anti-drug mass media campaign message exposure, they were more likely to talk to friends about the bad consequences of drugs, how to avoid drugs, and anti-drug ads. In turn, however, they were more likely to visit pro-drug websites, and subsequently, to smoke cigarettes.

An acetate prodrug of a pyridinol-based vitamin E analogue.

PubMed

Khdour, Omar M; Lu, Jun; Hecht, Sidney M

2011-11-01

To investigate of an approach to stabilize a novel pyridinol based α-tocopherol analogue (1) as a prodrug by acetylation of its phenol moiety. Biochemical indicators of oxidative stress in mitochondria were utilized to gain insight into the cytoprotective mechanism(s) of compound 1 acetate. Oxygen free radical scavenging activity was measured using DCF probe in a cultured cell model system that had been placed under oxidative stress. Lipid peroxidation was examined both in a cell-free system and in oxidatively stressed cultured cells. The bioenergetic parameters of mitochondria were evaluated by measuring mitochondrial membrane potential (Δψ(m)) and the MPT. The present results suggest strongly that the antioxidant efficacy of compound 1 can be improved by using it as a prodrug. The tested prodrug has shown to be activated as a function of time, presumably due to susceptibility to enzymatic hydrolysis, and exhibits an antioxidant effect in time-dependent manner, providing a compound that is more effective than α-tocopherol acetate with regard to all protective properties studied. An effective approach to stabilize compound 1 was realized by using its acetate as a prodrug.

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.

PubMed

Markowicz-Piasecka, Magdalena; Sikora, Joanna; Mateusiak, Łukasz; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M

2017-01-01

The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35  μ mol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC 50  = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC 50  = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC 50  = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

CancerHSP: anticancer herbs database of systems pharmacology

NASA Astrophysics Data System (ADS)

Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

2015-06-01

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

PubMed Central

2018-01-01

Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids. PMID:29468872

Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs

PubMed Central

Butt, Adeel Masood; Mohd Amin, Mohd Cairul Iqbal; Katas, Haliza

2015-01-01

Background Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells. Methods FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue® assay. Results The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX–DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX. Conclusion FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake. PMID:25709451

Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs.

PubMed

Butt, Adeel Masood; Mohd Amin, Mohd Cairul Iqbal; Katas, Haliza

2015-01-01

Doxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells. FA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue(®) assay. The size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX-DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX. FA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake.

A Novel Isoquinoline Derivative Anticancer Agent and Its Targeted Delivery to Tumor Cells Using Transferrin-Conjugated Liposomes

PubMed Central

Yang, Xuewei; Yang, Shuang; Chai, Hongyu; Yang, Zhaogang; Lee, Robert J.; Liao, Weiwei; Teng, Lesheng

2015-01-01

We have screened 11 isoquinoline derivatives and α-methylene-γ-butyrolactones using the 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay in HeLa and HEK-293T cells. Compound 2 was identified as potential anticancer agent. To further improve its therapeutic potential, this agent was incorporated into transferrin (Tf)-conjugated liposomes (LPs) for targeted delivery to tumor cells. We have demonstrated Tf-LP-Compound 2 have superior antitumor activity compared to non-targeted controls and the free drug. These data show Tf-LP-Compound 2 to be a promising agent that warrants further evaluation. PMID:26309138

Anticancer activity of seaweeds.

PubMed

Gutiérrez-Rodríguez, Anllely G; Juárez-Portilla, Claudia; Olivares-Bañuelos, Tatiana; Zepeda, Rossana C

2018-02-01

Cancer is a major health problem worldwide and still lacks fully effective treatments. Therefore, alternative therapies, using natural products, have been proposed. Marine algae are an important component of the marine environment, with high biodiversity, and contain a huge number of functional compounds, including terpenes, polyphenols, phlorotannins, and polysaccharides, among others. These compounds have complex structures that have shown several biological activities, including anticancer activity, using in vitro and in vivo models. Moreover, seaweed-derived compounds target important molecules that regulate cancer processes. Here, we review our current understanding of the anticancer activity of seaweeds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Flurbiprofen-antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling.

PubMed

Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

2016-01-01

Flurbiprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with phenolic -OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer's yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities with

Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells.

PubMed

Kaczmarek, Monika Z; Holland, Ryan J; Lavanier, Stephen A; Troxler, Jami A; Fesenkova, Valentyna I; Hanson, Charlotte A; Cmarik, Joan L; Saavedra, Joseph E; Keefer, Larry K; Ruscetti, Sandra K

2014-03-01

The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis. The arylating capability of JS-K appears to be sufficient for inducing these biological effects. Overall, these data suggest that JS-K kills tumor cells by arylating and inactivating signaling molecules that block the activation of a tumor suppressor. Published by Elsevier Ltd.

Anticancer drugs during pregnancy.

PubMed

Miyamoto, Shingo; Yamada, Manabu; Kasai, Yasuyo; Miyauchi, Akito; Andoh, Kazumichi

2016-09-01

Although cancer diagnoses during pregnancy are rare, they have been increasing with the rise in maternal age and are now a topic of international concern. In some cases, the administration of chemotherapy is unavoidable, though there is a relative paucity of evidence regarding the administration of anticancer drugs during pregnancy. As more cases have gradually accumulated and further research has been conducted, we are beginning to elucidate the appropriate timing for the administration of chemotherapy, the regimens that can be administered with relative safety, various drug options and the effects of these drugs on both the mother and fetus. However, new challenges have arisen, such as the effects of novel anticancer drugs and the desire to bear children during chemotherapy. In this review, we outline the effects of administering cytotoxic anticancer drugs and molecular targeted drugs to pregnant women on both the mother and fetus, as well as the issues regarding patients who desire to bear children while being treated with anticancer drugs. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Gastric-sparing nitric oxide-releasable 'true' prodrugs of aspirin and naproxen.

PubMed

Gund, Machhindra; Gaikwad, Parikshit; Borhade, Namdev; Burhan, Aslam; Desai, Dattatraya C; Sharma, Ankur; Dhiman, Mini; Patil, Mohan; Sheikh, Javed; Thakre, Gajanan; Tipparam, Santhosh G; Sharma, Somesh; Nemmani, Kumar V S; Satyam, Apparao

2014-12-15

Nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are gaining attention as potentially gastric-sparing NSAIDs. Herein, we report a novel class of '1-(nitrooxy)ethyl ester' group-containing NSAIDS as efficient NO releasing 'true' prodrugs of aspirin and naproxen. While an aspirin prodrug exhibited comparable oral bioavailability and antiplatelet activity (i.e., TXB2 inhibition) to those of aspirin, a naproxen prodrug exhibited better bioavailability than naproxen. These promising NO-NSAIDs protected experimental rats from gastric damage. We therefore believe that these promising NO-NSAIDs could represent a new class of potentially 'Safe NSAIDs' for the treatment of arthritic pain, inflammation and cardiovascular disorders in the case of NO-aspirin. Copyright © 2014 Elsevier Ltd. All rights reserved.

An Efficient Buchwald-Hartwig/Reductive Cyclization for the Scaffold Diversification of Halogenated Phenazines: Potent Antibacterial Targeting, Biofilm Eradication, and Prodrug Exploration.

PubMed

Garrison, Aaron T; Abouelhassan, Yasmeen; Kallifidas, Dimitris; Tan, Hao; Kim, Young S; Jin, Shouguang; Luesch, Hendrik; Huigens, Robert W

2018-05-10

Bacterial biofilms are surface-attached communities comprised of nonreplicating persister cells housed within a protective extracellular matrix. Biofilms display tolerance toward conventional antibiotics, occur in ∼80% of infections, and lead to >500000 deaths annually. We recently identified halogenated phenazine (HP) analogues which demonstrate biofilm-eradicating activities against priority pathogens; however, the synthesis of phenazines presents limitations. Herein, we report a refined HP synthesis which expedited the identification of improved biofilm-eradicating agents. 1-Methoxyphenazine scaffolds were generated through a Buchwald-Hartwig cross-coupling (70% average yield) and subsequent reductive cyclization (68% average yield), expediting the discovery of potent biofilm-eradicating HPs (e.g., 61: MRSA BAA-1707 MBEC = 4.69 μM). We also developed bacterial-selective prodrugs (reductively activated quinone-alkyloxycarbonyloxymethyl moiety) to afford HP 87, which demonstrated excellent antibacterial and biofilm eradication activities against MRSA BAA-1707 (MIC = 0.15 μM, MBEC = 12.5 μM). Furthermore, active HPs herein exhibit negligible cytotoxic or hemolytic effects, highlighting their potential to target biofilms.

Photoacoustic molecular imaging of angiogenesis using theranostic ανβ3-targeted copper nanoparticles incorporating a sn-2 lipase-labile fumagillin prodrug

NASA Astrophysics Data System (ADS)

Zhang, Ruiying; Cai, Xin; Yang, Xiaoxia; Senpan, Angana; Allen, John S.; Pan, Dipanjan; Lanza, Gregory M.; Wang, Lihong V.

2014-03-01

Photoacoustic (PA) tomography imaging is an emerging, versatile, and noninvasive imaging modality, which combines the advantages of both optical imaging and ultrasound imaging. It opens up opportunities for noninvasive imaging of angiogenesis, a feature of skin pathologies including cancers and psoriasis. In this study, high-density copper oleate encapsulated within a phospholipid surfactant (CuNPs) generated a soft nanoparticle with PA contrast comparable to gold. Within the near-infrared window, the copper nanoparticles can provide a signal more than 7 times higher that of blood. ανβ3-targeted of CuNPs in a Matrigel mouse model demonstrated prominent PA contrast enhancement of the neovasculature compared to mice given nontargeted or competitively inhibited CuNPs. Incorporation of a sn-2 lipase-labile fumagillin prodrug into the CuNPs produced marked antiangiogenesis in the same model, demonstrating the theranostic potential of a PA agent for the first time in vivo. With a PA signal comparable to gold-based nanoparticles yet a lower cost and demonstrated drug delivery potential, ανβ3-targeted CuNPs hold great promise for the management of skin pathologies with neovascular features.

Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review

PubMed Central

Porporato, Paolo E.; Dhup, Suveera; Dadhich, Rajesh K.; Copetti, Tamara; Sonveaux, Pierre

2011-01-01

Cancer is a metabolic disease and the solution of two metabolic equations: to produce energy with limited resources and to fulfill the biosynthetic needs of proliferating cells. Both equations are solved when glycolysis is uncoupled from oxidative phosphorylation in the tricarboxylic acid cycle, a process known as the glycolytic switch. This review addresses in a comprehensive manner the main molecular events accounting for high-rate glycolysis in cancer. It starts from modulation of the Pasteur Effect allowing short-term adaptation to hypoxia, highlights the key role exerted by the hypoxia-inducible transcription factor HIF-1 in long-term adaptation to hypoxia, and summarizes the current knowledge concerning the necessary involvement of aerobic glycolysis (the Warburg effect) in cancer cell proliferation. Based on the many observations positioning glycolysis as a central player in malignancy, the most advanced anticancer treatments targeting tumor glycolysis are briefly reviewed. PMID:21904528

Synthesis of pro-prodrugs L-lysine based for 5-aminosalicylic acid and 6-mercaptopurine colon specific release.

PubMed

Trombino, Sonia; Cassano, Roberta; Cilea, Alessia; Ferrarelli, Teresa; Muzzalupo, Rita; Picci, Nevio

2011-11-28

The aim of this work is to design, prepare and characterize L-lysine based prodrugs capable of targeting 6-mercaptopurine to the colon, an anti-tumor and immunosuppressant drug, and 5-aminosalicylic acid (5-ASA), drug of choice for inflammatory bowel disease (IBD). More specifically, Nɛ-feruloyl-S-(6-purinyl)-L-lysine and Nɛ-acryloyl-S-(6-purinyl)-L-lysine were synthesized and then characterized by FT-IR, (1)H-NMR and GC/MS spectroscopies. The ability of feruloyl derivative in inhibiting lipid peroxidation in rat liver microsomal membranes, induced in vitro by tert-butyl hydroperoxide as source of free radicals, was evaluated. Moreover, Nɛ-acryloyl-S-(6-purinyl)-L-lysine, polymerizable prodrug, was used to microspheres realization for 5-ASA release. These lasts, obtained by emulsion inverse technique, were characterized by light scattering and scanning electron microscopy (SEM) analysis. The microspheres equilibrium swelling degree was evaluated and showed good swelling behaviour in simulating colonic fluids. Results confirm the possibility that the application range of L-lysine prodrug can be extended to the treatment of intestinal diseases whose conventional therapy envisages medications with serious side effects that, thanks to this new strategy, can be minimized in an optimal way. Copyright © 2011 Elsevier B.V. All rights reserved.

Enhanced Cellular Uptake and Pharmacokinetic Characteristics of Doxorubicin-Valine Amide Prodrug.

PubMed

Park, Yohan; Park, Ju-Hwan; Park, Suryeon; Lee, Song Yi; Cho, Kwan Hyung; Kim, Dae-Duk; Shim, Won-Sik; Yoon, In-Soo; Cho, Hyun-Jong; Maeng, Han-Joo

2016-09-22

In this study, we synthesized the valine (Val)-conjugated amide prodrug of doxorubicin (DOX) by the formation of amide bonds between DOX and Val. The synthesis of the DOX-Val prodrug was identified by a proton nuclear magnetic resonance (¹H-NMR) assay. In the MCF-7 cells (human breast adenocarcinoma cell; amino acid transporter-positive cell), the cellular accumulation efficiency of DOX-Val was higher than that of DOX according to the flow cytometry analysis data. Using confocal laser scanning microscopy (CLSM) imaging, it was confirmed that DOX-Val as well as DOX was mainly distributed in the nucleus of cancer cells. DOX-Val was intravenously administered to rats at a dose of 4 mg/kg, and the plasma concentrations of DOX-Val (prodrug) and DOX (formed metabolite) were quantitatively determined. Based on the systemic exposure (represented as area under the curve (AUC) values) of DOX-Val (prodrug) and DOX (formed metabolite), approximately half of DOX-Val seemed to be metabolized into DOX. However, it is expected that the remaining DOX-Val may exert improved cellular uptake efficiency in cancer cells after its delivery to the cancer region.

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

PubMed Central

Andreol, Federico; Barbosa, Arménio Jorge Moura; Daniele Parenti, Marco; Rio, Alberto Del

2013-01-01

Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of small-molecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives. PMID:23016851

Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

PubMed Central

Ashraf, Zaman; Alamgeer; Kanwal, Munazza; Hassan, Mubashir; Abdullah, Sahar; Waheed, Mamuna; Ahsan, Haseeb; Kim, Song Ja

2016-01-01

Flurbiprofen–antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal (GI) effects associated with flurbiprofen. For reducing the GI toxicity, the free carboxylic group (–COOH) was temporarily masked by esterification with phenolic –OH of natural antioxidants vanillin, thymol, umbelliferone, and sesamol. The in vitro hydrolysis of synthesized prodrugs showed that they were stable in buffer solution at pH 1.2, indicating their stability in the stomach. The synthesized prodrugs undergo significant hydrolysis in 80% human plasma and thus release free flurbiprofen. The minimum reversion was observed at pH 1.2, suggesting that prodrugs are less irritating to the stomach than flurbiprofen. The anti-inflammatory, analgesic, antipyretic, and ulcerogenic activities of prodrugs were evaluated. All the synthesized prodrugs significantly (P<0.001) reduced the inflammation against carrageenan and egg albumin-induced paw edema at 4 hours of study. The reduction in the size of the inflamed paw showed that most of the compounds inhibited the later phase of inflammation. The prodrug 2-oxo-2H-chromen-7-yl-2-(2-fluorobiphenyl-4-yl)propanoate (4b) showed significant reduction in paw licking with percentage inhibition of 58%. It also exhibited higher analgesic activity, reducing the number of writhes with a percentage of 75%, whereas flurbiprofen showed 69% inhibition. Antipyretic activity was investigated using brewer’s yeast-induced pyrexia model, and significant (P<0.001) reduction in rectal temperature was shown by all prodrugs at all times of assessment. The results of ulcerogenic activity showed that all prodrugs produced less GI irritation than flurbiprofen. Molecular docking and simulation studies were carried out with cyclooxygenase (COX-1 and COX-2) proteins, and it was observed that our prodrugs have more potential to selectively bind to COX-2 than to COX-1. It is concluded that the synthesized prodrugs have promising pharmacological activities

Polyphosphoester-Camptothecin Prodrug with Reduction-Response Prepared via Michael Addition Polymerization and Click Reaction.

PubMed

Du, Xueqiong; Sun, Yue; Zhang, Mingzu; He, Jinlin; Ni, Peihong

2017-04-26

Polyphosphoesters (PPEs), as potential candidates for biocompatible and biodegradable polymers, play an important role in material science. Various synthetic methods have been employed in the preparation of PPEs such as polycondensation, polyaddition, ring-opening polymerization, and olefin metathesis polymerization. In this study, a series of linear PPEs has been prepared via one-step Michael addition polymerization. Subsequently, camptothecin (CPT) derivatives containing disulfide bonds and azido groups were linked onto the side chain of the PPE through Cu(I)-catalyzed azidealkyne cyclo-addition "click" chemistry to yield a reduction-responsive polymeric prodrug P(EAEP-PPA)-g-ss-CPT. The chemical structures were characterized by nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared, ultraviolet-visible spectrophotometer, and high performance liquid chromatograph analyses, respectively. The amphiphilic prodrug could self-assemble into micelles in aqueous solution. The average particle size and morphology of the prodrug micelles were measured by dynamic light scattering and transmission electron microscopy, respectively. The results of size change under different conditions indicate that the micelles possess a favorable stability in physiological conditions and can be degraded in reductive medium. Moreover, the studies of in vitro drug release behavior confirm the reduction-responsive degradation of the prodrug micelles. A methyl thiazolyl tetrazolium assay verifies the good biocompatibility of P(EAEP-PPA) not only for normal cells, but also for tumor cells. The results of cytotoxicity and the intracellular uptake about prodrug micelles further demonstrate that the prodrug micelles can efficiently release CPT into 4T1 or HepG2 cells to inhibit the cell proliferation. All these results show that the polyphosphoester-based prodrug can be used for triggered drug delivery system in cancer treatment.

Rational design of a dual-mode optical and chemical prodrug.

PubMed

McCoy, Colin P; Rooney, Clare; Jones, David S; Gorman, Sean P; Nieuwenhuyzen, Mark

2007-01-01

The purpose of this study is to demonstrate the rational design and behaviour of the first dual-mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system. A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution. The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30x10(-2) s-1, while chemical, hydrolytic liberation proceeded independently at 1.89x10(-3) s-1. The photochemical and hydrolytic reactions were both quantitative. This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability.

PubMed

Andersson, Vincent; Bergström, Fredrik; Brånalt, Jonas; Grönberg, Gunnar; Gustafsson, David; Karlsson, Staffan; Polla, Magnus; Bergman, Joakim; Kihlberg, Jan

2016-07-28

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy

PubMed Central

Crielaard, Bart J; van der Wal, Steffen; Lammers, Twan; Le, Huong Thu; Hennink, Wim E; Schiffelers, Raymond M; Storm, Gert; Fens, Marcel HAM

2011-01-01

Colchicinoids are very potent tubulin-binding compounds, which interfere with microtubule formation, giving them strong cytotoxic properties, such as cell mitosis inhibition and induction of microcytoskeleton depolymerization. While this makes them promising vascular disrupting agents (VDAs) in cancer therapy, their dose-limiting toxicity has prevented any clinical application for this purpose. Therefore, colchicinoids are considered attractive lead molecules for the development of novel vascular disrupting nanomedicine. In a previous study, a polymeric colchicinoid prodrug that showed favorable hydrolysis characteristics at physiological conditions was developed. In the current study, this polymeric colchicinoid prodrug was evaluated in vitro and in vivo for its toxicity and vascular disrupting potential. Cell viability studies with human umbilical vein endothelial cells, as an in vitro measure for colchicine activity, reflected the degradation kinetics of the prodrug accordingly. Upon intravenous treatment, in vivo, of B16F10 melanoma-bearing mice with colchicine or with the polymeric colchicinoid prodrug, apparent vascular disruption and consequent tumor necrosis was observed for the prodrug but not for free colchicine at an equivalent dose. Moreover, a five-times-higher dose of the prodrug was well tolerated, indicating reduced toxicity. These findings demonstrate that the polymeric colchicinoid prodrug has a substantially improved efficacy/toxicity ratio compared with that of colchicine, making it a promising VDA for cancer therapy. PMID:22114500

Pt(IV) complexes as prodrugs for cisplatin.

PubMed

Shi, Yi; Liu, Shu-An; Kerwood, Deborah J; Goodisman, Jerry; Dabrowiak, James C

2012-02-01

The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ((195))Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ((195))Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ((13))C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

Anti-cancer agents based on 4-(hetero)Ary1-1,2,5-oxadiazol-3-yl Amino derivatives and a method of making

DOEpatents

Gakh, Andrei A.; Krasavin, Mikhail; Karapetian, Ruben; Rufanov, Konstantin A.; Konstantinov, Igor; Godovykh, Elena; Soldatkina, Olga; Sosnov, Andrey V.

2013-01-29

The present disclosure relates to novel compounds that can be used as anti-cancer agents in the prostate cancer therapy. ##STR00001## In particular, the invention relates N-substituted derivatives of 4-(hetero)aryl-1,2,5-oxadiazol-3-yl amines having the structural Formula (I) and (II), stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof. Meaning of R1 and R2 in the Formula (I) and (II) are defined in claim 1. The invention also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

Construction of dual-functional polymer nanomaterials with near-infrared fluorescence imaging and polymer prodrug by RAFT-mediated aqueous dispersion polymerization.

PubMed

Tian, Chun; Niu, Jinyun; Wei, Xuerui; Xu, Yujie; Zhang, Lifen; Cheng, Zhenping; Zhu, Xiulin

2018-05-31

The performance of functional polymer nanomaterials is a vigorously discussed topic in polymer science. We devoted ourselves to investigating polymer nanomaterials based on near-infrared (NIR) fluorescence imaging and polymer prodrug in this study. Aza-boron dipyrromethene (BODIPY) is an important organic dye, having characteristics such as environmental resistance, light resistance, high molar extinction coefficient, and fluorescence quantum yield. We incorporated it into our target monomer, which can be polymerized without changing its parent structure in a polar solvent and copolymerized with water-soluble monomer to improve the solubility of the dye in an aqueous solution. At the same time, the hydrophobic drug camptothecin (CPT) was designed as a prodrug monomer, and the polymeric nanoparticles (NPs) with NIR fluorescence imaging and prodrug were synthesized in situ in reversible addition-fragmentation chain transfer (RAFT)-mediated aqueous dispersion polymerization. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed the final uniform size of the dual-functional polymeric NPs morphology. The dual-functional polymeric NPs had a strong absorption and emission signal in the NIR region (>650 nm) based on the fluorescence tests. In consideration of the long-term biological toxicity, confocal laser scanning microscopy (CLSM) results indicated that the dual-functional NPs with controlled drug content exhibited effective capability of killing HeLa cells. In addition, in vivo imaging of the dual-functional NPs was observed in real time, and the fluorescent signals clearly demonstrated the dynamic process of prodrug transfer.

The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization

PubMed Central

Ihmaid, Saleh; Ahmed, Hany E. A.; Zayed, Mohamed F.

2018-01-01

Some novel anthranilate diamides derivatives 4a–e, 6a–c and 9a–d were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, 1H nuclear magnetic resonance (NMR) and 13C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC50) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out. PMID:29385728

Effective gene silencing activity of prodrug-type 2'-O-methyldithiomethyl siRNA compared with non-prodrug-type 2'-O-methyl siRNA.

PubMed

Hayashi, Junsuke; Nishigaki, Misa; Ochi, Yosuke; Wada, Shun-Ichi; Wada, Fumito; Nakagawa, Osamu; Obika, Satoshi; Harada-Shiba, Mariko; Urata, Hidehito

2018-07-01

Small interfering RNAs (siRNAs) are an active agent to induce gene silencing and they have been studied for becoming a biological and therapeutic tool. Various 2'-O-modified RNAs have been extensively studied to improve the nuclease resistance. However, the 2'-O-modified siRNA activities were often decreased by modification, since the bulky 2'-O-modifications inhibit to form a RNA-induced silencing complex (RISC). We developed novel prodrug-type 2'-O-methyldithiomethyl (MDTM) siRNA, which is converted into natural siRNA in an intracellular reducing environment. Prodrug-type 2'-O-MDTM siRNAs modified at the 5'-end side including 5'-end nucleotide and the seed region of the antisense strand exhibited much stronger gene silencing effect than non-prodrug-type 2'-O-methyl (2'-O-Me) siRNAs. Furthermore, the resistances for nuclease digestion of siRNAs were actually enhanced by 2'-O-MDTM modifications. Our results indicate that 2'-O-MDTM modifications improve the stability of siRNA in serum and they are able to be introduced at any positions of siRNA. Copyright © 2018 Elsevier Ltd. All rights reserved.

Clearing the fog of anticancer patents from 1993-2013: through an in-depth technology landscape & target analysis from pioneer research institutes and universities worldwide.

PubMed

Dara, Ajay; Sangamwar, Abhay T

2014-01-01

In a search for an effective anticancer therapy the R&D units from leading universities and institutes reveal numerous technologies in the form of patent documents. The article addressed comparative anticancer patent landscape and technology assessment of Council of Scientific and Industrial Research (CSIR): India's largest R&D organisation with top twenty international public funded universities and institutes from eight different countries. The methodology include quantitative and qualitative assessment based on the bibliometric parameters and manual technology categorisation to understand the changing patent trends and recent novel technologies. The research finding analysed 25,254 patent documents from the year 1993 to 2013 and reported the insights of latest anticancer technologies and targets through categorisation studies at the level of drug discovery, development and treatment & diagnosis. The article has reported the technology correlation matrix of twelve secondary class technologies with 34 tertiary sub-class research area to identify the leading technologies and scope of future research through whitespaces analysis. In addition, the results have also addressed the target analysis, leading inventor, assignee, collaboration network, geographical distribution, patent trend analysis, citation maps and technology assessment with respect to international patent classification systems such as CPC, IPC and CPI codes. The result suggested peptide technology as the dominating research area next to gene therapy, vaccine and medical preparation containing organic compounds. The Indian CSIR has ranked itself at seventh position among the top 20 universities. Globally, the anticancer research was focused in the area of genetics and immunology, whereas Indian CSIR reported more patents related to plant extract and organic preparation. The article provided a glimpse of two decade anticancer scenario with respect to top public funded universities worldwide.

MSN anti-cancer nanomedicines: chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition.

PubMed

He, Qianjun; Shi, Jianlin

2014-01-22

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity.

PubMed

Zhou, Qing; Hou, Yilin; Zhang, Li; Wang, Jianlin; Qiao, Youbei; Guo, Songyan; Fan, Li; Yang, Tiehong; Zhu, Lin; Wu, Hong

2017-01-01

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity.

Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity

PubMed Central

Zhou, Qing; Hou, Yilin; Zhang, Li; Wang, Jianlin; Qiao, Youbei; Guo, Songyan; Fan, Li; Yang, Tiehong; Zhu, Lin; Wu, Hong

2017-01-01

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity. PMID:28638469

Propylene glycol-linked amino acid/dipeptide diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics.

PubMed

Cao, Feng; Gao, Yahan; Wang, Meng; Fang, Lei; Ping, Qineng

2013-04-01

In our previous studies, ethylene glycol-linked amino acid diester prodrugs of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity, and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing L-Val ester (7a), L-Phe ester (7b), L-Ile ester (7c), D-Val-L-Val ester (9a), L-Val-L-Val ester (9b), L-Ala-L-Val ester (9c), and L-Ala-L-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (P(eff)) of the prodrugs. P(eff) of 7a, 7b, 7c, 9a, 9b, 9c, and 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, and 1.4-fold, respectively) in 2-(N-morpholino)ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p < 0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH 7.4, except for 7c, 9a, and 9d, P(eff) of the other prodrugs containing 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (1.7-fold) exhibited significantly higher values than that of OA (p < 0.01). In inhibition studies with glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1), P(eff) of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (2.3-fold) had significantly reduced values (p < 0.01). Compared to the apparent permeability coefficient (P(app)) of OA with Caco-2 cell monolayer, significant enhancement of the P(app) of 7a (5.27-fold), 9b (3.31-fold), 9a (2.26-fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), and 9d (1.39-fold) was also observed (p < 0.01). Inhibition studies with Gly-Sar (1 mM) showed that P(app) of 7a, 9b, and

eIF3a: A new anticancer drug target in the eIF family.

PubMed

Yin, Ji-Ye; Zhang, Jian-Ting; Zhang, Wei; Zhou, Hong-Hao; Liu, Zhao-Qian

2018-01-01

eIF3a is the largest subunit of eIF3, which is a key player in all steps of translation initiation. During the past years, eIF3a is recognized as a proto-oncogene, which is an important discovery in this field. It is widely reported to be correlated with cancer occurrence, metastasis, prognosis, and therapeutic response. Recently, the mechanisms of eIF3a action in the carcinogenesis are unveiled gradually. A number of cellular, physiological, and pathological processes involving eIF3a are identified. Most importantly, it is emerging as a new potential drug target in the eIF family, and some small molecule inhibitors are being developed. Thus, we perform a critical review of recent advances in understanding eIF3a physiological and pathological functions, with specific focus on its role in cancer and anticancer drug targets. Copyright © 2017 Elsevier B.V. All rights reserved.

Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy.

PubMed

Xie, Ying; Murray-Stewart, Tracy; Wang, Yazhe; Yu, Fei; Li, Jing; Marton, Laurence J; Casero, Robert A; Oupický, David

2017-01-28

Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N 1 ,N 11 -bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infections

NASA Astrophysics Data System (ADS)

Drebes, Julia; Künz, Madeleine; Windshügel, Björn; Kikhney, Alexey G.; Müller, Ingrid B.; Eberle, Raphael J.; Oberthür, Dominik; Cang, Huaixing; Svergun, Dmitri I.; Perbandt, Markus; Betzel, Christian; Wrenger, Carsten

2016-03-01

Infections caused by the methicillin-resistant Staphylococcus aureus (MRSA) are today known to be a substantial threat for global health. Emerging multi-drug resistant bacteria have created a substantial need to identify and discover new drug targets and to develop novel strategies to treat bacterial infections. A promising and so far untapped antibiotic target is the biosynthesis of vitamin B1 (thiamin). Thiamin in its activated form, thiamin pyrophosphate, is an essential co-factor for all organisms. Therefore, thiamin analogous compounds, when introduced into the vitamin B1 biosynthetic pathway and further converted into non-functional co-factors by the bacterium can function as pro-drugs which thus block various co-factor dependent pathways. We characterized one of the key enzymes within the S. aureus vitamin B1 biosynthetic pathway, 5-(hydroxyethyl)-4-methylthiazole kinase (SaThiM; EC 2.7.1.50), a potential target for pro-drug compounds and analyzed the native structure of SaThiM and complexes with the natural substrate 5-(hydroxyethyl)-4-methylthiazole (THZ) and two selected substrate analogues.

Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles.

PubMed

Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

2016-05-06

Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 10(8) particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles

NASA Astrophysics Data System (ADS)

Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

2016-05-01

Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 108 particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

Natural flora and anticancer regime: milestones and roadmap.

PubMed

Bhatnagar, Ira; Thomas, Noel Vinay; Kim, Se-Kwon

2013-07-01

Cancer has long been an area of extensive research both at the molecular as well as pharmaceutical level. However, lack of understanding of the underlying molecular signalling and the probable targets of therapeutics is a major concern in successful treatment of cancer. The situation becomes even worse, with the increasing side effects of the existing synthetic commercial drugs. Natural compounds especially those derived from plants have been best explored for their anticancer properties and most of them have been efficient against the known molecular targets of cancer. However, advent of biotechnology and resulting advances in medical arena have let to the increasing knowledge of newer carcinogenic signaling agents which has made the anticancer drug discovery even more demanding. The present review aims to bring forward the molecular mediators of cancer and compiles the plant derived anticancer agents with special emphasis on their clinical status. Since marine arena has proved to be a tremendous source of pharmaceutical agents, this review also focuses on the anticancer potential of marine plants especially algae. This is a comprehensive review covering major aspects of cancer mediation and utilization of marine flora for remediation of this deadly disease.

Antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating Mycobacterium tuberculosis.

PubMed

Segretti, Natanael Dante; Simões, Cristina Kortstee; Corrêa, Michelle Fidelis; Felli, Veni Maria Andres; Miyata, Marcelo; Cho, Sang Hyun; Franzblau, Scott Gary; Fernandes, João Paulo Dos Santos

2016-07-01

Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Study on liver targeted drug delivery system of the effective anticancer component from Bolbstemma paniculatum].

PubMed

Sun, Yi-Yi; Ll, Tong-Hui; Tang, Chen-Kang; Zhu, Zi-Ping; Chi, Qun; Hou, Shi-Xiang

2005-06-01

To study the liver targeted drug delivery system of TBMS--the effective anticancer component from Bolbstemma paniculatum, and to discuss the system's function of decreasing toxicity. BCA was used as carrier material. The preparation through overall feedback dynamic techniques. The properties of preparation and toxicology were also technology of nanoparticles was optimized studied. Thenanoparticles' targeting in mice vivo was observed with transmission electron microscopy. The function of decreasing toxicity was researched by the XXTX-2000 automatic quantitative analysis management system. D50 was 0.68 microm. Drug-loading rate and entrapment rate were 37.3% and 88.6% respectively. The release in vitro accorded with Weibull equation. The reaching release balance time and the t 1/2 extended 26 times and 19 times respectively comparing with injection. Nanoparticles mainly distributed in liver tissue. Their toxicity to lung and liver was evidently lower than injection. Nanoparticles' LD50 exceeded injection's by 13.5% and their stimulus was much lower than injection. The TBMS can be targeted to liver by liver targeted drug delivery system. At the same time, the problem about the toxicity hindering clinical application could be solved, which lays the foundation for the further studies on TBMS.

Thermal and pH responsive polymer-tethered multifunctional magnetic nanoparticles for targeted delivery of anticancer drug.

PubMed

Sahoo, Banalata; Devi, K Sanjana P; Banerjee, Rakesh; Maiti, Tapas K; Pramanik, Panchanan; Dhara, Dibakar

2013-05-01

Targeted and efficient delivery of therapeutics to tumor cells is one of the key issues in cancer therapy. In the present work, we report a temperature and pH dual responsive core-shell nanoparticles comprising smart polymer shell coated on magnetic nanoparticles as an anticancer drug carrier and cancer cell-specific targeting agent. Magnetite nanoparticles (MNPs), prepared by a simple coprecipitation method, was surface modified by introducing amine groups using 3-aminopropyltriethoxysilane. Dual-responsive poly(N-isopropylacrylamide)-block-poly(acrylic acid) copolymer, synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, was then attached to the amine-functionalized MNPs via EDC/NHS method. Further, to accomplish cancer-specific targeting properties, folic acid was tethered to the surface of the nanoparticles. Thereafter, rhodamine B isothiocyanate was conjugated to endow fluorescent property to the MNPs required for cellular imaging applications. The nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA), zeta potential, vibrating sample magnetometer (VSM), X-ray photoelectron spectroscopy (XPS) measurements, and FTIR, UV-vis spectral analysis. Doxorubicin (DOX), an anticancer drug used for the present study, was loaded into the nanoparticles and its release behavior was subsequently studied. Result showed a sustained release of DOX preferentially at the desired lysosomal pH and temperature condition. The biological activity of the DOX-loaded MNPs was studied by MTT assay, fluorescence microscopy, and apoptosis. Intracellular-uptake studies revealed preferential uptake of these nanoparticles into cancer cells (HeLa cells) compared to normal fibroblast cells (L929 cells). The in vitro apoptosis study revealed that

In Vivo Fluorescence Resonance Energy Transfer Imaging for Targeted Anti-Cancer Drug Delivery Kinetics

NASA Astrophysics Data System (ADS)

Webb, Kevin; Gaind, Vaibhav; Tsai, Hsiaorho; Bentz, Brian; Chelvam, Venkatesh; Low, Philip

2012-02-01

We describe an approach for the evaluation of targeted anti-cancer drug delivery in vivo. The method emulates the drug release and activation process through acceptor release from a targeted donor-acceptor pair that exhibits fluorescence resonance energy transfer (FRET). In this case, folate targeting of the cancer cells is used - 40 % of all human cancers, including ovarian, lung, breast, kidney, brain and colon cancer, over-express folate receptors. We demonstrate the reconstruction of the spatially-dependent FRET parameters in a mouse model and in tissue phantoms. The FRET parameterization is incorporated into a source for a diffusion equation model for photon transport in tissue, in a variant of optical diffusion tomography (ODT) called FRET-ODT. In addition to the spatially-dependent tissue parameters in the diffusion model (absorption and diffusion coefficients), the FRET parameters (donor-acceptor distance and yield) are imaged as a function of position. Modulated light measurements are made with various laser excitation positions and a gated camera. More generally, our method provides a new vehicle for studying disease at the molecular level by imaging FRET parameters in deep tissue, and allows the nanometer FRET ruler to be utilized in deep tissue.

Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells.

PubMed

Subia, Bano; Dey, Tuli; Sharma, Shaily; Kundu, Subhas C

2015-02-04

To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research.

Targeted delivery of CYP2E1 recombinant adenovirus to malignant melanoma by bone marrow-derived mesenchymal stem cells as vehicles.

PubMed

Wang, Jishi; Ma, Dan; Li, Yan; Yang, Yuan; Hu, Xiaoyan; Zhang, Wei; Fang, Qin

2014-03-01

The aim of this study was to explore the effects of bone marrow-derived mesenchymal stem cells (BMSCs) as intermediate carriers on targeting of P450 gene recombinant adenovirus to malignant melanoma in vitro and in vivo. BMSCs were transduced with pAd5-CMV-CYP2E1 recombinant adenovirus. BMSC migration was detected by Transwell plates in vitro and by superparamagnetic iron oxide particles in vivo. Growth-inhibitory effect and apoptosis were determined by MTT and immunity fluorescence staining. Anticancer effects were examined by a human melanoma nude mouse model in vivo. BMSCs moved toward A375 cells in Transwell plates. Numerous superparamagnetic MSCs labeled with iron oxide were identified in the peripheral areas of the tumor, but were detected in primary organs by Prussian blue staining. BMSC-CYP2E1 cells mediated a bystander killing effect on CYP2E1-negative A375 cells during coculture (IC50 values for A375 cells cocultured with BMSC-EGFP and BMSC-CYP2E1 were 4.08 and 2.68 mmol/l, respectively). Intravenously injecting CYP2E1 recombinant adenovirus-loaded BMSCs in mice with established human melanoma managed to target the tumor site, and BMSCs with forced expression of CYP2E1 inhibited the growth of malignant cells in vivo by activating 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide. BMSCs may serve as a platform of P450 gene-directed enzyme prodrug therapy for the delivery of chemotherapeutic prodrugs to tumors.

Lead Phytochemicals for Anticancer Drug Development

PubMed Central

Singh, Sukhdev; Sharma, Bhupender; Kanwar, Shamsher S.; Kumar, Ashok

2016-01-01

Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function in vitro and in vivo. This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed. PMID:27877185

Apoptin towards safe and efficient anticancer therapies.

PubMed

Backendorf, Claude; Noteborn, Mathieu H M

2014-01-01

The chicken anemia virus derived protein apoptin harbors cancer-selective cell killing characteristics, essentially based on phosphorylation-mediated nuclear transfer in cancer cells and efficient cytoplasmic degradation in normal cells. Here, we describe a growing set of preclinical experiments underlying the promises of the anti-cancer potential of apoptin. Various non-replicative oncolytic viral vector systems have revealed the safety and efficacy of apoptin. In addition, apoptin enhanced the oncolytic potential of adenovirus, parvovirus and Newcastle disease virus vectors. Intratumoral injection of attenuated Salmonella typhimurium bacterial strains and plasmid-based systems expressing apoptin resulted in significant tumor regression. In-vitro and in-vivo experiments showed that recombinant membrane-transferring PTD4- or TAT-apoptin proteins have potential as a future anticancer therapeutics. In xenografted hepatoma and melanoma mouse models PTD4-apoptin protein entered both cancer and normal cells, but only killed cancer cells. Combinatorial treatment of PTD4-apoptin with various (chemo)therapeutic compounds revealed an additive or even synergistic effect, reducing the side effects of the single (chemo)therapeutic treatment. Degradable polymeric nanocapsules harboring MBP-apoptin fusion-protein induced tumor-selective cell killing in-vitro and in-vivo and revealed the potential of polymer-apoptin protein vehicles as an anticancer agent.Besides its direct use as an anticancer therapeutic, apoptin research has also generated novel possibilities for drug design. The nuclear location domains of apoptin are attractive tools for targeting therapeutic compounds into the nucleus of cancer cells. Identification of cancer-related processes targeted by apoptin can potentially generate novel drug targets. Recent breakthroughs important for clinical applications are reported inferring apoptin-based clinical trials as a feasible reality.

Molecular docking and dynamic simulation studies evidenced plausible immunotherapeutic anticancer property by Withaferin A targeting indoleamine 2,3-dioxygenase.

PubMed

Reddy, S V G; Reddy, K Thammi; Kumari, V Valli; Basha, Syed Hussain

2015-01-01

Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic drug target for the treatment of cancer characterized by pathological immune suppression. IDO catalyzes the rate-limiting step of tryptophan degradation along the kynurenine pathway. Reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to the immunosuppressive effects of IDO. Presence of IDO on dentritic cells in tumor-draining lymph nodes leading to the activation of T cells toward forming immunosuppressive microenvironment for the survival of tumor cells has confirmed the importance of IDO as a promising novel anticancer immunotherapy drug target. On the other hand, Withaferin A (WA) - active constituent of Withania Somnifera ayurvedic herb has shown to be having a wide range of targeted anticancer properties. In the present study conducted here is an attempt to explore the potential of WA in attenuating IDO for immunotherapeutic tumor arresting activity and to elucidate the underlying mode of action in a computational approach. Our docking and molecular dynamic simulation results predict high binding affinity of the ligand to the receptor with up to -11.51 kcal/mol of energy and 3.63 nM of IC50 value. Further, de novo molecular dynamic simulations predicted stable ligand interactions with critically important residues SER167; ARG231; LYS377, and heme moiety involved in IDO's activity. Conclusively, our results strongly suggest WA as a valuable small ligand molecule with strong binding affinity toward IDO.

Pharmacokinetics of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin, in Wistar Rats.

PubMed

Bangphumi, Kunan; Kittiviriyakul, Chuleeporn; Towiwat, Pasarapa; Rojsitthisak, Pornchai; Khemawoot, Phisit

2016-12-01

Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.

Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.

PubMed

Abdel-Azeem, Ahmed Z; Abdel-Hafez, Atef A; El-Karamany, Gamal S; Farag, Hassan H

2009-05-15

The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.

Bone marrow-derived CD13+ cells sustain tumor progression: A potential non-malignant target for anticancer therapy.

PubMed

Dondossola, Eleonora; Corti, Angelo; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2014-01-01

Non-malignant cells found within neoplastic lesions express alanyl (membrane) aminopeptidase (ANPEP, best known as CD13), and CD13-null mice exhibit limited tumor growth and angiogenesis. We have recently demonstrated that a subset of bone marrow-derived CD11b + CD13 + myeloid cells accumulate within neoplastic lesions in several murine models of transplantable cancer to promote angiogenesis. If these findings were confirmed in clinical settings, CD11b + CD13 + myeloid cells could become a non-malignant target for the development of novel anticancer regimens.

Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation.

PubMed

Chayrov, Radoslav L; Stylos, Evgenios K; Chatziathanasiadou, Maria V; Chuchkov, Kiril N; Tencheva, Aleksandra I; Kostagianni, Androniki D; Milkova, Tsenka S; Angelova, Assia L; Galabov, Angel S; Shishkov, Stoyan A; Todorov, Daniel G; Tzakos, Andreas G; Stankova, Ivanka G

2018-05-19

Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein-Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.

Clearing the Fog of Anticancer Patents from 1993–2013: Through an In-Depth Technology Landscape & Target Analysis from Pioneer Research Institutes and Universities Worldwide

PubMed Central

Dara, Ajay; Sangamwar, Abhay T.

2014-01-01

Background In a search for an effective anticancer therapy the R&D units from leading universities and institutes reveal numerous technologies in the form of patent documents. The article addressed comparative anticancer patent landscape and technology assessment of Council of Scientific and Industrial Research (CSIR): India’s largest R&D organisation with top twenty international public funded universities and institutes from eight different countries. Methodology/Principal Findings The methodology include quantitative and qualitative assessment based on the bibliometric parameters and manual technology categorisation to understand the changing patent trends and recent novel technologies. The research finding analysed 25,254 patent documents from the year 1993 to 2013 and reported the insights of latest anticancer technologies and targets through categorisation studies at the level of drug discovery, development and treatment & diagnosis. The article has reported the technology correlation matrix of twelve secondary class technologies with 34 tertiary sub-class research area to identify the leading technologies and scope of future research through whitespaces analysis. In addition, the results have also addressed the target analysis, leading inventor, assignee, collaboration network, geographical distribution, patent trend analysis, citation maps and technology assessment with respect to international patent classification systems such as CPC, IPC and CPI codes. Conclusions/Significance The result suggested peptide technology as the dominating research area next to gene therapy, vaccine and medical preparation containing organic compounds. The Indian CSIR has ranked itself at seventh position among the top 20 universities. Globally, the anticancer research was focused in the area of genetics and immunology, whereas Indian CSIR reported more patents related to plant extract and organic preparation. The article provided a glimpse of two decade anticancer scenario

Cube-shaped theranostic paclitaxel prodrug nanocrystals with surface functionalization of SPC and MPEG-DSPE for imaging and chemotherapy.

PubMed

Guo, Fuqiang; Shang, Jiajia; Zhao, Hai; Lai, Kangrong; Li, Yang; Fan, Zhongxiong; Hou, Zhenqing; Su, Guanghao

2017-12-01

As one of nanomedicine delivery systems (NDSs), drug nanocrystals exhibited an excellent anticancer effect. Recently, differences of internalization mechanisms and subcellular localization of both drug nanocrystals and small molecular free drug have drawn much attention. In this paper, paclitaxel (PTX) as a model anticancer drug was directly labeled with 4-chloro-7-nitro-1, 2, 3-benzoxadiazole (NBD-Cl) (a drug-fluorophore conjugate Ma et al. (2016) and Wang et al. (2016) [1,2] (PTX-NBD)). PTX-NBD was synthesized by nucleophilic substitution reaction of PTX with NBD-Cl in high yield and characterized by fluorescence, XRD, ESI-MS, and FT-IR analysis. Subsequently, the cube-shaped PTX-NBD nanocrystals were prepared with an antisolvent method followed by surface functionalization of SPC and MPEG-DSPE. The obtained specific shaped PTX-NBD@PC-PEG NCs had a hydrodynamic particle size of ∼50nm, excellent colloidal stability, and a high drug-loading content of ∼64%. Moreover, in comparison with free PTX-NBD and the sphere-shaped PTX-NBD nanocrystals with surface functionalization of SPC and MPEG-DSPE (PTX-NBD@PC-PEG NSs), PTX-NBD@PC-PEG NCs remarkably reduced burst release and improved cellular uptake efficiency and in vitro cancer cell killing ability. In a word, the work highlights the potential of theranostic prodrug nanocrystals based on the drug-fluorophore conjugates for cell imaging and chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Preparation, characterization and in vitro evaluation of a new nucleotide analogue prodrug cyclodextrin inclusion complexes.

PubMed

Diab, Roudayna; Jordheim, Lars P; Degobert, Ghania; Peyrottes, Suzanne; Périgaud, Christian; Dumontet, Charles; Fessi, Hatem

2009-01-01

Bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosophate is a new cytotoxic mononucleotide prodrug which have been developed to reverse the cellular resistance to nucleoside analogues. Unfortunately, its in vivo utilisation was hampered by its poor water solubility, raising the need of a molecular vector capable to mask its physicochemical characteristics although without affecting its cytotoxic activity. Hydroxypropyl-beta-cyclodextrin was used to prepare the prodrug inclusion complexes, allowing it to be solubilized in water and hence to be used for in vitro and in vivo experiments. A molar ratio of the cyclodextrin: prodrug of 3 was sufficient to obtain complete solubilization of the prodrug. The inclusion complex was characterized by differential scanning calorimetry, which revealed the disappearance of the melting peak of the prodrug suggesting the formation of inclusion complex. Proton Nuclear Magnetic Resonance spectroscopy provided a definitive proof of the inclusion complex formation, which was evidenced by the large chemical shift displacements observed for protons located in the interior of the hydrophobic cyclodextrin cavity. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells. These results provided a basis for potential therapeutic applications of co-formulation of this new nucleotide analogue with hydroxypropyl-beta-CD in cancer therapy.

Beta-lactams and their potential use as novel anticancer chemotherapeutics drugs.

PubMed

Kuhn, Deborah; Coates, Cristina; Daniel, Kenyon; Chen, Di; Bhuiyan, Mohammad; Kazi, Aslamuzzaman; Turos, Edward; Dou, Q Ping

2004-09-01

The discovery of natural and synthetic antibiotics is one of the most important medical breakthroughs in human history. Many diseases, such as bacterial meningitis, pneumonia, and septicemia, are now curable with the use of antibiotics. Antibiotics are efficacious, generally well tolerated in patients, and have a low toxicity level. It is for these reasons antibiotics remain an attractive target for drug discovery. Traditional beta-lactam antibiotics (e.g. penicillins, penems, cephalosporins) have a bicyclic ring structure that is conformationally rigid and functions to inhibit bacterial cell wall synthesis. In addition to the bactericidal action of antibiotics, it has been discovered that many antibiotics are capable of inhibiting tumor cell growth. There are currently many antitumor antibiotics approved for cancer therapy, which work to inhibit tumor cell growth by DNA intercalation. The use of beta-lactams as prodrugs has also met with success by aiding delivery of the chemotherapeutic directly to tumor sites. Recently, a novel class of N-thiolated monobactams, so termed because they possess a monocyclic ring instead of the bicyclic ring, has been found to induce apoptosis potently and specifically in many tumor cell lines but not in normal, non-transformed cell lines. Other beta-lactams, such as the polyaromatics, have been found to slow or inhibit tumor cell growth, and the 4-alkylidene beta-lactams are capable of inhibiting matrix metalloproteinases and leukocyte elactase activity. These data indicate that synthesis and evaluation of beta-lactams are a promising area for further development in anticancer research.

Targeting the membrane-anchored serine protease testisin with a novel engineered anthrax toxin prodrug to kill tumor cells and reduce tumor burden

PubMed Central

Martin, Erik W.; Buzza, Marguerite S.; Driesbaugh, Kathryn H.; Liu, Shihui; Fortenberry, Yolanda M.; Leppla, Stephen H.; Antalis, Toni M.

2015-01-01

The membrane-anchored serine proteases are a unique group of trypsin-like serine proteases that are tethered to the cell surface via transmembrane domains or glycosyl-phosphatidylinositol-anchors. Overexpressed in tumors, with pro-tumorigenic properties, they are attractive targets for protease-activated prodrug-like anti-tumor therapies. Here, we sought to engineer anthrax toxin protective antigen (PrAg), which is proteolytically activated on the cell surface by the proprotein convertase furin to instead be activated by tumor cell-expressed membrane-anchored serine proteases to function as a tumoricidal agent. PrAg's native activation sequence was mutated to a sequence derived from protein C inhibitor (PCI) that can be cleaved by membrane-anchored serine proteases, to generate the mutant protein PrAg-PCIS. PrAg-PCIS was resistant to furin cleavage in vitro, yet cytotoxic to multiple human tumor cell lines when combined with FP59, a chimeric anthrax toxin lethal factor-Pseudomonas exotoxin fusion protein. Molecular analyses showed that PrAg-PCIS can be cleaved in vitro by several serine proteases including the membrane-anchored serine protease testisin, and mediates increased killing of testisin-expressing tumor cells. Treatment with PrAg-PCIS also potently attenuated the growth of testisin-expressing xenograft tumors in mice. The data indicates PrAg can be engineered to target tumor cell-expressed membrane-anchored serine proteases to function as a potent tumoricidal agent. PMID:26392335

Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs

PubMed Central

Fouladi, Farnaz; Steffen, Kristine J.; Mallik, Sanku

2017-01-01

Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while, the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site. In this review, we mainly focus on the liposomes that are responsive to pathologically increased levels of enzymes at the target site. Enzyme-responsive liposomes release their cargo upon contact with the enzyme through several destabilization mechanisms: a) structural perturbation in the lipid bilayer, b) removal of a shielding polymer from the surface and increased cellular uptake, c) cleavage of a lipopeptide or lipopolymer incorporated in the bilayer, and d) activation of a prodrug in the liposomes. PMID:28201868

Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs.

PubMed

Fouladi, Farnaz; Steffen, Kristine J; Mallik, Sanku

2017-04-19

Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site. In this review, we mainly focus on the liposomes that are responsive to pathologically increased levels of enzymes at the target site. Enzyme-responsive liposomes release their cargo upon contact with the enzyme through several destabilization mechanisms: (1) structural perturbation in the lipid bilayer, (2) removal of a shielding polymer from the surface and increased cellular uptake, (3) cleavage of a lipopeptide or lipopolymer incorporated in the bilayer, and (4) activation of a prodrug in the liposomes.

A Comparative Evaluation of Hydroxycamptothecin Drug Nanorods With and Without Methotrexate Prodrug Functionalization for Drug Delivery

NASA Astrophysics Data System (ADS)

Guo, Fuqiang; Fan, Zhongxiong; Yang, Jinbin; Li, Yang; Wang, Yange; Zhao, Hai; Xie, Liya; Hou, Zhenqing

2016-08-01

We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells.

Phenethyl Isothiocyanate: A comprehensive review of anti-cancer mechanisms

PubMed Central

Gupta, Parul; Wright, Stephen E.; Kim, Sung-Hoon; Srivastava, Sanjay K.

2014-01-01

The epidemiological evidence suggests a strong inverse relationship between dietary intake of cruciferous vegetables and the incidence of cancer. Among other constituents of cruciferous vegetables, isothiocyanates (ITC) are the main bioactive chemicals present. Phenethyl isothiocyanate (PEITC) is present as gluconasturtiin in many cruciferous vegetables with remarkable anti-cancer effects. PEITC is known to not only prevent the initiation phase of carcinogenesis process but also to inhibit the progression of tumorigenesis. PEITC targets multiple proteins to suppress various cancer-promoting mechanisms such as cell proliferation, progression and metastasis. Pre-clinical evidence suggests that combination of PEITC with conventional anti-cancer agents is also highly effective in improving overall efficacy. Based on accumulating evidence, PEITC appears to be a promising agent for cancer therapy and is already under clinical trials for leukemia and lung cancer. This is the first review which provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of PEITC as a future anti-cancer agent. PMID:25152445

Implications of protein- and Peptide-based nanoparticles as potential vehicles for anticancer drugs.

PubMed

Elzoghby, Ahmed O; Elgohary, Mayada M; Kamel, Nayra M

2015-01-01

Protein-based nanocarriers have gained considerable attention as colloidal carrier systems for the delivery of anticancer drugs. Protein nanocarriers possess various advantages including their low cytotoxicity, abundant renewable sources, high drug-binding capacity, and significant uptake into the targeted tumor cells. Moreover, the unique protein structure offers the possibility of site-specific drug conjugation and tumor targeting using various ligands modifying the surface of protein nanocarriers. In this chapter, we highlight the most important applications of protein nanoparticles (NPs) for the delivery of anticancer drugs. We examine the various techniques that have been utilized for the preparation of anticancer drug-loaded protein NPs. Finally, the current chapter also reviews the major outcomes of the in vitro and in vivo investigations of surface-modified tumor-targeted protein NPs. © 2015 Elsevier Inc. All rights reserved.

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives.

PubMed

Scomparin, Anna; Florindo, Helena F; Tiram, Galia; Ferguson, Elaine L; Satchi-Fainaro, Ronit

2017-09-01

Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination. Copyright © 2017 Elsevier B.V. All rights reserved.

Metal complexes of curcumin for cellular imaging, targeting, and photoinduced anticancer activity.

PubMed

Banerjee, Samya; Chakravarty, Akhil R

2015-07-21

damaging the cancer cells on photoactivation in visible light while being minimally toxic in darkness. In this Account, we have made an attempt to review the current status of the chemistry of metal curcumin complexes and present results from our recent studies on curcumin complexes showing remarkable in vitro photocytotoxicity. The undesirable dark toxicity of the complexes can be reduced with suitable choice of the metal and the ancillary ligands in a ternary structure. The complexes can be directed to specific subcellular organelles. Selectivity by targeting cancer cells over normal cells can be achieved with suitable ligand design. We expect that this methodology is likely to provide an impetus toward developing curcumin-based photochemotherapeutics for anticancer treatment and cure.

Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity?

PubMed

Shah, Rashmi R

2017-03-01

Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy.

Investigation of mitigating effect of colon-specific prodrugs of boswellic acid on 2,4,6-trinitrobenzene sulfonic acid-induced colitis in Wistar rats: Design, kinetics and biological evaluation

PubMed Central

Sarkate, Ajinkya; Dhaneshwar, Suneela S

2017-01-01

AIM To develop a colon-targeting bioreversible delivery system for β-boswellic acid (BBA) and explore utility of its prodrugs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. METHODS Synthesis of 4 co-drugs of BBA with essential amino acids was achieved by CDI coupling, followed by their spectral characterization. In vitro kinetics were studied by HPLC in aqueous buffers, homogenates of gastrointestinal tract and fecal matter. In vivo kinetic studies were performed in Wistar rat plasma, urine and feces. The prodrugs were screened in TNBS-induced colitis modeled Wistar rats. Statistical significance was assumed at P < 0.05, P < 0.01, P < 0.001 when compared with disease controls using one-way and two-way ANOVAs. RESULTS Prodrugs were stable in 0.05 mol/L HCl buffer (pH 1.2) and stomach homogenates. Negligible hydrolysis was observed in phosphate buffer and intestinal homogenates. Substantial release (55%-72% and 68%-86%) of BBA was achieved in rat fecal matter and homogenates of colon. In vivo studies of BBA with L-tryptophan (BT) authenticated colon-specific release of BBA. But, surprisingly substantial concentration of BBA was seen to reach the systemic circulation due to probable absorption through colonic mucosa. Site-specifically enhanced bioavailability of BBA could be achieved in colon, which resulted in demonstration of significant mitigating effect on TNBS-induced colitis in rats without inducing any adverse effects on stomach, liver and pancreas. Prodrug of BT was found to be 1.7% (P < 0.001) superior than sulfasalazine in reducing the inflammation to colon among all prodrugs tested. CONCLUSION The outcome of this study strongly suggests that these prodrugs might have dual applicability to inflammatory bowel disease and chronotherapy of rheumatoid arthritis. PMID:28275295

Targeting of small molecule anticancer drugs to the tumour and its vasculature using cationic liposomes: lessons from gene therapy

PubMed Central

Dass, Crispin R; Choong, Peter FM

2006-01-01

Cationic (positively charged) liposomes have been tested in various gene therapy clinical trials for neoplastic and other diseases. They have demonstrated selectivity for tumour vascular endothelial cells raising hopes for both antiangiogenic and antivascular therapies. They are also capable of being selectively delivered to the lungs and liver when administered intravenously. These vesicles are being targeted to the tumour in various parts of the body by using advanced liposomal systems such as ligand-receptor and antibody-antigen combinations. At present, the transferrin receptor is commonly used for cancer-targeted drug delivery systems including cationic liposomes. This review looks at the growing utility of these vesicles for delivery of small molecule anticancer drugs. PMID:16792817

Nanomedicines based drug delivery systems for anti-cancer targeting and treatment.

PubMed

Jain, Vikas; Jain, Shikha; Mahajan, S C

2015-01-01

Cancer is defined as an uncontrolled growth of abnormal cells. Current treatment strategies for cancer include combination of radiation, chemotherapy and surgery. The long-term use of conventional drug delivery systems for cancer chemotherapy leads to fatal damage of normal proliferate cells and this is particularly used for the management of solid tumors, where utmost tumor cells are not invaded quickly. A targeted drug delivery system (TDDS) is a system, which releases the drug at a preselected biosite in a controlled manner. Nanotechnology based delivery systems are making a significant impact on cancer treatment and the polymers play key role in the development of nanopraticlulate carriers for cancer therapy. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) include prolonged half-life, improved bio-distribution, increased circulation time of the drug, controlled and sustained release of the drug, versatility of route of administration, increased intercellular concentration of drug and many more. This review covers the current research on polymer based anticancer agents, the rationale for development of these polymer therapeutical systems and discusses the benefits and challenges of cancer nanomedicines including polymer-drug conjugates, micelles, dendrimers, immunoconjugates, liposomes, nanoparticles.

Nanovectors for anticancer agents based on superparamagnetic iron oxide nanoparticles

PubMed Central

Douziech-Eyrolles, Laurence; Marchais, Hervé; Hervé, Katel; Munnier, Emilie; Soucé, Martin; Linassier, Claude; Dubois, Pierre; Chourpa, Igor

2007-01-01

During the last decade, the application of nanotechnologies for anticancer drug delivery has been extensively explored, hoping to improve the efficacy and to reduce side effects of chemotherapy. The present review is dedicated to a certain kind of anticancer drug nanovectors developed to target tumors with the help of an external magnetic field. More particularly, this work treats anticancer drug nanoformulations based on superparamagnetic iron oxide nanoparticles coated with biocompatible polymers. The major purpose is to focus on the specific requirements and technological difficulties related to controlled delivery of antitumoral agents. We attempt to state the problem and its possible perspectives by considering the three major constituents of the magnetic therapeutic vectors: iron oxide nanoparticles, polymeric coating and anticancer drug. PMID:18203422

Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrug of 5-aminosalicylic acid with D-phenylalanine for colon specific drug delivery in inflammatory bowel disease.

PubMed

Dhaneshwar, Suneela S; Gairola, Neha; Kandpal, Mini; Bhatt, Lokesh; Vadnerkar, Gaurav; Kadam, S S

2007-04-01

Mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine was synthesized by coupling D-phenylalanine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) only 15% release was observed over a period of 7h. In rat fecal matter the release of 5-aminosalicylic acid was almost complete (85%), with a half-life of 160.1 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-aminosalicylic acid.

Hydrazone linked doxorubicin-PLA prodrug nanoparticles with high drug loading

NASA Astrophysics Data System (ADS)

Gatti, Simone; Agostini, Azzurra; Capasso Palmiero, Umberto; Colombo, Claudio; Peviani, Marco; Biffi, Alessandra; Moscatelli, Davide

2018-07-01

An optimal drug delivery system should be characterized by biocompatibility, biodegradability, high drug loading and favorable drug release profile. To achieve this goal a hydrazone linked doxorubicin-poly(lactic acid) prodrug (PLA-DOX) was synthesized by the functionalization of a short polymer chain produced by ring opening polymerization. The hydrophobic prodrug generated in this way was nanoprecipitated using a block copolymer to form polymeric nanoparticles (NPs) with a quantitative loading efficiency and a high and tunable drug loading. The effects of the concentration of the PLA-DOX prodrug and surfactant were studied by dynamic light scattering showing a range of NP size between 50 and 90 nm and monodispersed size distributions with polydispersity indexes lower then 0.27 up to a maximum DOX concentration of 27% w/w. The release profile of DOX from these NPs, tested at different pH conditions, showed a higher release rate in acidic conditions, consistent with the nature of the hydrazone bond which was used to conjugate the drug to the polymer. In vitro cytotoxicity studies performed on BV2 microglia-like cell line highlighted a specific cytotoxic effect of these NPs suggesting the maintenance of the drug efficacy and a modified release profile upon encapsulation of DOX in the NPs.

A Synthetic MUC1 Anticancer Vaccine Containing Mannose Ligands for Targeting Macrophages and Dendritic Cells.

PubMed

Glaffig, Markus; Stergiou, Natascha; Hartmann, Sebastian; Schmitt, Edgar; Kunz, Horst

2018-01-08

A MUC1 anticancer vaccine equipped with covalently linked divalent mannose ligands was found to improve the antigen uptake and presentation by targeting mannose-receptor-positive macrophages and dendritic cells. It induced much stronger specific IgG immune responses in mice than the non-mannosylated reference vaccine. Mannose coupling also led to increased numbers of macrophages, dendritic cells, and CD4 + T cells in the local lymph organs. Comparison of di- and tetravalent mannose ligands revealed an increased binding of the tetravalent version, suggesting that higher valency improves binding to the mannose receptor. The mannose-coupled vaccine and the non-mannosylated reference vaccine induced IgG antibodies that exhibited similar binding to human breast tumor cells. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria.

PubMed

Frueh, Lisa; Li, Yuexin; Mather, Michael W; Li, Qigui; Pou, Sovitj; Nilsen, Aaron; Winter, Rolf W; Forquer, Isaac P; Pershing, April M; Xie, Lisa H; Smilkstein, Martin J; Caridha, Diana; Koop, Dennis R; Campbell, Robert F; Sciotti, Richard J; Kreishman-Deitrick, Mara; Kelly, Jane X; Vesely, Brian; Vaidya, Akhil B; Riscoe, Michael K

2017-10-13

ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multidose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 h before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.

Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan.

PubMed

Kawabata-Shoda, E; Masuda, S; Kimura, H

2012-10-01

Concern about the drug lag, the delay in marketing approval between one country and another, for anticancer drugs has increased in Japan. Although a number of studies have investigated the drug lag, none has investigated it in relation to the transition of anticancer therapy from traditional cytotoxic drugs to molecularly targeted agents. Our aim was to investigate current trend in oncology drug lag between the US and Japan and identify oncology drugs approved in only one of the two countries. Publicly and commercially available data sources were used to identify drugs approved in the US and Japan as of 31 December 2010 and the data used to calculate the drug lag for individual drugs. Fifty-one drugs were approved in both the US and Japan, whereas 34 and 19 drugs were approved only in the US or Japan, respectively. Of the 19 drugs approved only in Japan, 12 had not been subject to development for a cancer indication in the US, and all were approved before 1996 in Japan. Of the 34 drugs approved only in the US, 20 had not been subject to development in Japan, and none was in the top 25 by annual US anticancer drug-class sales. For drugs approved in both countries, the mean approval lag of the molecularly targeted drugs (MTDs) was significantly shorter than that of the non-molecularly targeted drugs (non-MTDs) (3·3 vs. 5·4 years). Further, mean R&D time of the MTDs was significantly shorter than that of non-MTDs (10·0 vs. 13·7 years). The price of MTDs had increased on average by 6·6% annually in the US, whereas it had decreased on average by 4·3% biyearly in Japan. The emergence of new molecularly targeted agents has contributed to reducing the approval lag, most likely due to improvements in R&D strategy. © 2012 Blackwell Publishing Ltd.

Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation.

PubMed

Gaudana, Ripal; Parenky, Ashwin; Vaishya, Ravi; Samanta, Swapan K; Mitra, Ashim K

2011-01-01

The objective of this study was to develop and characterize a nanoparticulate-based sustained release formulation of a water soluble dipeptide prodrug of dexamethasone, valine-valine-dexamethasone (VVD). Being hydrophilic in nature, it readily leaches out in the external aqueous medium and hence partitions poorly into the polymeric matrix resulting in minimal entrapment in nanoparticles. Hence, hydrophobic ion pairing (HIP) complexation of the prodrug was employed with dextran sulphate as a complexing polymer. A novel, solid in oil in water emulsion method was employed to encapsulate the prodrug in HIP complex form in poly(lactic-co-glycolic acid) matrix. Nanoparticles were characterized with respect to size, zeta potential, crystallinity of entrapped drug and surface morphology. A significant enhancement in the entrapment of the prodrug in nanoparticles was achieved. Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins.

Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation

PubMed Central

Gaudana, Ripal; Parenky, Ashwin; Vaishya, Ravi; Samanta, Swapan K.; Mitra, Ashim K.

2015-01-01

The objective of this study was to develop and characterize a nanoparticulate-based sustained release formulation of a water soluble dipeptide prodrug of dexamethasone, valine–valine-dexamethasone (VVD). Being hydrophilic in nature, it readily leaches out in the external aqueous medium and hence partitions poorly into the polymeric matrix resulting in minimal entrapment in nanoparticles. Hence, hydrophobic ion pairing (HIP) complexation of the prodrug was employed with dextran sulphate as a complexing polymer. A novel, solid in oil in water emulsion method was employed to encapsulate the prodrug in HIP complex form in poly(lactic-co-glycolic acid) matrix. Nanoparticles were characterized with respect to size, zeta potential, crystallinity of entrapped drug and surface morphology. A significant enhancement in the entrapment of the prodrug in nanoparticles was achieved. Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins. PMID:20939702

Nitric oxide: cancer target or anticancer agent?

PubMed

Mocellin, Simone

2009-03-01

Despite the improved understanding of nitric oxide (NO) biology and the large amount of preclinical experiments testing its role in cancer development and progression, it is still debated whether NO should be considered a potential anticancer agent or instead a carcinogen. The complexity of NO effects within a cell and the variability of the final biological outcome depending upon NO levels makes it highly challenging to determine the therapeutic value of interfering with the activity of this intriguing gaseous messenger. This uncertainty has so far halted the clinical implementation of NO-based therapeutics in the field of oncology. Accordingly, only an in depth knowledge of the mechanisms leading to experimental tumor regression or progression in response to NO will allow us to exploit this molecule to fight cancer.

The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways.

PubMed

Rengarajan, Thamaraiselvan; Yaacob, Nik Soriani

2016-10-15

Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

PubMed

Ge, Yanxiu; Ma, Yakun; Li, Lingbing

2016-10-01

Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. Copyright © 2016 Elsevier B.V. All rights reserved.

Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers.

PubMed

Giuffrida, Maria Chiara; Pignatello, Rosario; Castelli, Francesco; Sarpietro, Maria Grazia

2017-09-01

Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied. Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length. Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier. © 2017 Royal Pharmaceutical Society.

Comparative plasma disposition kinetics of albendazole and its new benzimidazol prodrug in dog.

PubMed

Khalil, Z; El Karbane, M; Faouzi, M E A; Ansar, M; Azougagh, M; El Harti, J; Taoufik, J

2016-01-01

The comparative pharmacokinetic behavior of albendazole (ABZ) and its new benzimidazol prodrug [1-tert-butyloxycarbonyl-5-propylthio-1-H-benzimidazol-2ylcarbamate of methyl] (ABZBoc), following their oral administration (10mg/kg) to healthy dogs was explored. Blood samples were obtained serially over a 24h period after treatment, then the plasma was analyzed by high-performance liquid chromatography (HPLC) to search the albendazole metabolites (ABZSO and ABZSO2). However, the albendazole parent drug was not detectable at any time after both treatments (ABZ and ABZBoc). By albendazole metabolites (ABZSO and ABZSO2) were the analytes recovered in the plasma after oral administration of ABZ and ABZBoc. Furthermore, some amounts of ABZBoc were also available in the plasma samples treated with this new produg. The plasma profile of each analyte followed a similar pattern after both treatments, the active metabolite (ABZSO) was the major analyte recovered in plasma (between 1 and 24h post-treatment). The pharmacokinetic parameters of both groups were calculated (Cmax, Tmax, t1/2, AUC0-›∞), and analyzed using the Student's t-test, P<0.05. Thus,the pharmacokinetic analysis indicated four statistically significant changes in the pharmacokinetic parameters defined above of the albendazole metabolites (ABZSO, ABZSO2) between the group treated with albendazole (group A) and that treated with ABZBoc prodrug (group B). Hence, the levels of the various pharmacokinetics parameters were low in the group treated with prodrug, as well they did not reach equivalent concentrations to that of albendazole. These differences between albendazole and its new prodrug may be explained by the fact that ABZBoc prodrug was not effectively reduced in the intestine of dogs. Copyright © 2015 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Anticancer Agents: Does a Phosphonium Behave Like a Gold(I) Phosphine Complex? Let a "Smart" Probe Answer!

PubMed

Ali, Moussa; Dondaine, Lucile; Adolle, Anais; Sampaio, Carla; Chotard, Florian; Richard, Philippe; Denat, Franck; Bettaieb, Ali; Le Gendre, Pierre; Laurens, Véronique; Goze, Christine; Paul, Catherine; Bodio, Ewen

2015-06-11

Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations.

Anticancer activity of metal complexes: involvement of redox processes.

PubMed

Jungwirth, Ute; Kowol, Christian R; Keppler, Bernhard K; Hartinger, Christian G; Berger, Walter; Heffeter, Petra

2011-08-15

Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of "activation by reduction" as well as the "hard and soft acids and bases" theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology.

Anticancer Activity of Metal Complexes: Involvement of Redox Processes

PubMed Central

Jungwirth, Ute; Kowol, Christian R.; Keppler, Bernhard K.; Hartinger, Christian G.; Berger, Walter; Heffeter, Petra

2012-01-01

Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of “activation by reduction” as well as the “hard and soft acids and bases” theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology. PMID:21275772

Pharmacokinetics of amino acid ester prodrugs of Acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

PubMed Central

Katragadda, Suresh; Jain, Ritesh; Kwatra, Deep; Hariharan, Sudharshan; Mitra, Ashim K.

2008-01-01

In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-Alanine-ACV (AACV), L-Serine-ACV (SACV), L-Isoleucine-ACV (IACV), γ-Glutamate-ACV (EACV) and L-Valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied. In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (λz). SACV and VACV exhibited approximately five fold increase in area under the curve (AUC) values relative to ACV (p<0.05). Cmax(T) (maximum concentration) of SACV was observed to be 39 ± 22 µM in plasma which is 2 times better than VACV and 15 times better than ACV. Clast(T) (concentration at the last time point) of SACV was observed to be 0.18 ± 0.06 µM in plasma which is 2 times better than VACV and 3 times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (Cmax) and eliminated at varying rates (λz) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections. PMID:18638532

Hyaluronic acid for anticancer drug and nucleic acid delivery.

PubMed

Dosio, Franco; Arpicco, Silvia; Stella, Barbara; Fattal, Elias

2016-02-01

Hyaluronic acid (HA) is widely used in anticancer drug delivery, since it is biocompatible, biodegradable, non-toxic, and non-immunogenic; moreover, HA receptors are overexpressed on many tumor cells. Exploiting this ligand-receptor interaction, the use of HA is now a rapidly-growing platform for targeting CD44-overexpressing cells, to improve anticancer therapies. The rationale underlying approaches, chemical strategies, and recent advances in the use of HA to design drug carriers for delivering anticancer agents, are reviewed. Comprehensive descriptions are given of HA-based drug conjugates, particulate carriers (micelles, liposomes, nanoparticles, microparticles), inorganic nanostructures, and hydrogels, with particular emphasis on reports of preclinical/clinical results. Copyright © 2015 Elsevier B.V. All rights reserved.

Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

PubMed

Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

2016-05-26

The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery.

Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance.

PubMed

Lanzi, Cinzia; Zaffaroni, Nadia; Cassinelli, Giuliana

2017-01-01

Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting both tumor cell growth and the supportive boost provided by the microenvironment. Moreover, accumulating evidence supports that an altered expression or function of HSPGs, or of the complex enzyme system regulating their activities, can also depress the tumor response to anticancer treatments in several tumor types. Thereby, targeting HSPGs or HSPG modifying enzymes appears an appealing approach to enhance chemotherapy efficacy. A great deal of effort from academia and industry has led to the development of agents mimicking HS, and/or inhibiting HSPG modifying enzymes. Inhibitors of Sulf-2, an endosulfatase that edits the HS sulfation pattern, and inhibitors of heparanase, the endoglycosidase that produces functional HS fragments, appear particularly promising. In fact, a Sulf-2 inhibitor (OKN-007), and two heparanase inhibitors/HS mimics (roneparstat, PG545) are currently under early clinical investigation. In this review, we summarized preclinical studies in experimental tumor models of the main chemical classes of Sulf-2 and heparanase inhibitors. We described examples of different mechanisms through which heparanase and HSPGs, often in cooperation, may impact tumor sensitivity to various antitumor agents. Finally, we reported a few preclinical studies showing increased antitumor efficacy obtained with the use of candidate clinical HS mimics in combination regimens. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nano-Chitosan Particles in Anticancer Drug Delivery: An Up-to-Date Review.

PubMed

Kamath, Pooja R; Sunil, Dhanya

2017-01-01

Cancer is one of the most awful lethal diseases all over the world and the success of its current chemotherapeutic treatment strategies is limited due to several associated drawbacks. The exploration of cancer cell physiology and its microenvironment has exposed the potential of various classes of nanocarriers to deliver anticancer chemotherapeutic agents at the tumor target site. These nanocarriers must evade the immune surveillance system and achieve target selectivity. Besides, they must gain access into the interior of cancerous cells, evade endosomal entrapment and discharge the drugs in a sustained manner. Chitosan, the second naturally abundant polysaccharide is a biocompatible, biodegradable and mucoadhesive cationic polymer which has been exploited extensively in the last few years in the effective delivery of anticancer chemotherapeutics to the target tumor cells. Therapeutic agent-loaded surface modified chitosan nanoparticles are established to be more stable, permeable and bioactive. This review will provide an up-to-date evidence-based background on recent pharmaceutical advancements in the transformation of chitosan nanoparticles for smart anticancer therapeutic drug delivery. • Efforts to improve cancer chemotherapy by exploiting the intrinsic differences between normal and neoplastic cells to achieve maximum effective drug delivery to target cancer cells through bioengineered chitosan nano delivery vectors are discussed. • The easy manipulation of surface characteristics of chitosan based nanoparticles by various functionalization methods to achieve targeted drug delivery proves its potential to be an essential tool for the advancement of anticancer drug-delivery vectors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Influence of Glutathione and Glutathione S-transferases on DNA Interstrand Cross-Link Formation by 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the Active Anticancer Moiety Generated by Laromustine

PubMed Central

2015-01-01

Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short-lived (t1/2 ∼ 30 s) chloroethylating agent that can generate high yields of oxophilic electrophiles responsible for the chloroethylation of the O-6 position of guanine in DNA. These guanine O-6 alkylations are believed to be responsible for the therapeutic effects of 90CE and its prodrugs. Thus, 90CE demonstrates high selectivity toward tumors with diminished levels of O6-alkylguanine-DNA alkyltransferase (MGMT), the resistance protein responsible for O6-alkylguanine repair. The formation of O6-(2-chloroethyl)guanine lesions ultimately leads to the generation of highly cytotoxic 1-(N3-cytosinyl),-2-(N1-guaninyl)ethane DNA interstrand cross-links via N1,O6-ethanoguanine intermediates. The anticancer activity arising from this sequence of reactions is thus identical to this component of the anticancer activity of the clinically used chloroethylnitrosoureas. Herein, we evaluate the ability of glutathione (GSH) and other low molecular weight thiols, as well as GSH coupled with various glutathione S-transferase enzymes (GSTs) to attenuate the final yields of cross-links generated by 90CE when added prior to or immediately following the initial chloroethylation step to determine the major point(s) of interaction. In contrast to studies utilizing BCNU as a chloroethylating agent by others, GSH (or GSH/GST) did not appreciably quench DNA interstrand cross-link precursors. While thiols alone offered little protection at either alkylation step, the GSH/GST couple was able to diminish the initial yields of cross-link precursors. 90CE exhibited a very different GST isoenzyme susceptibility to that reported for BCNU, this could have important implications in the relative resistance of tumor cells to these agents. The protection afforded by GSH/GST was compared to that produced by MGMT. PMID:25012050

Influence of glutathione and glutathione S-transferases on DNA interstrand cross-link formation by 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine, the active anticancer moiety generated by laromustine.

PubMed

Penketh, Philip G; Patridge, Eric; Shyam, Krishnamurthy; Baumann, Raymond P; Zhu, Rui; Ishiguro, Kimiko; Sartorelli, Alan C

2014-08-18

Prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) are promising anticancer agents. The 90CE moiety is a readily latentiated, short-lived (t1/2 ∼ 30 s) chloroethylating agent that can generate high yields of oxophilic electrophiles responsible for the chloroethylation of the O-6 position of guanine in DNA. These guanine O-6 alkylations are believed to be responsible for the therapeutic effects of 90CE and its prodrugs. Thus, 90CE demonstrates high selectivity toward tumors with diminished levels of O(6)-alkylguanine-DNA alkyltransferase (MGMT), the resistance protein responsible for O(6)-alkylguanine repair. The formation of O(6)-(2-chloroethyl)guanine lesions ultimately leads to the generation of highly cytotoxic 1-(N(3)-cytosinyl),-2-(N(1)-guaninyl)ethane DNA interstrand cross-links via N(1),O(6)-ethanoguanine intermediates. The anticancer activity arising from this sequence of reactions is thus identical to this component of the anticancer activity of the clinically used chloroethylnitrosoureas. Herein, we evaluate the ability of glutathione (GSH) and other low molecular weight thiols, as well as GSH coupled with various glutathione S-transferase enzymes (GSTs) to attenuate the final yields of cross-links generated by 90CE when added prior to or immediately following the initial chloroethylation step to determine the major point(s) of interaction. In contrast to studies utilizing BCNU as a chloroethylating agent by others, GSH (or GSH/GST) did not appreciably quench DNA interstrand cross-link precursors. While thiols alone offered little protection at either alkylation step, the GSH/GST couple was able to diminish the initial yields of cross-link precursors. 90CE exhibited a very different GST isoenzyme susceptibility to that reported for BCNU, this could have important implications in the relative resistance of tumor cells to these agents. The protection afforded by GSH/GST was compared to that produced by MGMT.

The curcumin analog EF24 targets NF-κB and miRNA-21, and has potent anticancer activity in vitro and in vivo.

PubMed

Yang, Chuan He; Yue, Junming; Sims, Michelle; Pfeffer, Lawrence M

2013-01-01

EF24 is a curcumin analog that has improved anticancer activity over curcumin, but its therapeutic potential and mechanism of action is unknown, which is important to address as curcumin targets multiple signaling pathways. EF24 inhibits the NF-κB but not the JAK-STAT signaling pathway in DU145 human prostate cancer cells and B16 murine melanoma cells. EF24 induces apoptosis in these cells apparently by inhibiting miR-21 expression, and also enhances the expression of several miR-21 target genes, PTEN and PDCD4. EF24 treatment significantly suppressed the growth of DU145 prostate cancer xenografts in immunocompromised mice and resulted in tumor regression. EF24 enhanced the expression of the miR-21 target PTEN in DU145 tumor tissue, but suppressed the expression of markers of proliferating cells (cyclin D1 and Ki67). In syngeneic mice injected with B16 cells, EF24 treatment inhibited the formation of lung metastasis, prolonged animal survival, inhibited miR-21 expression and increased the expression of miR-21 target genes. Expression profiling of miRNAs regulated by EF24 in vitro and in vivo showed that the antitumor activity of EF24 reflected the enhanced expression of potential tumor suppressor miRNAs as well as the suppressed expression of oncogenic miRNAs, including miR-21. Taken together, our data suggest that EF24 is a potent anticancer agent and selectively targets NF-κB signaling and miRNA expression, indicating that EF24 has significant potential as a therapeutic agent in various cancers.

N,N'-dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines.

PubMed

Reeh, Christiane; Wundt, Judith; Clement, Bernd

2007-12-27

N, N'-dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, and porcine hepatocytes. In vivo, the bioavailability of benzamidine after oral application of N, N'-dihydroxybenzamidine was about 91% and exceeded that of benzamidine after oral application of benzamidoxime, being about 74% (Liu, L.; Ling, Y.; Havel, C.; Bashnick, L.; Young, W.; Rai, R.; Vijaykumar, D.; Riggs, J. R.; Ton, T.; Shaghafi, M.; Graupe, D.; Mordenti, J.; Sukbuntherng, J. Species comparison of in vitro and in vivo conversion of five N-hydroxyamidine prodrugs of fVIIA inhibitors to their corresponding active amidines. Presented at the 13th North America ISSX Meeting, Maui, HI, 2005).

In vitro evaluation of dendrimer prodrugs for oral drug delivery.

PubMed

Najlah, Mohammad; Freeman, Sally; Attwood, David; D'Emanuele, Antony

2007-05-04

Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond. The stability of G0 prodrugs was evaluated in 80% human plasma and 50% rat liver homogenate. The cytotoxicity of conjugates towards Caco-2 cells was determined and the transport of the conjugates across Caco-2 monolayers (37 degrees C) was reported. In addition, one lauroyl chain (L) was attached to the surface group of G0 PAMAM dendrimer of the diethylene glycol ester conjugate (G0-deg-NAP) to enhance permeability. The lactic ester conjugate, G0-lact-NAP, hydrolyzed slowly in 80% human plasma and in 50% rat liver homogenate (t(1/2)=180 min). G0-deg-NAP was hydrolyzed more rapidly in 80% human plasma (t(1/2)=51 min) and was rapidly cleaved in 50% liver homogenate (t(1/2)=4.7 min). The conjugates were non-toxic when exposed to Caco-2 cells for 3h. Permeability studies showed a significant enhancement in the transport of naproxen when conjugated to dendrimers; L-G0-deg-NAP yielding the highest permeability. Dendrimer-based prodrugs with appropriate linkers have potential as carriers for the oral delivery of low solubility drugs such as naproxen.

Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone

PubMed Central

Daley-Yates, P. T.; Gregory, A. J.; Brooks, C. D.

1997-01-01

Aims The aim of this study was to establish whether pharmacokinetic differences between two pro-drugs of methylprednisolone (MP) are likely to be of clinical significance. Methods This study was a single-blind, randomized, crossover design comparing the bioequivalence of MP released from the pro-drugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) after a single 250 mg (MP equivalent) intramuscular injection to 20 healthy male volunteers. Bioequivalence was assessed by conventional pharmacokinetic analysis, by measuring pharmacodynamic responses plus a novel approach using pharmacokinetic/pharmacodynamic modeling. The main measure of pharmacodynamic response was whole blood histamine (WBH), a measure of basophil numbers. Results The MP Cmax was less for MP suleptanate due to a longer absorption half-life of the prodrug from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102–114%). For Cmax the MP suleptanate median was 81% of the MP succinate value (90% CI: 75–88%). The tmax for MP from MP suleptanate was delayed relative to MP succinate. The median difference was 200% (90% non-parametric CI: 141–283%). The area under the WBH effect-time curve (AUEC) and the maximum response (Emax ) were found to be equivalent (90% CI: 98–113% and 93–109% respectively). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid Emax model (EC50, Emax and γ) were also not significantly different between prodrugs. Conclusions MP suleptanate is an acceptable pharmaceutical alternative to MP succinate. The use of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacokinetic bioequivalence analysis. PMID:9205819

Reduction of in-source collision-induced dissociation and thermolysis of sulopenem prodrugs for quantitative liquid chromatography/electrospray ionization mass spectrometric analysis by promoting sodium adduct formation.

PubMed

Wujcik, Chad E; Kadar, Eugene P

2008-10-01

Six chromatographically resolved sulopenem prodrugs were monitored for their potential to undergo both in-source collision-induced dissociation (CID) and thermolysis. Initial Q1 scans for each prodrug revealed the formation of intense [Prodrug2 + H]+, [Prodrug2 + Na]+, [Prodrug + Na]+, and [Sulopenem + Na]+ ions. Non-adduct-associated sulopenem ([Sulopenem + H]+) along with several additional lower mass ions were also observed. Product ion scans of [Prodrug3 + Na]+ showed the retention of the sodium adduct in the collision cell continuing down to opening of the beta-lactam ring. In-source CID and temperature experiments were conducted under chromatographic conditions while monitoring several of the latter ion transitions (i.e., adducts, dimers and degradants/fragments) for a given prodrug. The resulting ion profiles indicated the regions of greatest stability for temperature and declustering potential (DP) that provided the highest signal intensity for each prodrug and minimized in-source degradation. The heightened stability of adduct ions, relative to their appropriate counterpart (i.e., dimer to dimer adduct and prodrug to prodrug adduct ions), was observed under elevated temperature and DP conditions. The addition of 100 microM sodium to the mobile phase further enhanced the formation of these more stable adduct ions, yielding an optimal [Prodrug + Na]+ ion signal at temperatures from 400 to 600 degrees C. A clinical liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay for sulopenem prodrug PF-04064900 in buffered whole blood was successfully validated using sodium-fortified mobile phase and the [PF-04064900 + Na]+ ion for quantitation. A conservative five-fold increase in sensitivity from previously validated preclinical assays using the [PF-04064900 + H]+ precursor ion was achieved.

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors.

PubMed

Guillen, Katrin P; Ruben, Eliza A; Virani, Needa; Harrison, Roger G

2017-02-01

Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme β-glucuronidase (βG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted βG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting. To create fusion proteins, human annexin A1/A5 was genetically fused to the activity-enhancing 16a3 mutant of human βG, expressed in chemically defined, fed-batch suspension culture, and chromatographically purified. All fusion constructs achieved >95% purity with yields up to 740 μg/l. Fusion proteins displayed cancer selective cell-surface binding with cell line-dependent binding stability. One fusion protein in combination with the prodrug SN-38 glucuronide was as effective as the drug SN-38 on Panc-1 pancreatic cancer cells and HAAE-1 endothelial cells, and demonstrated efficacy against MCF-7 breast cancer cells. βG fusion proteins effectively enable localized combination therapy that can be tailored to each patient via prodrug selection, with promising clinical potential based on their near fully human design. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines.

PubMed

Mocellin, Simone; Nitti, Donato

2008-05-01

Despite the evidence that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells evade immune surveillance in most cases. Considering that anticancer vaccination has reached a plateau of results and currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed at reverting the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted. In addition, the latest therapeutic strategies devised to overcome tumor immune escape are described, with special regard to those entering clinical phase investigation. Copyright (c) 2007 Wiley-Periodicals, Inc.

Anti-Cancer Phytometabolites Targeting Cancer Stem Cells

PubMed Central

Torquato, Heron F.V.; Goettert, Márcia I.; Justo, Giselle Z.; Paredes-Gamero, Edgar J.

2017-01-01

Medicinal plants are a plentiful source of bioactive molecules with much structural diversity. In cancer treatment, molecules obtained from plants represent an attractive alternative to other treatments because several plant-derived compounds have exhibited lower toxicity and higher selectivity against cancer cells. In this review, we focus on the possible application of bioactive molecules obtained from plants against more primitive cell populations in cancers, cancer stem cells. Cancer stem cells are present in several kinds of tumors and are responsible for recurrences and metastases. Common anti-cancer drugs exhibit lower effectiveness against cancer stem cells because of their biological features. However, recently discovered natural phytometabolites exert cytotoxic effects on this rare population of cells in cancers. Therefore, this review presents the latest research on promising compounds from plants that can act as antitumor drugs and that mainly affect stem cell populations in cancers. PMID:28367074

Effect of Simvastatin Prodrug on Experimental Periodontitis.

PubMed

Bradley, Aaron D; Zhang, Yijia; Jia, Zhenshan; Zhao, Gang; Wang, Xiaobei; Pranke, Laura; Schmid, Marian J; Wang, Dong; Reinhardt, Richard A

2016-05-01

Local application of statins has shown potential in preventing and regenerating bone loss associated with experimental periodontitis. This study evaluates the effect of a novel simvastatin (SIM) prodrug (capable of delivering high doses to periodontitis inflammatory lesion and cells) on experimental periodontitis bone loss and inflammation. Forty mature female Sprague Dawley rats were subjected to ligature-induced experimental periodontitis between maxillary first and second molars (M1-M2). Equal groups were treated with three weekly doses of: 1) prodrug carrier alone (mPEG); 2) 0.5 mg SIM dose equivalent in carrier (SIM/SIM-mPEG); 3) 1.0 mg SIM/SIM-mPEG; 4) 1.5 mg SIM/SIM-mPEG; or 5) ligature alone. Contralateral molars served as unmanipulated controls. Four weeks after initiation of periodontitis, animals were euthanized, the M1-M2 interproximal was evaluated with microcomputed tomography and histology, and data were analyzed with one-way analysis of variance. Ligature alone caused a mean bone loss of 1.01 ± 0.06 mm from the cemento-enamel junction, whereas all doses of SIM/SIM-mPEG reduced bone loss, especially 1.5 mg SIM/SIM-mPEG (0.68 ± 0.05 mm, P <0.001), which was not statistically different from contralateral control (0.47 ± 0.06 mm). A dose of 1.5 mg SIM/SIM-mPEG also reduced percentage of neutrophils compared with carrier alone (2.0% ± 1.0% versus 5.7% ± 1.1%; P <0.05), and increased amount of uninflamed connective tissue in the M1-M2 interproximal area (65.2% ± 3.3% versus 46.3% ± 3.3%; P <0.001). The mPEG carrier alone did not have bone-sparing or anti-inflammatory properties. Multiple local 1.5-mg doses of a macromolecular SIM prodrug decreases amount of experimental periodontitis bone loss and inflammation in rats.

Biotransformations of Antidiabetic Vanadium Prodrugs in Mammalian Cells and Cell Culture Media: A XANES Spectroscopic Study

PubMed Central

2016-01-01

The antidiabetic activities of vanadium(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with components of biological media. The first X-ray absorption spectroscopic study of the reactivity of typical vanadium (V) antidiabetics, vanadate ([VVO4]3–, A) and a vanadium(IV) bis(maltolato) complex (B), with mammalian cell cultures has been performed using HepG2 (human hepatoma), A549 (human lung carcinoma), and 3T3-L1 (mouse adipocytes and preadipocytes) cell lines, as well as the corresponding cell culture media. X-ray absorption near-edge structure data were analyzed using empirical correlations with a library of model vanadium(V), -(IV), and -(III) complexes. Both A and B ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate VV species (∼75% total V) in a cell culture medium within 24 h at 310 K. Speciation of V in intact HepG2 cells also changed with the incubation time (from ∼20% to ∼70% VIV of total V), but it was largely independent of the prodrug used (A or B) or of the predominant V oxidation state in the medium. Subcellular fractionation of A549 cells suggested that VV reduction to VIV occurred predominantly in the cytoplasm, while accumulation of VV in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear VV is likely to modulate the transcription process and to be ultimately related to cell death at high concentrations of V, which may be important in anticancer activities. Mature 3T3-L1 adipocytes (unlike for preadipocytes) showed a higher propensity to form VIV species, despite the prevalence of VV in the medium. The distinct V biochemistry in these cells is consistent with their crucial role in insulin-dependent glucose and fat metabolism and may also point to an endogenous role of V in adipocytes. PMID:25906315

Biotransformations of Antidiabetic Vanadium Prodrugs in Mammalian Cells and Cell Culture Media: A XANES Spectroscopic Study.

PubMed

Levina, Aviva; McLeod, Andrew I; Pulte, Anna; Aitken, Jade B; Lay, Peter A

2015-07-20

The antidiabetic activities of vanadium(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with components of biological media. The first X-ray absorption spectroscopic study of the reactivity of typical vanadium (V) antidiabetics, vanadate ([V(V)O4](3-), A) and a vanadium(IV) bis(maltolato) complex (B), with mammalian cell cultures has been performed using HepG2 (human hepatoma), A549 (human lung carcinoma), and 3T3-L1 (mouse adipocytes and preadipocytes) cell lines, as well as the corresponding cell culture media. X-ray absorption near-edge structure data were analyzed using empirical correlations with a library of model vanadium(V), -(IV), and -(III) complexes. Both A and B ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate V(V) species (∼75% total V) in a cell culture medium within 24 h at 310 K. Speciation of V in intact HepG2 cells also changed with the incubation time (from ∼20% to ∼70% V(IV) of total V), but it was largely independent of the prodrug used (A or B) or of the predominant V oxidation state in the medium. Subcellular fractionation of A549 cells suggested that V(V) reduction to V(IV) occurred predominantly in the cytoplasm, while accumulation of V(V) in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear V(V) is likely to modulate the transcription process and to be ultimately related to cell death at high concentrations of V, which may be important in anticancer activities. Mature 3T3-L1 adipocytes (unlike for preadipocytes) showed a higher propensity to form V(IV) species, despite the prevalence of V(V) in the medium. The distinct V biochemistry in these cells is consistent with their crucial role in insulin-dependent glucose and fat metabolism and may also point to an endogenous role of V in adipocytes.

Biotransformations of antidiabetic vanadium prodrugs in mammalian cells and cell culture media: A XANES spectroscopic study

DOE PAGES

Levina, Aviva; McLeod, Andrew I.; Pulte, Anna; ...

2015-04-23

The antidiabetic activities of vanadium(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with components of biological media. The first X-ray absorption spectroscopic study of the reactivity of typical vanadium (V) antidiabetics, vanadate ([V VO 4] 3–, A) and a vanadium(IV) bis(maltolato) complex (B), with mammalian cell cultures has been performed using HepG2 (human hepatoma), A549 (human lung carcinoma), and 3T3-L1 (mouse adipocytes and preadipocytes) cell lines, as well as the corresponding cell culture media. X-ray absorption near-edge structure data were analyzed using empirical correlations with a library of model vanadium(V), -(IV), and -(III)more » complexes. Both A and B ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate VV species (~75% total V) in a cell culture medium within 24 h at 310 K. Speciation of V in intact HepG2 cells also changed with the incubation time (from ~20% to ~70% V IV of total V), but it was largely independent of the prodrug used (A or B) or of the predominant V oxidation state in the medium. Subcellular fractionation of A549 cells suggested that V V reduction to V IV occurred predominantly in the cytoplasm, while accumulation of V V in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear V V is likely to modulate the transcription process and to be ultimately related to cell death at high concentrations of V, which may be important in anticancer activities. Mature 3T3-L1 adipocytes (unlike for preadipocytes) showed a higher propensity to form V IV species, despite the prevalence of V V in the medium. Lastly, the distinct V biochemistry in these cells is consistent with their crucial role in insulin-dependent glucose and fat metabolism and may also point to an endogenous role of V in adipocytes.« less

Development of novel small molecules for imaging and drug release

NASA Astrophysics Data System (ADS)

Cao, Yanting

Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the

Decoration of gold nanoparticles with thiolated pH-responsive polymeric (PEG-b-p(2-dimethylamio ethyl methacrylate-co-itaconic acid) shell: A novel platform for targeting of anticancer agent.

PubMed

Ghorbani, Marjan; Hamishehkar, Hamed

2017-12-01

The aim of this study was to design and develop a new pH-responsive nano-platform for controlled and targeted delivery of anticancer drugs. Engineering of pH-responsive nanocarriers was prepared via decoration of gold nanoparticles (NPs) by thiolated (methoxy-poly(ethylene glycol)-b-poly((2-dimethylamino) ethyl methacrylate-co-itaconic acid) (mPEG-b-p(DMAEMA-co-IA) copolymer and fully characterized by various techniques and subsequently used for loading and targeted delivery of anticancer agent, methotrexate (MTX). By conjugation of MTX with the amino groups of polymeric shell of gold NPs (with the high loading capacity of 31%), since MTX is also the target ligand of folate receptors, the targeted performance of NPs examined through the cell uptake study. The results indicated that MTX-loaded NPs showed 1.3 times more cell internalization than MTX free NPs. Cell cytotoxicity studies pointed out ~1.5 and 3 times higher cell cytotoxicity after 24h for MTX-loaded nanoparticles than MTX in MTT assay and cell cycle arrest experiments, respectively. Additionally, mPEG was used as the outer shell of NPs which caused the long-term dispersibility of the NPs even under high ionic strength. The in-vitro pH-triggered drug release of MTX showed that MTX released more than three times in simulated cancerous tissue (40°C, pH5.3) than physiologic condition (37°C, pH7.4) during 48h. The results of various experiments determined that the developed smart nanocarrier proposed as a promising nanocarrier for active and passive targeting of anionic anti-cancer agents such as MTX. Copyright © 2017. Published by Elsevier B.V.

Oligonucleotide aptamers against tyrosine kinase receptors: Prospect for anticancer applications.

PubMed

Camorani, Simona; Crescenzi, Elvira; Fedele, Monica; Cerchia, Laura

2018-04-01

Transmembrane receptor tyrosine kinases (RTKs) play crucial roles in cancer cell proliferation, survival, migration and differentiation. Area of intense research is searching for effective anticancer therapies targeting these receptors and, to date, several monoclonal antibodies and small-molecule tyrosine kinase inhibitors have entered the clinic. However, some of these drugs show limited efficacy and give rise to acquired resistance. Emerging highly selective compounds for anticancer therapy are oligonucleotide aptamers that interact with their targets by recognizing a specific three-dimensional structure. Because of their nucleic acid nature, the rational design of advanced strategies to manipulate aptamers for both diagnostic and therapeutic applications is greatly simplified over antibodies. In this manuscript, we will provide a comprehensive overview of oligonucleotide aptamers as next generation strategies to efficiently target RTKs in human cancers. Copyright © 2018 Elsevier B.V. All rights reserved.

Bi-functional prodrugs of 5-aminolevulinic acid and butyric acid increase erythropoiesis in anemic mice in an erythropoietin-independent manner.

PubMed

Rephaeli, Ada; Tarasenko, Nataly; Fibach, Eitan; Rozic, Gabriela; Lubin, Ido; Lipovetsky, Julia; Furman, Svetlana; Malik, Zvi; Nudelman, Abraham

2016-08-25

Anemia is a major cause of morbidity and mortality worldwide resulting from a wide variety of pathological conditions. In severe cases it is treated by blood transfusions or injection of erythroid stimulating agents, e.g., erythropoietin (Epo), which can be associated with serious adverse effects. Therefore, there is a need to develop new treatment modalities. We recently reported that treatment of erythroleukemic cells with the novel the bi-functional prodrugs of 5-aminolevulinic acid (ALA) and butyric acid (BA), AN233 and AN908, enhanced hemoglobin (Hb) synthesis to a substantially higher level than did ALA and BA individually or their mixture. Herein, we describe that these prodrugs when given orally to mice induced histone deacetylase inhibition in the kidneys, bone marrow and spleen, thus, indicating good penetrability to the tissues. In mice where anemia was chemically induced, treatment with the prodrugs increased the Hb, the number of red blood cells (RBCs) and the percentage of reticulocytes to normal levels. The prodrugs had no adverse effects even after repeated treatment at 100-200mg/kg for 50days. The lack of increased levels of Epo in the blood of mice that were treated with the prodrugs suggests that AN233 and AN908 affected the Hb and RBC levels in an Epo-independent manner. Taken together with our previous studies, we propose that the prodrugs increase globin expression by BA inhibition of histone deacetylase and elevation heme synthesis by ALA. These results support an Epo-independent approach for treating anemia with these prodrugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy.

PubMed

Chen, Dan; Li, Bowen; Cai, Songhua; Wang, Peng; Peng, Shuwen; Sheng, Yuanzhi; He, Yuanyuan; Gu, Yueqing; Chen, Haiyan

2016-09-01

Dual targeting towards both extracellular and intracellular receptors specific to tumor is a significant approach for cancer diagnosis and therapy. In the present study, a novel nano-platform (AuNC-cRGD-Apt) with dual targeting function was initially established by conjugating gold nanocluster (AuNC) with cyclic RGD (cRGD) that is specific to αvβ3integrins over-expressed on the surface of tumor tissues and aptamer AS1411 (Apt) that is of high affinity to nucleolin over-expressed in the cytoplasm and nucleus of tumor cells. Then, AuNC-cRGD-Apt was further functionalized with near infrared (NIR) fluorescence dye (MPA), giving a NIR fluorescent dual-targeting probe AuNC-MPA-cRGD-Apt. AuNC-MPA-cRGD-Apt displays low cytotoxicity and favorable tumor-targeting capability at both in vitro and in vivo level, suggesting its clinical potential for tumor imaging. Additionally, Doxorubicin (DOX), a widely used clinical chemotherapeutic drug that kill cancer cells by intercalating DNA in cellular nucleus, was immobilized onto AuNC-cRGD-Apt forming a pro-drug, AuNC-DOX-cRGD-Apt. The enhanced tumor affinity, deep tumor penetration and improved anti-tumor activity of this pro-drug were demonstrated in different tumor cell lines, tumor spheroid and tumor-bearing mouse models. Results in this study suggest not only the prospect of non-toxic AuNC modified with two targeting ligands for tumor targeted imaging, but also confirm the promising future of dual targeting AuNC as a core for the design of prodrug in the field of cancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Curcumin Analog EF24 Targets NF-κB and miRNA-21, and Has Potent Anticancer Activity In Vitro and In Vivo

PubMed Central

Yang, Chuan He; Yue, Junming; Sims, Michelle; Pfeffer, Lawrence M.

2013-01-01

EF24 is a curcumin analog that has improved anticancer activity over curcumin, but its therapeutic potential and mechanism of action is unknown, which is important to address as curcumin targets multiple signaling pathways. EF24 inhibits the NF-κB but not the JAK-STAT signaling pathway in DU145 human prostate cancer cells and B16 murine melanoma cells. EF24 induces apoptosis in these cells apparently by inhibiting miR-21 expression, and also enhances the expression of several miR-21 target genes, PTEN and PDCD4. EF24 treatment significantly suppressed the growth of DU145 prostate cancer xenografts in immunocompromised mice and resulted in tumor regression. EF24 enhanced the expression of the miR-21 target PTEN in DU145 tumor tissue, but suppressed the expression of markers of proliferating cells (cyclin D1 and Ki67). In syngeneic mice injected with B16 cells, EF24 treatment inhibited the formation of lung metastasis, prolonged animal survival, inhibited miR-21 expression and increased the expression of miR-21 target genes. Expression profiling of miRNAs regulated by EF24 in vitro and in vivo showed that the antitumor activity of EF24 reflected the enhanced expression of potential tumor suppressor miRNAs as well as the suppressed expression of oncogenic miRNAs, including miR-21. Taken together, our data suggest that EF24 is a potent anticancer agent and selectively targets NF-κB signaling and miRNA expression, indicating that EF24 has significant potential as a therapeutic agent in various cancers. PMID:23940701

Therapeutic Effectiveness of Anticancer Phytochemicals on Cancer Stem Cells

PubMed Central

Oh, Jisun; Hlatky, Lynn; Jeong, Yong-Seob; Kim, Dohoon

2016-01-01

Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals on heterogeneous cancer cell populations as well as on specific targeting of CSCs. PMID:27376325

In situ cross-linkable high molecular weight hyaluronan-bisphosphonate conjugate for localized delivery and cell-specific targeting: a hydrogel linked prodrug approach.

PubMed

Varghese, Oommen P; Sun, Weilun; Hilborn, Jöns; Ossipov, Dmitri A

2009-07-01

We present here a novel synthesis route to functionalize high molecular weight hyaluronan (HMW-HA) with a hydrazide group and a bioactive ligand, namely bisphosphonate (BP). For this purpose, a new symmetrical self-immolative biscarbazate linker has been devised. The hydrazide group was used to form hydrazone cross-linked hydrogel upon treating with previously described aldehyde modified hyaluronan. The 1:1 weight ratio of these two polymers gave hydrogel in less than 30 s. In this communication we present the first in vitro results showing that even though HA can target CD44 positive cancer cells (HCT-116), receptor mediated endocytosis could only occur by cleavage of high molecular weight HA with an ubiquitous enzyme, hyaluronidase (Hase). The cancer cells are known to overexpress CD44 receptors and also increase the hyaluronidase activity in vivo. Thus the pro-drug design, based on drug conjugation to HMW-HA, represents a new drug delivery platform where the drug potency is triggered by Hase mediated degradation of the HA-drug conjugate. We have successfully demonstrated that the cross-linkable HA-BP conjugate first undergoes Hase-mediated scission to the fragments of suitable sizes so as to be internalized by CD44 positive cells. The specificity of this targeting was proven by comparing the results with less CD44 positive HEK-293T cells. The localized delivery of such drugs at the surgical resection site opens up avenues to control tumor recurrence after removal of the tumor. In the form of hydrogel it would prevent systemic exposure of the drug and would allow its controlled release.

Seeking new anti-cancer agents from autophagy-regulating natural products.

PubMed

Hua, Fang; Shang, Shuang; Hu, Zhuo-Wei

2017-04-01

Natural products are an important original source of many widely used drugs, including anti-cancer drugs. Early research efforts for seeking anti-cancer therapy from the natural products are mainly focused on the compounds with cytotoxicity capability. The good examples include vinblastine, vincristine, the camptothecin derivatives; topotecan, irinotecan, epipodophyllotoxin derivatives and paclitaxel. In a recent decade, the fundamental progression has been made in the understanding of molecular and cellular mechanisms regarding tumor initiation, metastasis, therapeutic resistance, immune escape, and relapse, which provide a great opportunity for the development of new mechanism-based anticancer drugs, especially drugs against new molecular and cellular targets. Autophagy, a critical cell homeostasis mechanism and promising drug target involved in a verity of human diseases including cancer, can be modulated by many compounds derived from natural products. In this review, we'll give a short introduction of autophagy and discuss the roles of autophagy in the tumorigenesis and progression. And then, we summarize the accumulated evidences to show the anti-tumor effects of several compounds derived from natural products through modulation of autophagy activity.

Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

PubMed Central

Zhang, Yong; Jiang, Peixin; Ye, Min; Kim, Sung-Hoon; Jiang, Cheng; Lü, Junxuan

2012-01-01

Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far, human clinical trials have been far from ideal in their design and execution for the purpose of supporting an anti-cancer indication of tanshinones. PMID:23202971

Modeling of hyaluronic acid containing anti-cancer drugs-loaded polylactic-co-glycolic acid bioconjugates for targeted delivery to cancer cells

NASA Astrophysics Data System (ADS)

Gul-e-Saba, Adulphakdee, A.; Madthing, A.; Zafar, M. N.; Abdullah, M. A.

2012-09-01

Molecular modeling of hyaluronan (HA), polylactic-co-glycolic acid (PLGA), polyethylene glycol-bis-amine (PEG-bis-amine), Curcumin, Cisplatin and the conjugate HA-PEG-PLGA containing Curcumin/Cisplatin were performed using Discovery Studio 2.5 to better understand issues and constraints related to targeted delivery of potent anticancer drugs to cancer cells. HA, a versatile biopolymer is a ligand of cancer cell receptor, CD44 that can be particularly useful in a receptor-mediated cellular uptake of drug-incorporated nanoparticles. Biocompatible and biodegradable polymers, PLGA and PEG, serve as polymeric micelles for controlled-release of drug. Curcumin as a natural anticancer agent has poor solubility that limits its use in drug therapeutics, while platinum-based Cisplatin exhibits systemic cytotoxicity. These can be overcome via drug delivery in polymeric biocompatible vehicles. The PLGA-PEG-HA conjugate shows the total measurement of 105 bond length with average bond length of 1.274163 Å. The conjugation between PEG and HA occurs at C8-O1 atoms and can be manipulated to improve properties.

Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies

PubMed Central

Foo, Jasmine; Michor, Franziska

2009-01-01

The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type. PMID:19893626

Effects of different carboxylic ester spacers on chemical stability, release characteristics, and anticancer activity of mono-PEGylated curcumin conjugates.

PubMed

Wichitnithad, Wisut; Nimmannit, Ubonthip; Callery, Patrick S; Rojsitthisak, Pornchai

2011-12-01

We investigated the effects of different carboxylic ester spacers of mono-PEGylated curcumin conjugates on chemical stability, release characteristics, and anticancer activity. Three novel conjugates were synthesized with succinic acid, glutaric acid, and methylcarboxylic acid as the respective spacers between curcumin and monomethoxy polyethylene glycol of molecular weight 2000 (mPEG(2000) ): mPEG(2000) -succinyl-curcumin (PSC), mPEG(2000) -glutaryl-curcumin (PGC), and mPEG(2000) -methylcarboxyl-curcumin (PMC), respectively. Hydrolysis of all conjugates in buffer and human plasma followed pseudo first-order kinetics. In phosphate buffer, the overall degradation rate constant and half-life values indicated an order of stability of PGC > PSC > PMC > curcumin. In human plasma, more than 90% of curcumin was released from the esters after incubation for 0.25, 1.5, and 2 h, respectively. All conjugates exhibited cytotoxicity against four human cancer cell lines: Caco-2 (colon), KB (oral cavity), MCF7 (breast), and NCI-H187 (lung) with half maximal inhibitory concentration (IC(50) ) values in the range of 1-6 µM, similar to that observed for curcumin itself. Our results suggest that mono-PEGylation of curcumin produces prodrugs that are stable in buffer at physiological pH, release curcumin readily in human plasma, and show anticancer activity. Copyright © 2011 Wiley-Liss, Inc.

Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells.

PubMed

Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Yune; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai

2015-09-28

Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.

Investigation of alternative prodrugs for use with E. coli nitroreductase in 'suicide gene' approaches to cancer therapy.

PubMed

Bailey, S M; Knox, R J; Hobbs, S M; Jenkins, T C; Mauger, A B; Melton, R G; Burke, P J; Connors, T A; Hart, I R

1996-12-01

The most commonly employed 'suicide' gene/prodrug system used in cancer gene therapy is the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir system. We have examined the efficacy of an alternative approach utilising the E. coli nitroreductase B enzyme with CB1954 and a variety of other prodrugs. V79 cells transfected with a nitroreductase expression vector were up to 770-fold more sensitive to CB1954 than control non-expressing cells. In general other prodrugs which were found by HPLC to act as substrates for purified E. coli nitroreductase also exhibited increased cytotoxicity against the nitroreductase-expressing cells, although this correlation was not absolute. In particular nitrofurazone (97-fold) and additional aromatic nitro-compounds (nine- to 50-fold) showed a large differential whereas the quinones and the antimetabolite, B-FU, were less effective (< three-fold). The results support the possibility of using nitroreductase and CB1954 for 'suicide gene' therapy and in addition suggest that alternative prodrugs, such as nitrofurazone, warrant further investigation in this novel approach.

Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats

PubMed Central

Vacondio, Federica; Bassi, Michele; Silva, Claudia; Castelli, Riccardo; Carmi, Caterina; Scalvini, Laura; Lodola, Alessio; Vivo, Valentina; Flammini, Lisa; Barocelli, Elisabetta; Mor, Marco; Rivara, Silvia

2015-01-01

Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization. PMID:26053855

Evidence That P-glycoprotein Inhibitor (Elacridar)-Loaded Nanocarriers Improve Epidermal Targeting of an Anticancer Drug via Absorptive Cutaneous Transporters Inhibition.

PubMed

Giacone, Daniela V; Carvalho, Vanessa F M; Costa, Soraia K P; Lopes, Luciana B

2018-02-01

Because P-glycoprotein (P-gp) plays an absorptive role in the skin, its pharmacological inhibition represents a strategy to promote cutaneous localization of anticancer agents that serve as its substrates, improving local efficacy while reducing systemic exposure. Here, we evaluated the ability of a nanoemulsion (NE) coencapsulating a P-gp inhibitor (elacridar) with the antitumor drug paclitaxel to promote epidermal targeting. Loaded NE displayed a nanometric size (45.2 ± 4.0 nm) and negative zeta potential (-4.2 ± 0.8 mV). Elacridar improved NE ability to inhibit verapamil-induced ATPase activity of P-gp; unloaded NE-inhibited P-gp when used at a concentration of 1500 μM, while elacridar encapsulation decreased this concentration by 3-fold (p <0.05). Elacridar-loaded NE reduced paclitaxel penetration into the dermis of freshly excised mice skin and its percutaneous permeation by 1.5- and 1.7-fold (p <0.05), respectively at 6 h, whereas larger drug amounts (1.4-fold, p <0.05) were obtained in viable epidermis. Assessment of cutaneous distribution of a fluorescent paclitaxel derivative confirmed the smaller delivery into the dermis at elacridar presence. In conclusion, we have provided novel evidence that NE containing elacridar exhibited a clear potential for P-gp inhibition and enabled epidermal targeting of paclitaxel, which in turn, can potentially reduce adverse effects associated with systemic exposure to anticancer therapy. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Melanoma-targeted delivery system (part 1): design, synthesis and evaluation of releasable disulfide drug by glutathione.

PubMed

El Aissi, Radhia; Chezal, Jean-Michel; Tarrit, Sébastien; Chavignon, Olivier; Moreau, Emmanuel

2015-08-28

Here we describe the design and synthesis of a prodrug developed for pigmented melanoma therapy, consisting of a Melanin-Targeting Probe (MTP) conjugated to 5-iodo-2'-deoxyuridine (IUdR) with a reduction-sensitive pre-determined breaking point. Compared with the non-cleavable conjugate (17b), prodrug (17a) bearing a self-immolative disulfide linker achieved complete release of IUdR within 20 min in the presence of reducing agents such as DTT or glutathione. Analytical results also showed that prodrug (17a) was more sensitive than parent non-cleavable conjugate (17b) for a concentration range of glutathione similar to that found in the intracellular compartment of tumours. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical Proteomics Identifies Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1 as the Molecular Target of Quercetin in Its Anti-cancer Effects in PC-3 Cells*

PubMed Central

Ko, Chia-Chen; Chen, Yun-Ju; Chen, Chih-Ta; Liu, Yu-Chih; Cheng, Fong-Chi; Hsu, Kai-Chao; Chow, Lu-Ping

2014-01-01

Quercetin, a flavonoid abundantly present in plants, is widely used as a phytotherapy in prostatitis and prostate cancer. Although quercetin has been reported to have a number of therapeutic effects, the cellular target(s) responsible for its anti-cancer action has not yet been clearly elucidated. Here, employing affinity chromatography and mass spectrometry, we identified heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) as a direct target of quercetin. A specific interaction between quercetin and hnRNPA1 was validated by immunoblotting and in vitro binding experiments. We found that quercetin bound the C-terminal region of hnRNPA1, impairing the ability of hnRNPA1 to shuttle between the nucleus and cytoplasm and ultimately resulting in its cytoplasmic retention. In addition, hnRNPA1 was recruited to stress granules after treatment of cells with quercetin for up to 48 h, and the levels of cIAP1 (cellular inhibitor of apoptosis), an internal ribosome entry site translation-dependent protein, were reduced by hnRNPA1 regulation. This is the first report that anti-cancer effects of quercetin are mediated, in part, by impairing functions of hnRNPA1, insights that were obtained using a chemical proteomics strategy. PMID:24962584

Anticancer Molecular Mechanisms of Resveratrol

PubMed Central

Varoni, Elena M.; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

2016-01-01

Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment. PMID:27148534

Anticancer Molecular Mechanisms of Resveratrol.

PubMed

Varoni, Elena M; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

2016-01-01

Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment.

Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity?

PubMed

Ashwood, Brennan; Jockusch, Steffen; Crespo-Hernández, Carlos E

2017-02-28

6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug's overall photoreactivity. However, 6-thioguanine itself has proven to be cytotoxic following UVA irradiation, warranting further investigation into its excited-state dynamics. In this contribution, the excited-state dynamics and photochemical properties of 6-thioguanine are studied in aqueous solution following UVA excitation at 345 nm in order to provide mechanistic insight regarding its photochemical reactivity and to scrutinize whether N9-glycosylation modulates its phototoxicity in solution. The experimental results are complemented with time-dependent density functional calculations that include solvent dielectric effects by means of a reaction-field solvation model. UVA excitation results in the initial population of the S₂(ππ*) state, which is followed by ultrafast internal conversion to the S₁(nπ*) state and then intersystem crossing to the triplet manifold within 560 ± 60 fs. A small fraction (ca. 25%) of the population that reaches the S₁(nπ*) state repopulates the ground state. The T₁(ππ*) state decays to the ground state in 1.4 ± 0.2 μs under N₂-purged conditions, using a 0.2 mM concentration of 6-thioguanine, or it can sensitize singlet oxygen in 0.21 ± 0.02 and 0.23 ± 0.02 yields in air- and O₂-saturated solution, respectively. This demonstrates the efficacy of 6-thioguanine to act as a Type II photosensitizer. N9-glycosylation increases the rate of intersystem crossing from the singlet to triplet manifold, as well as from the T₁(ππ*) state to the ground state, which lead to a ca. 40% decrease in the singlet oxygen yield under air-saturated conditions. Enhanced vibronic coupling between the singlet and triplet manifolds due to a higher density of vibrational states is proposed to be responsible for the observed

Supramolecular curcumin-barium prodrugs for formulating with ceramic particles.

PubMed

Kamalasanan, Kaladhar; Anupriya; Deepa, M K; Sharma, Chandra P

2014-10-01

A simple and stable curcumin-ceramic combined formulation was developed with an aim to improve curcumin stability and release profile in the presence of reactive ceramic particles for potential dental and orthopedic applications. For that, curcumin was complexed with barium (Ba(2+)) to prepare curcumin-barium (BaCur) complex. Upon removal of the unbound curcumin and Ba(2+) by dialysis, a water-soluble BaCur complex was obtained. The complex was showing [M+1](+) peak at 10,000-20,000 with multiple fractionation peaks of MALDI-TOF-MS studies, showed that the complex was a supramolecular multimer. The (1)H NMR and FTIR studies revealed that, divalent Ba(2+) interacted predominantly through di-phenolic groups of curcumin to form an end-to-end complex resulted in supramolecular multimer. The overall crystallinity of the BaCur was lower than curcumin as per XRD analysis. The complexation of Ba(2+) to curcumin did not degrade curcumin as per HPLC studies. The fluorescence spectrum was blue shifted upon Ba(2+) complexation with curcumin. Monodisperse nanoparticles with size less than 200dnm was formed, out of the supramolecular complex upon dialysis, as per DLS, and upon loading into pluronic micelles the size was remaining in similar order of magnitude as per DLS and AFM studies. Stability of the curcumin was improved greater than 50% after complexation with Ba(2+) as per UV/Vis spectroscopy. Loading of the supramloecular nanoparticles into pluronic micelles had further improved the stability of curcumin to approx. 70% in water. These BaCur supramolecule nanoparticles can be considered as a new class of prodrugs with improved solubility and stability. Subsequently, ceramic nanoparticles with varying chemical composition were prepared for changing the material surface reactivity in terms of the increase in, degradability, surface pH and protein adsorption. Further, these ceramic particles were combined with curcumin prodrug formulations and optimized the curcumin release

CNS Anticancer Drug Discovery and Development Conference White Paper

PubMed Central

Levin, Victor A.; Tonge, Peter J.; Gallo, James M.; Birtwistle, Marc R.; Dar, Arvin C.; Iavarone, Antonio; Paddison, Patrick J.; Heffron, Timothy P.; Elmquist, William F.; Lachowicz, Jean E.; Johnson, Ted W.; White, Forest M.; Sul, Joohee; Smith, Quentin R.; Shen, Wang; Sarkaria, Jann N.; Samala, Ramakrishna; Wen, Patrick Y.; Berry, Donald A.; Petter, Russell C.

2015-01-01

Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric “Accelerating Drug Discovery and Development for Brain Tumors,” further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167

Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities.

PubMed

Wang, Changhao; Carter-Cooper, Brandon; Du, Yixuan; Zhou, Jie; Saeed, Musabbir A; Liu, Jinbing; Guo, Min; Roembke, Benjamin; Mikek, Clinton; Lewis, Edwin A; Lapidus, Rena G; Sintim, Herman O

2016-08-08

G-quadruplex ligands have been touted as potential anticancer agents, however, none of the reported G-quadruplex-interactive small molecules have gone past phase II clinical trials. Recently it was revealed that diminazene (berenil, DMZ) actually binds to G-quadruplexes 1000 times better than DNA duplexes, with dissociation constants approaching 1 nM. DMZ however does not have strong anticancer activities. In this paper, using a panel of biophysical tools, including NMR, FRET melting assay and FRET competition assay, we discovered that monoamidine analogues of DMZ bearing alkyne substitutes selectively bind to G-quadruplexes. The lead DMZ analogues were shown to be able to target c-MYC G-quadruplex both in vitro and in vivo. Alkyne DMZ analogues display respectable anticancer activities (single digit micromolar GI50) against ovarian (OVCAR-3), prostate (PC-3) and triple negative breast (MDA-MB-231) cancer cell lines and represent interesting new leads to develop anticancer agents. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives.

PubMed

Singh, Rajesh K; Kumar, Sahil; Prasad, D N; Bhardwaj, T R

2018-05-10

Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The application of polysaccharide-based nanogels in peptides/proteins and anticancer drugs delivery.

PubMed

Zhang, Lin; Pan, Jifei; Dong, Shibo; Li, Zhaoming

2017-09-01

Finding adequate carriers for proteins/peptides and anticancer drugs delivery has become an urgent need, owing to the growing number of therapeutic macromolecules and the increasing amount of cancer incidence. Polysaccharide-based nanogels have attracted interest as carriers for proteins/peptides and anticancer drugs because of their characteristic properties like biodegradability, biocompatibility, stimuli-responsive behaviour, softness and swelling to help achieve a controlled, triggered response at the target site. In addition, the groups of the polysaccharide backbone are able to be modified to develop functional nanogels. Some polysaccharides have the intrinsic ability to recognise specific cell types, allowing the design of targeted drug delivery systems through receptor-mediated endocytosis. This review is aimed at describing and exploring the potential of polysaccharides that are used in nanogels which can help to deliver proteins/peptides and anticancer drugs.

Hierarchical mesosilicalite nanoformulation integrated with cisplatin exhibits target-specific efficient anticancer activity

NASA Astrophysics Data System (ADS)

Jermy, B. Rabindran; Acharya, Sadananda; Ravinayagam, Vijaya; Alghamdi, Hajer Saleh; Akhtar, Sultan; Basuwaidan, Rehab S.

2018-04-01

Hierarchically structured zeolitic ZSM-5 and meso MCM-41 interlinked domain had an impeccable use as catalysis in many applications. The aim of the study was to develop a new drug delivery nanoformulation, specifically, cisplatin/mesosilicalite using top-down approach for cancer therapy. Hierarchical mesosilicalite with variable porosity was synthesized using alkaline molar solution (0.2 and 0.7 M NaOH) and was loaded with cisplatin through equilibrium adsorption technique. Physico-chemical properties of the nanoformulation (IAUM-56—Imam Abdulrahman Bin Faisal University Mesosilicalite-56) were characterized using X-ray diffraction, surface area analysis (BET), Fourier transformed infrared spectroscopy (FT-IR), diffuse reflectance UV-Vis spectroscopy, and transmission electron microscopy. Drug release study and anticancer activity were assayed on HeLa and MCF7 cancer cells using MTT assay. X-ray diffraction pattern showed interrelated meso- and microphases, while BET analysis revealed considerable mesoporosity formation with a remodulation of isotherm hysteresis indicating the presence of hierarchical pores. FT-IR showed the presence of nanozeolitic subunits into mesostructure with a band at about 550 cm-1. IAUM-56 demonstrated high cytotoxic activity against HeLa cancer cells with an LC50 of 0.02 mg/ml, MCF7 cancer cells with an LC50 of 0.05 mg/ml, and less toxic to normal fibroblast cells with an LC50 of approximately ten times higher at 0.5 mg/ml. Overall, IAUM-56 showed a high rate of sustained release of cisplatin imparting target specific cytotoxic effect against tumor cells with at least tenfold lower toxicity on normal fibroblast cells. Our nanoformulation has the potential use in cancer therapy as a targeted drug delivery system.

Polymeric anticancer drugs with pH-controlled activation.

PubMed

Ulbrich, Karel; Subr, Vladimír

2004-04-23

Use of macromolecular water-soluble carriers of anti-cancer drugs represents a promising approach to cancer therapy. Release of drugs from the carrier system is a prerequisite for therapeutic activity of most macromolecular anti-cancer conjugates. Incorporation of acid-sensitive spacers between the drug and carrier enables release of an active drug from the carrier in a tumor tissue, either in slightly acidic extracellular fluids or, after endocytosis, in endosomes or lysosomes of cancer cells. This paper reviews advances in development and study of properties of various acid-sensitive macromolecular drug delivery systems, starting from simple polymer-drug conjugates to ending with site-specific antibody-targeted polymer-drug conjugates.

Actively targeted delivery of anticancer drug to tumor cells by redox-responsive star-shaped micelles.

PubMed

Shi, Chunli; Guo, Xing; Qu, Qianqian; Tang, Zhaomin; Wang, Yi; Zhou, Shaobing

2014-10-01

In cancer therapy nanocargos based on star-shaped polymer exhibit unique features such as better stability, smaller size distribution and higher drug capacity in comparison to linear polymeric micelles. In this study, we developed a multifunctional star-shaped micellar system by combination of active targeting ability and redox-responsive behavior. The star-shaped micelles with good stability were self-assembled from four-arm poly(ε-caprolactone)-poly(ethylene glycol) copolymer. The redox-responsive behaviors of these micelles triggered by glutathione were evaluated from the changes of micellar size, morphology and molecular weight. In vitro drug release profiles exhibited that in a stimulated normal physiological environment, the redox-responsive star-shaped micelles could maintain good stability, whereas in a reducing and acid environment similar with that of tumor cells, the encapsulated agent was promptly released. In vitro cellular uptake and subcellular localization of these micelles were further studied with confocal laser scanning microscopy and flow cytometry against the human cervical cancer cell line HeLa. In vivo and ex vivo DOX fluorescence imaging displayed that these FA-functionalized star-shaped micelles possessed much better specificity to target solid tumor. Both the qualitative and quantitative results of the antitumor effect in 4T1 tumor-bearing BALB/c mice demonstrated that these redox-responsive star-shaped micelles have a high therapeutic efficiency to artificial solid tumor. Therefore, the multifunctional star-shaped micelles are a potential platform for targeted anticancer drug delivery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Study of glycol chitosan-carboxymethyl β-cyclodextrins as anticancer drugs carrier.

PubMed

Tan, Haina; Qin, Fei; Chen, Dongfeng; Han, Songbai; Lu, Wu; Yao, Xin

2013-04-02

Efficient target delivery system for insoluble anticancer drugs to increase the intracellular drug concentration has become a focus in cancer therapy. Herein, glycol chitosan-carboxymethyl β-cyclodextrins (G-chitosan-CM-dextrins) was synthesized for delivering different hydrophobic anticancer drugs. Surface plasmon resonance and UV-vis spectroscopy results showed that all the three anticancer drugs (5-fluorouracil, doxorubicin, and vinblastine) could be successfully loaded into the cavities of the covalently linked CM-dextrins. Moreover, the free carboxymethyl groups could enhance the binding interactions between the covalently linked CM-dextrins and anticancer drugs. Release behaviors with pH changes of the three drugs were also explored, result showed different drugs would be released by different ways, as for doxorubicin, pH sensitive release has been realized. The obtained G-chitosan-CM-dextrins carrier has both mucoadhesive property of G-chitosan and hydrophobic cavities of β-cyclodextrins. Therefore, the new synthesized G-chitosan-CM-dextrins carrier exhibits a promising potential capability for anticancer drug delivery in tumor therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Alkaloids as Cyclooxygenase Inhibitors in Anticancer Drug Discovery.

PubMed

Hashmi, Muhammad Ali; Khan, Afsar; Farooq, Umar; Khan, Sehroon

2018-01-01

Cancer is the leading cause of death worldwide and anticancer drug discovery is a very hot area of research at present. There are various factors which control and affect cancer, out of which enzymes like cyclooxygenase-2 (COX-2) play a vital role in the growth of tumor cells. Inhibition of this enzyme is a very useful target for the prevention of various types of cancers. Alkaloids are a diverse group of naturally occurring compounds which have shown great COX-2 inhibitory activity both in vitro and in vivo. In this mini-review, we have discussed different alkaloids with COX-2 inhibitory activities and anticancer potential which may act as leads in modern anticancer drug discovery. Different classes of alkaloids including isoquinoline alkaloids, indole alkaloids, piperidine alkaloids, quinazoline alkaloids, and various miscellaneous alkaloids obtained from natural sources have been discussed in detail in this review. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Identification of anti-cancer targets of eco-friendly waste Punica granatum peel by dual reverse virtual screening and binding analysis.

PubMed

Usha, Talambedu; Goyal, Arvind Kumar; Lubna, Syed; Prashanth, Hp; Mohan, T Madhan; Pande, Veena; Middha, Sushil Kumar

2014-01-01

Punica granatum (family: Lythraceae) is mainly found in Iran, which is considered to be its primary centre of origin. Studies on pomegranate peel have revealed antioxidant, anti-inflammatory, anti- angiogenesis activities, with prevention of premature aging and reducing inflammation. In addition to this it is also useful in treating various diseases like diabetes, maintaining blood pressure and treatment of neoplasms such as prostate and breast cancer. In this study we identified anti-cancer targets of active compounds like corilagin (tannins), quercetin (flavonoids) and pseudopelletierine (alkaloids) present in pomegranate peel by employing dual reverse screening and binding analysis. The potent targets of the pomegranate peel were annotated by the PharmMapper and ReverseScreen 3D, then compared with targets identified from different Bioassay databases (NPACT and HIT's). Docking was then further employed using AutoDock pyrx and validated through discovery studio for studying molecular interactions. A number of potent anti-cancerous targets were attained from the PharmMapper server according to their fit score and from ReverseScreen 3D server according to decreasing 3D scores. The identified targets now need to be further validated through in vitro and in vivo studies.

Multimodal HDAC Inhibitors with Improved Anticancer Activity.

PubMed

Schobert, Rainer; Biersack, Bernhard

2018-01-01

Histone deacetylases (HDACs) play a significant role in the proliferation and dissemination of cancer and represent promising epigenetic drug targets. The HDAC inhibitor vorinostat featuring a zinc-binding hydroxamate fragment was already clinically approved. However, HDAC inhibitors containing hydroxamic acids are often hampered by acquired or intrinsic drug resistance and may lead to enhanced tumor aggressiveness. In order to overcome these drawbacks of hydroxamate HDAC inhibitors, a series of multimodal derivatives of this compound class, including such with different zinc-binding groups, was recently developed and showed promising anticancer activity. This review provides an overview of the chemistry and pleiotropic anticancer modes of action of these conceptually new HDAC inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): Formulation design and optimization studies

PubMed Central

Yang, Yu-Tsai; Di Pasqua, Anthony J.; Zhang, Yong; Sueda, Katsuhiko; Jay, Michael

2015-01-01

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion.. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone. PMID:24047113

Redesigned Spider Peptide with Improved Antimicrobial and Anticancer Properties.

PubMed

Troeira Henriques, Sónia; Lawrence, Nicole; Chaousis, Stephanie; Ravipati, Anjaneya S; Cheneval, Olivier; Benfield, Aurélie H; Elliott, Alysha G; Kavanagh, Angela Maria; Cooper, Matthew A; Chan, Lai Yue; Huang, Yen-Hua; Craik, David J

2017-09-15

Gomesin, a disulfide-rich antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against melanoma cells. In a recent study, a backbone cyclized analogue of gomesin was shown to be as active but more stable than its native form. In the current study, we were interested in improving the antimicrobial properties of the cyclic gomesin, understanding its selectivity toward melanoma cells and elucidating its antimicrobial and anticancer mode of action. Rationally designed analogues of cyclic gomesin were examined for their antimicrobial potency, selectivity toward cancer cells, membrane-binding affinity, and ability to disrupt cell and model membranes. We improved the activity of cyclic gomesin by ∼10-fold against tested Gram-negative and Gram-positive bacteria without increasing toxicity to human red blood cells. In addition, we showed that gomesin and its analogues are more toxic toward melanoma and leukemia cells than toward red blood cells and act by selectively targeting and disrupting cancer cell membranes. Preference toward some cancer types is likely dependent on their different cell membrane properties. Our findings highlight the potential of peptides as antimicrobial and anticancer leads and the importance of selectively targeting cancer cell membranes for drug development.

Recent discoveries of anticancer flavonoids.

PubMed

Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Plescia, Fabiana; Daidone, Giuseppe

2017-12-15

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Folate-decorated anticancer drug and magnetic nanoparticles encapsulated polymeric carrier for liver cancer therapeutics.

PubMed

Li, Yu-Ji; Dong, Ming; Kong, Fan-Min; Zhou, Jian-Ping

2015-07-15

Nanoparticulate system with theranostic applications has attracted significant attention in cancer therapeutics. In the present study, we have developed a novel composite PLGA NP co-encapsulated with anticancer drug (sorafenib) and magnetic NP (SPION). We have successfully developed nanosized folate-conjugated PEGylated PLGA nanoparticles (SRF/FA-PEG-PLGA NP) with both anticancer and magnetic resonance property. We have showed that FA-conjugated NP exhibits sustained drug release and enhanced cellular uptake in BEL7402 cancer cells. The targeted NP effectively suppressed the tumor cell proliferation and has improved the anticancer efficacy than that of free drug or non-targeted one. Additionally, enhanced MRI properties demonstrate this formulation has good imaging agent characteristics. Finally, SRF/FA-PEG-PLGA NP effectively inhibited the colony forming ability indicating its superior anticancer effect. Together, these multifunctional nanoparticles would be most ideal to improve the therapeutic response in cancer and holds great potential to be a part of future nanomedicine. Our unique approach could be extended for multiple biomedical applications. Copyright © 2015. Published by Elsevier B.V.

Improved synthesis of N-benzylaminoferrocene-based prodrugs and evaluation of their toxicity and antileukemic activity.

PubMed

Daum, Steffen; Chekhun, Vasiliy F; Todor, Igor N; Lukianova, Natalia Yu; Shvets, Yulia V; Sellner, Leopold; Putzker, Kerstin; Lewis, Joe; Zenz, Thorsten; de Graaf, Inge A M; Groothuis, Geny M M; Casini, Angela; Zozulia, Oleksii; Hampel, Frank; Mokhir, Andriy

2015-02-26

We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied. The obtained data are in agreement with the hypothesis that the toxicity of aminoferrocenes is not dependent upon p53 status. Subsequently the toxicity of a selected prodrug (4) was investigated ex vivo using rat precision cut liver slices and in vivo on hybrid male mice BDF1. In both experiments no toxicity was observed: ex vivo, up to 10 μM; in vivo, up to 6 mg/kg. Finally, prodrug 4 was shown to extend the survival of BDF1 mice carrying L1210 leukemia from 13.7 ± 0.6 days to 17.5 ± 0.7 days when injected daily 6 times at a dose of 26 μg/kg starting from the second day after injection of L1210 cells.

Synthesis of mutual azo prodrugs of anti-inflammatory agents and peptides facilitated by α-aminoisobutyric acid.

PubMed

Kennedy, David A; Vembu, Nagarajan; Fronczek, Frank R; Devocelle, Marc

2011-12-02

Reported is the synthesis of azo mutual prodrugs of the nonsteroidal anti-inflammatory agents (NSAIDs) 4-aminophenylacetic acid (4-APAA) or 5-aminosalicylic acid (5-ASA) with peptides, including an antibiotic peptide temporin analogue modified at the amino terminal by an α-aminoisobutyric acid (Aib) residue. These prodrugs are designed for colonic delivery of two agents to treat infection and inflammation by the bacterial pathogen Clostridium difficile . © 2011 American Chemical Society

A prodrug approach to enhance azelaic acid percutaneous availability.

PubMed

Al-Marabeh, Sara; Khalil, Enam; Khanfar, Mohammad; Al-Bakri, Amal G; Alzweiri, Muhammed

2017-06-01

Azelaic acid is a dicarboxylic acid compound used in treatment of acne vulgaris. However, high concentration (ca 20%) is needed to guarantee the drug availability in the skin. The latter increases the incidence of side effects such as local irritation. The prodrug strategy to enhance azelaic acid diffusion through skin was not reported before. Thus, a lipophilic prodrug of azelaic acid (diethyl azelate [DEA]) was synthesized and investigated to improve percutaneous availability of azelaic acid, with a subsequent full physical, chemical, and biological characterization. Expectedly, DEA exhibited a significant increase in diffusion compared to azelaic acid through silicone membrane. In contrast, the diffusion results through human stratum corneum (SC) displayed weaker permeation for DEA with expected retention in the SC. Therefore, a desorption study of DEA from SC was conducted to examine the reservoir behavior in SC. Results showed an evidence of sustained release behavior of DEA from SC. Consequently, enhancement of keratolytic effect is expected due to azelaic acid produced from enzymatic conversion of DEA released from SC.

Neuropeptide Y Y1 receptors meditate targeted delivery of anticancer drug with encapsulated nanoparticles to breast cancer cells with high selectivity and its potential for breast cancer therapy.

PubMed

Li, Juan; Shen, Zheyu; Ma, Xuehua; Ren, Wenzhi; Xiang, Lingchao; Gong, An; Xia, Tian; Guo, Junming; Wu, Aiguo

2015-03-11

By enabling nanoparticle-based drug delivery system to actively target cancer cells with high selectivity, active targeted molecules have attracted great attention in the application of nanoparticles for anticancer drug delivery. However, the clinical application of most active targeted molecules in breast cancer therapy is limited, due to the low expression of their receptors in breast tumors or coexpression in the normal and tumor breast tissues. Here, a neuropeptide Y Y1 receptors ligand PNBL-NPY, as a novel targeted molecule, is conjugated with anticancer drug doxorubicin encapsulating albumin nanoparticles to investigate the effect of Y1 receptors on the delivery of drug-loaded nanoparticles to breast cancer cells and its potential for breast cancer therapy. The PNBL-NPY can actively recognize and bind to the Y1 receptors that are significantly overexpressed on the surface of the breast cancer cells, and the drug-loaded nanoparticles are delivered directly into the cancer cells through internalization. This system is highly selective and able to distinguish the breast cancer cells from the normal cells, due to normal breast cells that express Y2 receptors only. It is anticipated that this study may provide a guidance in the development of Y1 receptor-based nanoparticulate drug delivery system for a safer and more efficient breast cancer therapy.

Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies.

PubMed

Yoon, Kyoung Jin P; Krull, Erik J; Morton, Christopher L; Bornmann, William G; Lee, Richard E; Potter, Philip M; Danks, Mary K

2003-11-01

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan, CPT-11) is a camptothecin prodrug that is metabolized by carboxylesterases (CE) to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor. CPT-11 has shown encouraging antitumor activity against a broad spectrum of tumor types in early clinical trials, but hematopoietic and gastrointestinal toxicity limit its administration. To increase the therapeutic index of CPT-11 and to develop other prodrug analogues for enzyme/prodrug gene therapy applications, our laboratories propose to develop camptothecin prodrugs that will be activated by specific CEs. Specific analogues might then be predicted to be activated, for example, predominantly by human liver CE(hCE1), by human intestinal CE (hiCE), or in gene therapy approaches using a rabbit liver CE (rCE). This study describes a molecular modeling approach to relate the structure of rCE-activated camptothecin prodrugs with their biological activation. Comparative molecular field analysis, comparative molecular similarity index analysis, and docking studies were used to predict the biological activity of a 4-benzylpiperazine derivative of CPT-11 [7-ethyl-10-[4-(1-benzyl)-1-piperazino]carbonyloxycamptothecin (BP-CPT)] in U373MG glioma cell lines transfected with plasmids encoding rCE or hiCE. BP-CPT has been reported to be activated more efficiently than CPT-11 by a rat serum esterase activity; however, three-dimensional quantitative structure-activity relationship studies predicted that rCE would activate BP-CPT less efficiently than CPT-11. This was confirmed by both growth inhibition experiments and kinetic studies. The method is being used to design camptothecin prodrugs predicted to be activated by specific CEs.

Biotin Decorated Gold Nanoparticles for Targeted Delivery of a Smart-Linked Anticancer Active Copper Complex: In Vitro and In Vivo Studies.

PubMed

Pramanik, Anup K; Siddikuzzaman; Palanimuthu, Duraippandi; Somasundaram, Kumaravel; Samuelson, Ashoka G

2016-12-21

The synthesis and anticancer activity of a copper(II) diacetyl-bis(N4-methylthiosemicarbazone) complex and its nanoconjugates are reported. The copper(II) complex is connected to a carboxylic acid group through a cleavable disulfide link to enable smart delivery. The copper complex is tethered to highly water-soluble 20 nm gold nanoparticles (AuNPs), stabilized by amine terminated lipoic acid-polyethylene glycol (PEG). The gold nanoparticle carrier was further decorated with biotin to achieve targeted action. The copper complex and the conjugates with and without biotin, were tested against HeLa and HaCaT cells. They show very good anticancer activity against HeLa cells, a cell line derived from cervical cancer and are less active against HaCaT cells. Slow and sustained release of the complex from conjugates is demonstrated through cleavage of disulfide linker in the presence of glutathione (GSH), a reducing agent intrinsically present in high concentrations within cancer cells. Biotin appended conjugates do not show greater activity than conjugates without biotin against HeLa cells. This is consistent with drug uptake studies, which suggests similar uptake profiles for both conjugates in vitro. However, in vivo studies using a HeLa cell xenograft tumor model shows 3.8-fold reduction in tumor volume for the biotin conjugated nanoparticle compared to the control whereas the conjugate without biotin shows only 2.3-fold reduction in the tumor volume suggesting significant targeting.

Trends in the Cost and Use of Targeted Cancer Therapies for the Privately Insured Nonelderly: 2001 to 2011

PubMed Central

Shih, Ya-Chen Tina; Smieliauskas, Fabrice; Geynisman, Daniel M.; Kelly, Ronan J.; Smith, Thomas J.

2015-01-01

Purpose This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. Methods We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. Results We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. Conclusion Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment. PMID:25987701

Target engagement and drug residence time can be observed in living cells with BRET

PubMed Central

Robers, Matthew B.; Dart, Melanie L.; Woodroofe, Carolyn C.; Zimprich, Chad A.; Kirkland, Thomas A.; Machleidt, Thomas; Kupcho, Kevin R.; Levin, Sergiy; Hartnett, James R.; Zimmerman, Kristopher; Niles, Andrew L.; Ohana, Rachel Friedman; Daniels, Danette L.; Slater, Michael; Wood, Monika G.; Cong, Mei; Cheng, Yi-Qiang; Wood, Keith V.

2015-01-01

The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment. PMID:26631872

Development and characterization of PLGA nanoparticles as delivery systems of a prodrug of zidovudine obtained by its conjugation with ursodeoxycholic acid.

PubMed

Dalpiaz, Alessandro; Contado, Catia; Mari, Lara; Perrone, Daniela; Pavan, Barbara; Paganetto, Guglielmo; Hanuskovà, Miriam; Vighi, Eleonora; Leo, Eliana

2014-05-01

Zidovudine (AZT) is employed against AIDS and hepatitis; its use is limited by active efflux transporters (AETs) that induce multidrug resistance for intracellular therapies and hamper AZT to reach the brain. Ursodeoxycholic acid (UDCA) conjugation with AZT (prodrug UDCA-AZT) allows to elude the AET systems. To investigate the effect of the Pluronic F68 coating on the loading, release and stability of poly(D,L lactide-co-glicolide) nanoparticles (NPs) embedded with UDCA-AZT. The mean diameter of the NP prepared by nanoprecipitation or emulsion/solvent evaporation methods was determined using both photon correlation spectroscopy and sedimentation field-flow fractionation; particle morphology was detected by scanning electron microscope. The stability of the free and encapsulated UDCA-AZT was evaluated in rat liver homogenates by high-performance liquid chromatography analysis. The mean diameter of the NPs was found to be ∼ 600 nm with a relatively high polydispersity. The NPs obtained by emulsion/solvent evaporation were not able to control the prodrug release, differently from NPs obtained by nanoprecipitation. The presence of the Pluronic coating did not substantially modify the kinetics of the drug release, or the extent of the burst effect that were instead only influenced by the preparation parameters. UDCA-AZT incorporated in the NPs was more stable in the rat liver homogenates than the free prodrug and no influence of the Pluronic coating was observed. Considering the different potential applications of nanoparticles coated and uncoated with Pluronic (brain and macrophage targeting, respectively), both of these nanoparticle systems could be useful in the therapies against HIV.

Anti-cancer agents based on N-acyl-2, 3-dihydro-1H-pyrrolo[2,3-b] quinoline derivatives and a method of making

DOEpatents

Gakh, Andrei; Krasavin, Mikhail; Karapetian, Ruben; Rufanov, Konstantin A; Konstantinov, Igor; Godovykh, Elena; Soldatkina, Olga; Sosnov, Andrey V

2013-04-16

The present disclosure relates to novel compounds that can be used as anti-cancer agents in the prostate cancer therapy. In particular, the invention relates to N-acyl derivatives of 2,3-dihydro-1H-pyrrolo[2,3-b]quinolines having the structural Formula (I), ##STR00001## stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof. The meaning of R1 is independently selected from H; C1-C6 Alkyl, cyclo-Alkyl or iso-Alkyl substituents; R2 is selected from C1-C6 Alkyl, cyclo-Alkyl or iso-Alkyl; substituted or non-substituted, fused or non-fused to substituted or non-substituted aromatic ring, aryl or heteroaryl groups. The invention also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

Combined enzyme/prodrug treatment by genetically engineered AT-MSC exerts synergy and inhibits growth of MDA-MB-231 induced lung metastases.

PubMed

Matuskova, Miroslava; Kozovska, Zuzana; Toro, Lenka; Durinikova, Erika; Tyciakova, Silvia; Cierna, Zuzana; Bohovic, Roman; Kucerova, Lucia

2015-04-09

Metastatic spread of tumor cells remains a serious problem in cancer treatment. Gene-directed enzyme/prodrug therapy mediated by tumor-homing genetically engineered mesenchymal stromal cells (MSC) represents a promising therapeutic modality for elimination of disseminated cells. Efficacy of gene-directed enzyme/prodrug therapy can be improved by combination of individual systems. We aimed to define the combination effect of two systems of gene therapy mediated by MSC, and evaluate the ability of systemically administered genetically engineered mesenchymal stromal cells to inhibit the growth of experimental metastases derived from human breast adenocarcinoma cells MDA-MB-231/EGFP. Human adipose tissue-derived mesenchymal stromal cells (AT-MSC) were retrovirally transduced with fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT) or with Herpes simplex virus thymidine kinase (HSVtk). Engineered MSC were cocultured with tumor cells in the presence of prodrugs 5-fluorocytosin (5-FC) and ganciclovir (GCV). Combination effect of these enzyme/prodrug approaches was calculated. SCID/bg mice bearing experimental lung metastases were treated with CD::UPRT-MSC, HSVtk-MSC or both in combination in the presence of respective prodrug(s). Treatment efficiency was evaluated by EGFP-positive cell detection by flow cytometry combined with real-time PCR quantification of human cells in mouse organs. Results were confirmed by histological and immunohistochemical examination. We demonstrated various extent of synergy depending on tested cell line and experimental setup. The strongest synergism was observed on breast cancer-derived cell line MDA-MB-231/EGFP. Systemic administration of CD::UPRT-MSC and HSVtk-MSC in combination with 5-FC and GCV inhibited growth of MDA-MB-231 induced lung metastases. Combined gene-directed enzyme/prodrug therapy mediated by MSC exerted synergic cytotoxic effect and resulted in high therapeutic efficacy in vivo.

Integrin-targeted pH-responsive micelles for enhanced efficiency of anticancer treatment in vitro and in vivo

NASA Astrophysics Data System (ADS)

Liu, Jinjian; Deng, Hongzhang; Liu, Qiang; Chu, Liping; Zhang, Yumin; Yang, Cuihong; Zhao, Xuefei; Huang, Pingsheng; Deng, Liandong; Dong, Anjie; Liu, Jianfeng

2015-02-01

The key to developing more nanocarriers for the delivery of drugs in clinical applications is to consider the route of the carrier from the administration site to the target tissue and to look for a simple design to complete this whole journey. We synthesized the amphiphilic copolymer cRGDfK-poly(ethylene glycol)-b-poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate) (cRGD-PETM) to construct multifunctional micelles. These micelles combined enhanced drug-loading efficiency with tumor-targeting properties, visual detection and controllable intracellular drug release, resulting in an improved chemotherapeutic effect in vivo. Doxorubicin (DOX) was encapsulated within the cRGD-PETM micelles as a model drug (termed as cRGD-PETM/DOX Ms). The size and morphology of the micelles were characterized systematically. As a result of the hydrophobic interaction and the π-π conjugation between the DOX molecules and the PTTMA copolymers, the cRGD-PETM/DOX Ms showed an excellent drug-loading capacity. The results of in vitro drug-release studies indicated that the cumulative release of DOX from cRGD-PETM/DOX Ms at pH 5.0 was twice that at pH 7.4. The results of fluorescent microscopic analysis showed that the cRGD-PETM/DOX Ms could be internalized by 4T1 and HepG2 cells via receptor-mediated endocytosis with rapid intracellular drug release, which resulted in increased cytotoxicity compared with free DOX. Ex vivo imaging studies showed that the cRGD-PETM/DOX Ms improved the accumulation and retention of the drug in tumor tissues. Studies of the in vivo anticancer effects showed that the cRGD-PETM/DOX Ms had a significantly higher therapeutic efficacy with lower side-effects than free DOX and PETM/DOX Ms. These results show that the multifunctional cRGD-PETM/DOX Ms have great potential as vehicles for the delivery of hydrophobic anticancer drugs.

The prince and the pauper. A tale of anticancer targeted agents.

PubMed

Dueñas-González, Alfonso; García-López, Patricia; Herrera, Luis Alonso; Medina-Franco, Jose Luis; González-Fierro, Aurora; Candelaria, Myrna

2008-10-23

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited

Selenium and Iron Oxide Nanocomposites for Magnetically-Targeted Anti-Cancer Applications.

PubMed

Hauksdóttir, Halla Laufey; Webster, Thomas J

2018-03-01

introduces a brand new composite nanoparticle consisting of iron oxide and selenium which should be further studied for a wide range of magnetically targeted anticancer applications.

Taxane anticancer agents: a patent perspective

PubMed Central

Ojima, Iwao; Lichtenthal, Brendan; Lee, Siyeon; Wang, Changwei; Wang, Xin

2016-01-01

Introduction Paclitaxel and docetaxel were two epoch-making anticancer drugs and have been successfully used in chemotherapy for a variety of cancer types. In 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Albumin-bound paclitaxel (nab™-paclitaxel; abraxane) nanodroplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast cancer). Abraxane in combination with gemcitabine for the treatment of pancreatic cancer was approved by FDA in 2013. Accordingly, there have been a huge number of patent applications dealing with taxane anticancer agents in the last five years. Thus, it is a good time to review the progress in this area and find the next wave for new developments. Area covered This review article covers the patent literature from 2010 to early 2015 on various aspects of taxane-based chemotherapies and drug developments. Expert opinion Three FDA-approved taxane anticancer drugs will continue to expand their therapeutic applications, especially through drug combinations and new formulations. Inspired by the success of abraxane, new nano-formulations are emerging. Highly potent new-generation taxanes will play a key role in the development of efficacious tumor-targeted drug delivery systems. PMID:26651178

[Novel Anticancer Strategy Targeting Switch Mechanisms in Two Types of Cell Death: Necrosis and Apoptosis].

PubMed

Sato, Akira

2017-01-01

 Two types of cell death, necrosis and apoptosis, are defined in terms of cell death morphological features. We have been studying the mechanisms by which cell death processes are switched during the treatment of mouse tumor FM3A with anticancer, 5-fluoro-2'-deoxyuridine (FUdR): it induces original clone F28-7 to necrosis, but its sub-clone F28-7-A to apoptosis. We identified several such switch regulators of cell death: heat shock protein 90 (HSP90), lamin-B1, cytokeratin-19, and activating transcription factor 3 (ATF3), by using transcriptomic, proteomic analyses and siRNA screening. For example, the inhibition of HSP90 by its inhibitor geldanamycin in F28-7 caused a shift from necrosis to apoptosis. We also observed that the knockdown of lamin-B1, cytokeratin-19, or ATF3 expression in F28-7 resulted in a shift from necrosis to apoptosis. Recently, we used microRNA (miRNA, miR) microarray analyses to investigate the miRNA expression profiles in these sister cells. The miR-351 and miR-743a were expressed at higher levels in F28-7-A than in F28-7. Higher expression of miR-351 or miR-743a in F28-7, induced by transfecting the miR mimics, resulted in a switch of cell death mode: necrosis to apoptosis. Furthermore, transfection of an miR-351 inhibitor into F28-7-A resulted in morphological changes, and mode of cell death from apoptosis to necrosis. These findings suggest that the identified cell death regulators may have key roles in switching cell death mode. Possible mechanisms involving cell death regulators in the switch of necrosis or apoptosis are discussed. We propose a novel anticancer strategy targeting the switch regulators of necrosis or apoptosis.

Construction and cellular uptake behavior of redox-sensitive docetaxel prodrug-loaded liposomes.

PubMed

Ren, Guolian; Jiang, Mengjuan; Guo, Weiling; Sun, Bingjun; Lian, He; Wang, Yongjun; He, Zhonggui

2018-01-01

A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

PubMed

Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

1993-04-01

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

PubMed Central

Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

1993-01-01

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system. PMID:8494380

Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents

PubMed Central

Tanpure, Rajendra P.; George, Clinton S.; Strecker, Tracy E.; Devkota, Laxman; Tidmore, Justin K.; Lin, Chen-Ming; Herdman, Christine A.; MacDonough, Matthew T.; Sriram, Madhavi; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

2014-01-01

Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 M) and strongly cytotoxic against selected human cancer cell lines (for example, GI50 = 5.47 nM against NCI-H460 cells with fluorobenzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18

Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?

PubMed

Yeo, Chien Ing; Ooi, Kah Kooi; Tiekink, Edward R T

2018-06-11

A new era of metal-based drugs started in the 1960s, heralded by the discovery of potent platinum-based complexes, commencing with cisplatin [(H₃N)₂PtCl₂], which are effective anti-cancer chemotherapeutic drugs. While clinical applications of gold-based drugs largely relate to the treatment of rheumatoid arthritis, attention has turned to the investigation of the efficacy of gold(I) and gold(III) compounds for anti-cancer applications. This review article provides an account of the latest research conducted during the last decade or so on the development of gold compounds and their potential activities against several cancers as well as a summary of possible mechanisms of action/biological targets. The promising activities and increasing knowledge of gold-based drug metabolism ensures that continued efforts will be made to develop gold-based anti-cancer agents.

Abrogation of Microsatellite-instable Tumors Using a Highly Selective Suicide Gene/Prodrug Combination

PubMed Central

Ferrás, Cristina; Oude Vrielink, Joachim AF; Verspuy, Johan WA; te Riele, Hein; Tsaalbi-Shtylik, Anastasia; de Wind, Niels

2009-01-01

A substantial fraction of sporadic and inherited colorectal and endometrial cancers in humans is deficient in DNA mismatch repair (MMR). These cancers are characterized by length alterations in ubiquitous simple sequence repeats, a phenotype called microsatellite instability. Here we have exploited this phenotype by developing a novel approach for the highly selective gene therapy of MMR-deficient tumors. To achieve this selectivity, we mutated the VP22FCU1 suicide gene by inserting an out-of-frame microsatellite within its coding region. We show that in a significant fraction of microsatellite-instable (MSI) cells carrying the mutated suicide gene, full-length protein becomes expressed within a few cell doublings, presumably resulting from a reverting frameshift within the inserted microsatellite. Treatment of these cells with the innocuous prodrug 5-fluorocytosine (5-FC) induces strong cytotoxicity and we demonstrate that this owes to multiple bystander effects conferred by the suicide gene/prodrug combination. In a mouse model, MMR-deficient tumors that contained the out-of-frame VP22FCU1 gene displayed strong remission after treatment with 5-FC, without any obvious adverse systemic effects to the mouse. By virtue of its high selectivity and potency, this conditional enzyme/prodrug combination may hold promise for the treatment or prevention of MMR-deficient cancer in humans. PMID:19471249

Ocular drug metabolism of the bioactivating antioxidant N-acetylcarnosine for vision in ophthalmic prodrug and codrug design and delivery.

PubMed

Babizhayev, Mark A

2008-10-01

The basic idea in this study relates to the interesting research problem to employ with the knowledgeable pharmacy staff N-acetylcarnosine (NAC) in the developed suitable compounded prodrug ophthalmic preparations, which are currently used for the treatment of cataract and have antioxidant effect, in order to provide the molecular support to one of the most popular beliefs of the growing market for the treatment of senile cataract in patients and animals with efficacious NAC drug formulations worldwide patented by the author. This work presents the progress in ocular NAC prodrug and codrug design and delivery in light of revealed ocular metabolic activities. There is a considerable interest in the ophthalmic codrug design including NAC prodrug based on the strategies to improve ophthalmic drug delivery of the active peptide principal L-carnosine through the sustained intraocular metabolic activation of a dipeptide while making it resistant to enzymatic hydrolysis. Novel approaches to ocular NAC drug delivery, developed by Innovative Vision Products, Inc. (IVP), aim at enhancing the drug bioavailability by ensuring a prolonged retention of the medication in the eye, and/or by facilitating transcorneal penetration. IVP team studied the effects of lubricant eye drops designed as 1% NAC prodrug of L-carnosine containing a mucoadhesive cellulose-based and corneal absorption promoters in a drug delivery system. The predicted responses of the corneal and conjunctival penetrations to the synergistic promoters are useful in controlling the extent and pathway of the ocular and systemic absorptions of instilled NAC prodrug in designed ophthalmic formulations thereof. Utility of peptidase enzyme inhibitors in the codrug formulation to modulate the transport and metabolism of NAC prodrug appears to be a promising strategy for enhancing dipeptide drug transport across the cornea. The developed and officially CE mark registered by IVP NAC prodrug and codrug lubricating eye drop

Enzyme Prodrug Therapy Engineered into Electrospun Fibers with Embedded Liposomes for Controlled, Localized Synthesis of Therapeutics.

PubMed

Chandrawati, Rona; Olesen, Morten T J; Marini, Thatiane C C; Bisra, Gurpal; Guex, Anne Géraldine; de Oliveira, Marcelo G; Zelikin, Alexander N; Stevens, Molly M

2017-09-01

Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the envisioned therapeutic application. β-glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β-glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks. It is further shown that liposomes provide the highly beneficial stabilization of the enzyme when incubated in cell culture media. The assembled biocatalytic materials successfully produce antiproliferative drugs (SN-38) using externally administered prodrugs (SN-38-glucuronide) and effectively suppress cell proliferation, with envisioned utility in the design of cardiovascular grafts. © 2017 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug.

PubMed

Ding, Xuan; Day, Jeffrey S; Sperry, David C

2016-11-01

Absorption modeling has demonstrated its great value in modern drug product development due to its utility in understanding and predicting in vivo performance. In this case, we integrated physiologically based modeling in the development processes to effectively design extended-release (ER) clinical products for an ester prodrug LY545694. By simulating the trial results of immediate-release products, we delineated complex pharmacokinetics due to prodrug conversion and established an absorption model to describe the clinical observations. This model suggested the prodrug has optimal biopharmaceutical properties to warrant developing an ER product. Subsequently, we incorporated release profiles of prototype ER tablets into the absorption model to simulate the in vivo performance of these products observed in an exploratory trial. The models suggested that the absorption of these ER tablets was lower than the IR products because the extended release from the formulations prevented the drug from taking advantage of the optimal absorption window. Using these models, we formed a strategy to optimize the ER product to minimize the impact of the absorption window limitation. Accurate prediction of the performance of these optimized products by modeling was confirmed in a third clinical trial.

Direct chemical grafted curcumin on halloysite nanotubes as dual-responsive prodrug for pharmacological applications.

PubMed

Massaro, M; Amorati, R; Cavallaro, G; Guernelli, S; Lazzara, G; Milioto, S; Noto, R; Poma, P; Riela, S

2016-04-01

Covalently functionalized halloysite nanotubes (HNTs) were successfully employed as dual-responsive nanocarriers for curcumin (Cur). Particularly, we synthesized HNT-Cur prodrug with a controlled curcumin release on dependence of both intracellular glutathione (GSH) and pH conditions. In order to obtain HNT-Cur produgs, halloysite was firstly functionalized with cysteamine through disulphide linkage. Afterwards, curcumin molecules were chemically conjugated to the amino end groups of halloysite via Schiff's base formation. The successful functionalization of halloysite was proved by thermogravimetric analysis, FT-IR spectroscopy, dynamic light scattering and scanning electron microscopy. Experimental data confirmed the presence of curcumin on HNT external surface. Moreover, we investigated the kinetics of curcumin release by UV-vis spectroscopy, which highlighted that HNT-Cur prodrug possesses dual stimuli-responsive ability upon exposure to GSH-rich or acidic environment. In vitro antiproliferative and antioxidant properties of HNT-Cur prodrug were studied with the aim to explore their potential applications in pharmaceutics. This work puts forward an efficient strategy to prepare halloysite based nanocarriers with controlled drug delivery capacity through direct chemical grafting with stimuli-responsive linkage. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and biological evaluation of novel 10-substituted-7-ethyl-10-hydroxycamptothecin (SN-38) prodrugs.

PubMed

Zhou, Mo; Liu, Meixia; He, Xinhua; Yu, Hong; Wu, Di; Yao, Yishan; Fan, Shiyong; Zhang, Ping; Shi, Weiguo; Zhong, Bohua

2014-11-27

In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.

Inhaled Micro/Nanoparticulate Anticancer Drug Formulations: An Emerging Targeted Drug Delivery Strategy for Lung Cancers.

PubMed

Islam, Nazrul; Richard, Derek

2018-05-24

Local delivery of drug to the target organ via inhalation offers enormous benefits in the management of many diseases. Lung cancer is the most common of all cancers and it is the leading cause of death worldwide. Currently available treatment systems (intravenous or oral drug delivery) are not efficient in accumulating the delivered drug into the target tumor cells and are usually associated with various systemic and dose-related adverse effects. The pulmonary drug delivery technology would enable preferential accumulation of drug within the cancer cell and thus be superior to intravenous and oral delivery in reducing cancer cell proliferation and minimising the systemic adverse effects. Site-specific drug delivery via inhalation for the treatment of lung cancer is both feasible and efficient. The inhaled drug delivery system is non-invasive, produces high bioavailability at low dose and avoids first pass metabolism of the delivered drug. Various anticancer drugs including chemotherapeutics, proteins and genes have been investigated for inhalation in lung cancers with significant outcomes. Pulmonary delivery of drugs from dry powder inhaler (DPI) formulation is stable and has high patient compliance. Herein, we report the potential of pulmonary drug delivery from dry powder inhaler (DPI) formulations inhibiting lung cancer cell proliferation at very low dose with reduced unwanted adverse effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Potential Anticancer Properties of Osthol: A Comprehensive Mechanistic Review

PubMed Central

Shokoohinia, Yalda; Jafari, Fataneh; Mohammadi, Zeynab; Bazvandi, Leili; Hosseinzadeh, Leila; Chow, Nicholas; Bhattacharyya, Piyali; Farzaei, Mohammad Hosein; Farooqi, Ammad Ahmad; Nabavi, Seyed Mohammad; Bishayee, Anupam

2018-01-01

Cancer is caused by uncontrolled cell proliferation which has the potential to occur in different tissues and spread into surrounding and distant tissues. Despite the current advances in the field of anticancer agents, rapidly developing resistance against different chemotherapeutic drugs and significantly higher off-target effects cause millions of deaths every year. Osthol is a natural coumarin isolated from Apiaceaous plants which has demonstrated several pharmacological effects, such as antineoplastic, anti-inflammatory and antioxidant properties. We have attempted to summarize up-to-date information related to pharmacological effects and molecular mechanisms of osthol as a lead compound in managing malignancies. Electronic databases, including PubMed, Cochrane library, ScienceDirect and Scopus were searched for in vitro, in vivo and clinical studies on anticancer effects of osthol. Osthol exerts remarkable anticancer properties by suppressing cancer cell growth and induction of apoptosis. Osthol’s protective and therapeutic effects have been observed in different cancers, including ovarian, cervical, colon and prostate cancers as well as chronic myeloid leukemia, lung adenocarcinoma, glioma, hepatocellular, glioblastoma, renal and invasive mammary carcinoma. A large body of evidence demonstrates that osthol regulates apoptosis, proliferation and invasion in different types of malignant cells which are mediated by multiple signal transduction cascades. In this review, we set spotlights on various pathways which are targeted by osthol in different cancers to inhibit cancer development and progression. PMID:29301373

CNS Anticancer Drug Discovery and Development: 2016 conference insights

PubMed Central

Levin, Victor A; Abrey, Lauren E; Heffron, Timothy P; Tonge, Peter J; Dar, Arvin C; Weiss, William A; Gallo, James M

2017-01-01

CNS Anticancer Drug Discovery and Development, 16-17 November 2016, Scottsdale, AZ, USA The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669–286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time- and cost-efficient clinical trials based on surrogate end points. PMID:28718326

Fluorogenic reaction-based prodrug conjugates as targeted cancer theranostics.

PubMed

Lee, Min Hee; Sharma, Amit; Chang, Min Jung; Lee, Jinju; Son, Subin; Sessler, Jonathan L; Kang, Chulhun; Kim, Jong Seung

2018-01-02

Theranostic systems are receiving ever-increasing attention due to their potential therapeutic utility, imaging enhancement capability, and promise for advancing the field of personalized medicine, particularly as it relates to the diagnosis, staging, and treatment of cancer. In this Tutorial Review, we provide an introduction to the concepts of theranostic drug delivery effected via use of conjugates that are able to target cancer cells selectively, provide cytotoxic chemotherapeutics, and produce readily monitored imaging signals in vitro and in vivo. The underlying design concepts, requiring the synthesis of conjugates composed of imaging reporters, masked chemotherapeutic drugs, cleavable linkers, and cancer targeting ligands, are discussed. Particular emphasis is placed on highlighting the potential benefits of fluorogenic reaction-based targeted systems that are activated for both imaging and therapy by cellular entities, e.g., thiols, reactive oxygen species and enzymes, which are present at relatively elevated levels in tumour environments, physiological characteristics of cancer, e.g., hypoxia and acidic pH. Also discussed are systems activated by an external stimulus, such as light. The work summarized in this Tutorial Review will help define the role fluorogenic reaction-based, cancer-targeting theranostics may have in advancing drug discovery efforts, as well as improving our understanding of cellular uptake and drug release mechanisms.

Solid lipid nanoparticles by coacervation loaded with a methotrexate prodrug: preliminary study for glioma treatment.

PubMed

Battaglia, Luigi; Muntoni, Elisabetta; Chirio, Daniela; Peira, Elena; Annovazzi, Laura; Schiffer, Davide; Mellai, Marta; Riganti, Chiara; Salaroglio, Iris Chiara; Lanotte, Michele; Panciani, Pierpaolo; Capucchio, Maria Teresa; Valazza, Alberto; Biasibetti, Elena; Gallarate, Marina

2017-03-01

Methotrexate-loaded biocompatible nanoparticles were tested for preliminary efficacy in glioma treatment. Behenic acid nanoparticles, prepared by the coacervation method, were loaded with the ester prodrug didodecylmethotrexate, which was previously tested in vitro against glioblastoma human primary cultures. Nanoparticle conjugation with an ApoE mimicking chimera peptide was performed to obtain active targeting to the brain. Biodistribution studies in healthy rats assessed the superiority of ApoE-conjugated formulation, which was tested on an F98/Fischer glioma model. Differences were observed in tumor growth rate (measured by MRI) between control and treated rats. In vitro tests on F98 cultured cells assessed their susceptibility to treatment, with consequent apoptosis, and allowed us to explain the apoptosis observed in glioma models.

Hypoxia-activated prodrug enhances therapeutic effect of sunitinib in melanoma

PubMed Central

Liu, Shujing; Tetzlaff, Michael T.; Wang, Tao; Chen, Xiang; Yang, Ruifeng; Kumar, Suresh M.; Vultur, Adina; Li, Pengxiang; Martin, James S.; Herlyn, Meenhard; Amaravadi, Ravi

2017-01-01

Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia—a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume. Here, we show that melanoma cells grown under hypoxic conditions exhibit increased resistance to a wide variety of therapeutic agents in vitro and generate larger and more aggressive tumors in vivo than melanoma cells grown under normoxic conditions. However, hypoxic melanoma cells exhibit a pronounced sensitivity to TH-302 which is further enhanced by the addition of sunitinib. Short term sunitinib treatment fails to prolong the survival of melanoma bearing genetically engineered mice (Tyr::CreER; BRafCA;Ptenlox/lox) but increases tumor hypoxia. Long term TH-302 alone modestly prolongs the overall survival of melanoma bearing mice. Combination therapy of TH-302 with sunitinib further increases the survival of treated mice. These studies provide a translational rationale for combining hypoxic tumor cell targeted therapies with anti-angiogenics for treatment of melanoma. PMID:29383148

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins.

PubMed

de J Hiller, Noemi; A A E Silva, Nayane; Faria, Robson X; Souza, André Luís A; Resende, Jackson A L C; Borges Farias, André; Correia Romeiro, Nelilma; de Luna Martins, Daniela

2018-06-01

Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)-(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine-phosphorylation-regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of salicylic acid fatty ester prodrugs for UV protection.

PubMed

Im, Jong Seob; Balakrishnan, Prabagar; Oh, Dong Hoon; Kim, Jung Sun; Jeon, Eun-Mi; Kim, Dae-Duk; Yong, Chul Soon; Choi, Han-Gon

2011-07-01

The purpose of this study was to investigate the physicochemical properties and in vitro evaluation of fatty ester prodrugs of salicylic acid for ultraviolet (UV) protection. The physicochemical properties such as lipophilicity, chemical stability and enzymatic hydrolysis were investigated with the following fatty ester prodrugs of salicylic acid: octanoyl (C8SA), nonanoyl (C9SA), decanoyl (C10SA), lauroyl (C12SA), myristoyl (C14SA) and palmitoyl oxysalicylate (C16SA). Furthermore, their skin permeation and accumulation were evaluated using a combination of common permeation enhancing techniques such as the use of a lipophilic receptor solution, removal of stratum corneum and delipidization of skin. Their k' values were proportional to the degree of carbon-carbon saturation in the side chain. All these fatty esters were highly stable in 2-propanol, acetonitrile and glycerin, but unstable in methanol and ethanol. They were relatively unstable in liver and skin homogenates. In particular, C16SA was mostly hydrolyzed to its parent compound in hairless mouse liver and skin homogenates, suggesting that it might be converted to salicylic acid after its topical administration. In the skin permeation and accumulation study, C16SA showed the poorest permeation in all skins, suggesting that it could not be permeated in the skin. Furthermore, C14SA and C16SA were less accumulated in delipidized skin compared with normal skin or stripped skin, suggesting that these esters had relatively strong affinities for lipids compared with the other prodrugs in the skin. C16SA showed significantly higher dermal accumulation in all skins compared with its parent salicylic acid. Thus, the palmitoyl oxysalicylate (C16SA) might be a potential candidate for UV protection due to its absence of skin permeation, smaller uptake in the lipid phase and relatively lower skin accumulation.

Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions

NASA Astrophysics Data System (ADS)

Karaman, Rafik; Ghareeb, Hiba; Dajani, Khuloud Kamal; Scrano, Laura; Hallak, Hussein; Abu-Lafi, Saleh; Mecca, Gennaro; Bufo, Sabino A.

2013-07-01

Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives four tranexamic acid prodrugs were designed. The DFT results on the acid catalyzed hydrolysis revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. When the amine leaving group was a primary amine or tranexamic acid moiety, the tetrahedral intermediate collapse was the rate-limiting step, whereas in the cases by which the amine leaving group was aciclovir or cefuroxime the rate-limiting step was the tetrahedral intermediate formation. The linear correlation between the calculated DFT and experimental rates for N-methylmaleamic acids 1- 7 provided a credible basis for designing tranexamic acid prodrugs that have the potential to release the parent drug in a sustained release fashion. For example, based on the calculated B3LYP/6-31G(d,p) rates the predicted t1/2 (a time needed for 50 % of the prodrug to be converted into drug) values for tranexamic acid prodrugs ProD 1- ProD 4 at pH 2 were 556 h [50.5 h as calculated by B3LYP/311+G(d,p)] and 6.2 h as calculated by GGA: MPW1K), 253 h, 70 s and 1.7 h, respectively. Kinetic study on the interconversion of the newly synthesized tranexamic acid prodrug ProD 1 revealed that the t1/2 for its conversion to the parent drug was largely affected by the pH of the medium. The experimental t1/2 values in 1 N HCl, buffer pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h, respectively.

p53-Mdm2 interaction inhibitors as novel nongenotoxic anticancer agents.

PubMed

Nayak, Surendra Kumar; Khatik, Gopal L; Narang, Rakesh; Monga, Vikramdeep; Chopra, Harish Kumar

2017-06-23

Cancer is a major global health problem with high mortality rate. Most of clinically used anticancer agents induce apoptosis through genotoxic stress at various stages of cell cycle and activation of p53. Acting as a tumor suppressor p53 plays a vital role in preventing tumor development. Tumor suppressor function of p53 is effectively antagonized by its direct interaction with murine double minute 2 (Mdm2) proteins via multiple mechanisms. Thus, p53-Mdm2 interaction has been found to be an important target for the development of novel anticancer agents. Currently, nutlin, spirooxindole, isoquilinone and piperidinone analogues inhibiting p53-Mdm2 interaction are found to be promising in the treatment of cancer. The current review focused to scrutinize the structural aspects of p53-Mdm2 interaction inhibitors. The present study provides a detailed collection of published information on different classes of inhibitors of p53-Mdm2 interaction as potential anticancer agents. The review highlighted the structural aspects of various reported p53-Mdm2 inhibitor for optimization. In the last few years, different classes of inhibitors of p53-Mdm2 have been designed and developed, and seven such compounds are being evaluated in clinical trials as new anticancer drugs. Further, to explore the role of p53 protein as a potential target for anticancer drug development, in this review, the mechanism of Mdm2 mediated inactivation of p53 and recent developments on p53-Mdm2 interactions inhibitors are discussed. Agents designed to block the p53-Mdm2 interaction may have a therapeutic potential for treatment of a subset of human cancers retaining wild-type p53. We review herein the recent advances in the design and development of potent small molecules as p53-Mdm2 inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Anthracycline-Formaldehyde Conjugates and Their Targeted Prodrugs

NASA Astrophysics Data System (ADS)

Koch, Tad H.; Barthel, Benjamin L.; Kalet, Brian T.; Rudnicki, Daniel L.; Post, Glen C.; Burkhart, David J.

The sequence of research leading to a proposal for anthracycline cross-linking of DNA is presented. The clinical anthracycline antitumor drugs are anthraquinones, and as such are redox active. Their redox chemistry leads to induction of oxidative stress and drug metabolites. An intermediate in reductive glycosidic cleavage is a quinone methide, once proposed as an alkylating agent of DNA. Subsequent research now implicates formaldehyde as a mediator of anthracycline-DNA cross-linking. The cross-link at 5'-GC-3' sites consists of a covalent linkage from the amino group of the anthracycline to the 2-amino group of the G-base through a methylene from formaldehyde, hydrogen bonding from the 9-OH to the G-base on the opposing strand, and hydrophobic interactions through intercalation of the anthraquinone. The combination of these interactions has been described as a virtual cross-link of DNA. The origin of the formaldehyde in vivo remains a mystery. In vitro, doxorubicin reacts with formaldehyde to give firstly a monomeric oxazolidine, doxazolidine, and secondly a dimeric oxazolidine, doxoform. Doxorubicin reacts with formaldehyde in the presence of salicylamide to give the N-Mannich base conjugate, doxsaliform. Doxsaliform is several fold more active in tumor cell growth inhibition than doxorubicin, but doxazolidine and doxoform are orders of magnitude more active than doxorubicin. Exploratory research on the potential for doxsaliform and doxazolidine as targeted cytotoxins is presented. A promising lead design is pentyl PABC-Doxaz, targeted to a carboxylesterase enzyme overexpressed in liver cancer cells and/or colon cancer cells.

Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite

PubMed Central

Zhou, Yan; Zhang, Genyan; Wang, Feng; Wang, Jin; Ding, Yanwei; Li, Xinyu; Shi, Chongtie; Li, Jiakui; Shih, Chengkon; You, Song

2017-01-01

This study presents a process of developing a novel PI3K–mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future. PMID:29118584

Pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses.

PubMed

Tsujimura, Koji; Yamada, Masayuki; Nagata, Shun-ichi; Yamanaka, Takashi; Nemoto, Manabu; Kondo, Takashi; Kurosawa, Masahiko; Matsumura, Tomio

2010-03-01

We investigated the pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses. Following an oral dose of famciclovir at 20 mg/kg, maximum plasma concentrations of penciclovir occurred between 0.75 and 1.5 hr (mean 0.94 + or - 0.38 hr) after dosing and were in the range 2.22 to 3.56 microg/ml (mean 2.87 + or - 0.61 microg/ml). The concentrations of penciclovir declined in a biphasic manner after the peak concentration was attained. The mean half-life of the rapid elimination phase was 1.73 + or - 0.34 hr whereas that of the slow elimination phase was 34.34 + or - 13.93 hr. These pharmacokinetic profiles observed were similar to those of another antiherpesvirus drug, acyclovir, previously reported in horses following oral dosing of its prodrug valacyclovir.

Synthesis, characterisation, and in vitro anticancer activity of curcumin analogues bearing pyrazole/pyrimidine ring targeting EGFR tyrosine kinase.

PubMed

Ahsan, Mohamed Jawed; Khalilullah, Habibullah; Yasmin, Sabina; Jadav, Surender Singh; Govindasamy, Jeyabalan

2013-01-01

In search of potential therapeutics for cancer, we described herein the synthesis, characterization, and in vitro anticancer activity of a novel series of curcumin analogues. The anticancer effects were evaluated on a panel of 60 cell lines, according to the National Cancer Institute (NCI) screening protocol. There were 10 tested compounds among 14 synthesized compounds, which showed potent anticancer activity in both one-dose and 5-dose assays. The most active compound of the series was 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-yl(phenyl)methanone which showed mean growth percent of -28.71 in one-dose assay and GI₅₀ values between 0.0079 and 1.86 µM in 5-dose assay.

Retrovolution: HIV-driven evolution of cellular genes and improvement of anticancer drug activation.

PubMed

Rossolillo, Paola; Winter, Flore; Simon-Loriere, Etienne; Gallois-Montbrun, Sarah; Negroni, Matteo

2012-08-01

In evolution strategies aimed at isolating molecules with new functions, screening for the desired phenotype is generally performed in vitro or in bacteria. When the final goal of the strategy is the modification of the human cell, the mutants selected with these preliminary screenings may fail to confer the desired phenotype, due to the complex networks that regulate gene expression in higher eukaryotes. We developed a system where, by mimicking successive infection cycles with HIV-1 derived vectors containing the gene target of the evolution in their genome, libraries of gene mutants are generated in the human cell, where they can be directly screened. As a proof of concept we created a library of mutants of the human deoxycytidine kinase (dCK) gene, involved in the activation of nucleoside analogues used in cancer treatment, with the aim of isolating a variant sensitizing cancer cells to the chemotherapy compound Gemcitabine, to be used in gene therapy for anti-cancer approaches or as a poorly immunogenic negative selection marker for cell transplantation approaches. We describe the isolation of a dCK mutant, G12, inducing a 300-fold sensitization to Gemcitabine in cells originally resistant to the prodrug (Messa 10K), an effect 60 times stronger than the one induced by the wt enzyme. The phenotype is observed in different tumour cell lines irrespective of the insertion site of the transgene and is due to a change in specificity of the mutated kinase in favour of the nucleoside analogue. The mutations characterizing G12 are distant from the active site of the enzyme and are unpredictable on a rational basis, fully validating the pragmatic approach followed. Besides the potential interest of the G12 dCK variant for therapeutic purposes, the methodology developed is of interest for a large panel of applications in biotechnology and basic research.

Mechanistic Basis of Sensitivity/Resistance Towards Anti-Cancer Drugs Targeting Topoisomerase II

DTIC Science & Technology

2005-04-01

alkylation of hstopo Ilac by both anticancer drugs such as menadione and chemopreventive compounds such as diallyl trisulfide (DAT), which has been...putatively identified menadione as having reacted with Cys427 by matrix-assisted laser desorption ionization (MALDI) MS. Preliminary results from LC-ESI-MS...suggest that menadione reacts with additional thiol residues, albeit through indirect evidence. The indirect evidence is similar to that mentioned

Mechanistic Basis of Sensitivity/Resistance Towards Anti-cancer Drugs Targeting Topoisomerase II

DTIC Science & Technology

2006-04-01

of hstopo IIα by both anticancer drugs such as menadione and chemopreventive compounds such as 9 diallyl trisulfide (DAT), which has been shown to...we putatively identified menadione as having reacted with Cys427 by matrix-assisted laser desorption ionization (MALDI) MS. Preliminary results...from LC- ESI-MS suggest that menadione reacts with additional thiol residues, albeit through indirect evidence. The indirect evidence is similar to

Hybrid anticancer 1,2-diazine derivatives with multiple mechanism of action. Part 3.

PubMed

Antoci, Vasilichia; Mantu, Dorina; Cozma, Danut Gabriel; Usru, Cornelia; Mangalagiu, Ionel I

2014-01-01

Antitumour chemotherapy is nowadays a very active field of research, DNA targeting drugs being the most widely used group in therapy. The design, synthesis and anticancer activity of a new class of anticancer derivatives with pyrrolo-1,2-diazine and benzoquinone skeleton is presented. The synthesis is direct and efficient, involving an alkylation followed by a [3+2] dipolar cycloaddition. The penta- and tetra-cyclic pyrrolo-1,2-diazine were evaluated for their in vitro anticancer activity against an NCI 60 human tumour cell line panel. The pentacyclic-1,2-diazine exhibit a significant anticancer activity against Non-Small Cell Lung Cancer NCI-H460, Leukemia MOLT-4, Leukemia CCRF-CEM and Breast Cancer MCF7. We hypothesize that these molecules will exert their anticancer activity through multiple mechanisms of action: intercalating the DNA, inhibiting the topoisomerase enzymes and, destroying the DNA strands via electron transfer mechanism. However, the intercalation with the DNA seems to prevail in competition with the others mechanisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

PubMed

Bauer, Matthias R; Joerger, Andreas C; Fersht, Alan R

2016-09-06

The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

PhytoNanotechnology: Enhancing Delivery of Plant Based Anti-cancer Drugs.

PubMed

Khan, Tabassum; Gurav, Pranav

2017-01-01

Natural resources continue to be an invaluable source of new, novel chemical entities of therapeutic utility due to the vast structural diversity observed in them. The quest for new and better drugs has witnessed an upsurge in exploring and harnessing nature especially for discovery of antimicrobial, antidiabetic, and anticancer agents. Nature has historically provide us with potent anticancer agents which include vinca alkaloids [vincristine (VCR), vinblastine, vindesine, vinorelbine], taxanes [paclitaxel (PTX), docetaxel], podophyllotoxin and its derivatives [etoposide (ETP), teniposide], camptothecin (CPT) and its derivatives (topotecan, irinotecan), anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), and others. In fact, half of all the anti-cancer drugs approved internationally are either natural products or their derivatives and were developed on the basis of knowledge gained from small molecules or macromolecules that exist in nature. Three new anti-cancer drugs introduced in 2007, viz. trabectedin, epothilone derivative ixabepilone, and temsirolimus were obtained from microbial sources. Selective drug targeting is the need of the current therapeutic regimens for increased activity on cancer cells and reduced toxicity to normal cells. Nanotechnology driven modified drugs and drug delivery systems are being developed and introduced in the market for better cancer treatment and management with good results. The use of nanoparticulate drug carriers can resolve many challenges in drug delivery to the cancer cells that includes: improving drug solubility and stability, extending drug half-lives in the blood, reducing adverse effects in non-target organs, and concentrating drugs at the disease site. This review discusses the scientific ventures and explorations involving application of nanotechnology to some selected plant derived molecules. It presents a comprehensive review of formulation strategies of phytoconstituents in development of novel

Anti-Cancer Drug Delivery Using Carbohydrate-Based Polymers.

PubMed

Ranjbari, Javad; Mokhtarzadeh, Ahad; Alibakhshi, Abbas; Tabarzad, Maryam; Hejazi, Maryam; Ramezani, Mohammad

2018-02-12

Polymeric drug delivery systems in the form of nanocarriers are the most interesting vehicles in anticancer therapy. Among different types of biocompatible polymers, carbohydrate-based polymers or polysaccharides are the most common natural polymers with complex structures consisting of long chains of monosaccharide or disaccharide units bound by glycosidic linkages. Their appealing properties such as availability, biocompatibility, biodegradability, low toxicity, high chemical reactivity, facile chemical modification and low cost led to their extensive applications in biomedical and pharmaceutical fields including development of nano-vehicles for delivery of anti-cancer therapeutic agents. Generally, reducing systemic toxicity, increasing short half-lives and tumor localization of agents are the top priorities for a successful cancer therapy. Polysaccharide-based or - coated nanosystems with respect to their advantageous features as well as accumulation in tumor tissue due to enhanced permeation and retention (EPR) effect can provide promising carrier systems for the delivery of noblest impressive agents. Most challenging factor in cancer therapy was the toxicity of anti-cancer therapeutic agents for normal cells and therefore, targeted delivery of these drugs to the site of action can be considered as an interesting therapeutic strategy. In this regard, several polysaccharides exhibited selective affinity for specific cell types, and so they can act as a targeting agent in drug delivery systems. Accordingly, different aspects of polysaccharide applications in cancer treatment or diagnosis were reviewed in this paper. In this regard, after a brief introduction of polysaccharide structure and its importance, the pharmaceutical usage of carbohydrate-based polymers was considered according to the identity of accompanying active pharmaceutical agents. It was also presented that the carbohydrate based polymers have been extensively considered as promising materials in

Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes.

PubMed

Tao, Wenhui; Zhao, Dongyang; Sun, Mengchi; Wang, Ziyu; Lin, Bin; Bao, Yu; Li, Yingying; He, Zhonggui; Sun, Yinghua; Sun, Jin

2018-04-25

Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5'-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in P eff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic K m : 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the

Synthesis and in vitro evaluation of methotrexate conjugated O, N-carboxymethyl chitosan via peptidyl spacers

NASA Astrophysics Data System (ADS)

Li, Dan; Lu, Bo; Zhang, Hong; Huang, Zhijun; Xu, Peihu; Zheng, Hua; Yin, Yihua; Xu, Haixing; Liu, Xia; Lou, Yiceng; Zhang, Xueqiong; Xiong, Fuliang

2014-09-01

The use of methotrexate (MTX), an anticancer drug for the treatment of hematologic malignancies, has been limited in the clinical application due to its poor water solubility, high clearance rate, and lack of target specificity. To solve these problems, O, N-carboxymethyl chitosan-dipeptide-MTX conjugates have been synthesized and characterized by fourier transform infrared radiation spectroscopy and proton nuclear magnetic resonance (1H NMR). All polymeric conjugates showed satisfactory water solubility. The results of the study revealed that drug release and toxicity were affected by employing polymeric conjugation strategy and dipeptide spacers [glycylglycine (Gly-Gly), glycyl- l-phenylalanine (Gly-Phe), glycyl- l-tyrosine (Gly-Tyr)]. It has been found that drugs could be effectively loaded and released when polymeric prodrugs were combined with a dipeptide spacer. In conclusion, O, N-CMCS-dipeptide-MTX polymeric prodrugs could potentially be used as responsive drug delivery systems.

Synthesis and evaluation of macromolecule-bound derivatives of a peptidyl-1-beta-D-arabinofuranosylcytosine prodrug.

PubMed

Balajthy, Zoltan

2008-04-01

Macromolecule-bound Val-Leu-Lys-ara-C (1) prodrugs were synthesized with spacers (-HN-(CH(2))(x)-CO-; x =1,3,5) between the dextran carrier (T-70) and 1, in order to achieve a sustained-release drug delivery system dextran-NH-(CH(2))(x:1,3,5)-CO-Val-Leu-Lys-ara-C (5, 6 and 7). The conjugation increased the stability of 1 in aqueous buffer solutions by three times (t((1/2)) 53.0 h, pH 7.4). The length of spacer also regulated the rate of hydrolysis of the prodrugs in serum. The shortest spacer (-HN-(CH(2))-CO-, (2)) in 5 provided the best protection of 1 against the hydrolyzing ability of proteinase- alpha(2)-macroglobulin complexes, increasing its half-life approximately 30-fold. The conjugation procedure resulted in a growth arrest ability for macromolecular-bound prodrugs 5, 6 and 7 against L1210 with IC(50) of 0.01 microM in vitro, which is significantly lower than that of other ara-C-macromolecule conjugates. 5 and 6 arrested cell growth in a broader range of concentration, between 1 x 10(-5)-1.0 microM, than ara-C could.

Multifunctional Surface-Enhanced Raman Spectroscopy-Detectable Silver Nanoparticles Combined Photodynamic Therapy and pH-Triggered Chemotherapy.

PubMed

Srinivasan, Supriya; Bhardwaj, Vinay; Nagasetti, Abhignyan; Fernandez-Fernandez, Alicia; McGoron, Anthony J

2016-12-01

This research paper reports the development of a multifunctional anti-cancer prodrug system based on silver nanoparticles. This prodrug system is composed of 70-nm sized nanoparticles and features photodynamic therapeutic properties and active, pH-triggered drug release. The silver nanoparticles are decorated with a folic acid (FA) targeting ligand via an amide bond, and also conjugated to the chemotherapeutic drug doxorubicin (DOX) via an acid-cleavable hydrazone bond. Both FA and DOX are attached to the silver nanoparticles through a polyethylene glycol (PEG) spacer. This prodrug system can preferentially enter cells that over-express folic acid receptors, with subsequent intracellular drug release triggered by reduced intracellular pH. Moreover, the silver nanoparticle carrier system exhibits photodynamic therapeutic (PDT) activity, so that the cell viability of cancer cells that overexpress folate receptors can be further reduced upon light irradiation. The dual effects of pH-triggered drug release and PDT increase the therapeutic efficacy of this system. The multifunctional nanoparticles can be probed intracellularly through Surface-Enhanced Raman Spectroscopy (SERS) and fluorescence spectroscopy. The current report explores the applicability of this multifunctional silver nanoparticle-based system for cancer theranostics.

Unraveling the Anticancer Effect of Curcumin and Resveratrol

PubMed Central

Pavan, Aline Renata; da Silva, Gabriel Dalio Bernardes; Jornada, Daniela Hartmann; Chiba, Diego Eidy; Fernandes, Guilherme Felipe dos Santos; Man Chin, Chung; dos Santos, Jean Leandro

2016-01-01

Resveratrol and curcumin are natural products with important therapeutic properties useful to treat several human diseases, including cancer. In the last years, the number of studies describing the effect of both polyphenols against cancer has increased; however, the mechanism of action in all of those cases is not completely comprehended. The unspecific effect and the ability to interfere in assays by both polyphenols make this challenge even more difficult. Herein, we analyzed the anticancer activity of resveratrol and curcumin reported in the literature in the last 11 years, in order to unravel the molecular mechanism of action of both compounds. Molecular targets and cellular pathways will be described. Furthermore, we also discussed the ability of these natural products act as chemopreventive and its use in association with other anticancer drugs. PMID:27834913

Unraveling the Anticancer Effect of Curcumin and Resveratrol.

PubMed

Pavan, Aline Renata; Silva, Gabriel Dalio Bernardes da; Jornada, Daniela Hartmann; Chiba, Diego Eidy; Fernandes, Guilherme Felipe Dos Santos; Man Chin, Chung; Dos Santos, Jean Leandro

2016-11-10

Resveratrol and curcumin are natural products with important therapeutic properties useful to treat several human diseases, including cancer. In the last years, the number of studies describing the effect of both polyphenols against cancer has increased; however, the mechanism of action in all of those cases is not completely comprehended. The unspecific effect and the ability to interfere in assays by both polyphenols make this challenge even more difficult. Herein, we analyzed the anticancer activity of resveratrol and curcumin reported in the literature in the last 11 years, in order to unravel the molecular mechanism of action of both compounds. Molecular targets and cellular pathways will be described. Furthermore, we also discussed the ability of these natural products act as chemopreventive and its use in association with other anticancer drugs.

Carnosol: a promising anti-cancer and anti-inflammatory agent.

PubMed

Johnson, Jeremy J

2011-06-01

The Mediterranean diet and more specifically certain meats, fruits, vegetables, and olive oil found in certain parts of the Mediterranean region have been associated with a decreased cardiovascular and diabetes risk. More recently, several population based studies have observed with these lifestyle choices have reported an overall reduced risk for several cancers. One study in particular observed an inverse relationship between consumption of Mediterranean herbs such as rosemary, sage, parsley, and oregano with lung cancer. In light of these findings there is a need to explore and identify the anti-cancer properties of these medicinal herbs and to identify the phytochemicals therein. One agent in particular, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals. This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug.

PubMed

Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

2014-11-01

Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

pH-sensitive pHluorins as a molecular sensor for in situ monitoring of enzyme-catalyzed prodrug activation.

PubMed

Liu, Hui; Cao, Xiaodan; Wang, Ping; Ma, Xingyuan

2017-07-01

This work examines the feasibility of using a pH-sensitive fluorescent protein as a molecular reporter for enzyme-catalyzed prodrug activation reaction. Specifically, a ratiometric pHluorins was examined for detection of the activity of horseradish peroxidase (HRP) for the activation of indole-3-acetic acid. The pHluorins and HRP were conjugated chemically, forming a biocatalyst with a self-reporting function. Results showed that the characteristic fluorescence intensity ratio of the conjugate shifted from 1.47 to 1.40 corresponding to the progress of the prodrug activation reaction. The effectiveness of applying the conjugate for inhibition of the growth of Bcap-37 cells was also demonstrated simultaneously with reaction monitoring. The results reveal a very promising approach to realizing in situ monitoring of enzyme activities based on pH shifting for enzyme-based prodrug therapy applications. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Anticancer activity of drug conjugates in head and neck cancer cells.

PubMed

Majumdar, Debatosh; Rahman, Mohammad Aminur; Chen, Zhuo Georgia; Shin, Dong M

2016-06-01

Sexually transmitted oral cancer/head and neck cancer is increasing rapidly. Human papilloma virus (HPV) is playing a role in the pathogenesis of a subset of squamous cell carcinoma of head and neck (SCCHN). Paclitaxel is a widely used anticancer drug for breast, ovarian, testicular, cervical, non-small cell lung, head and neck cancer. However, it is water insoluble and orally inactive. We report the synthesis of water soluble nanosize conjugates of paclitaxel, branched PEG, and EGFR-targeting peptide by employing native chemical ligation. We performed a native chemical ligation between the N-hydroxy succinimide (NHS) ester of paclitaxel succinate and cysteine at pH 6.5 to give the cysteine-conjugated paclitaxel derivative. The thiol functionality of cysteine was activated and subsequently conjugated to multiarm thiol-PEG to obtain the paclitaxel branched PEG conjugate. Finally, we conjugated an EGFR-targeting peptide to obtain conjugates of paclitaxel, branched PEG, and EGFR-targeting peptide. These conjugates show anticancer activity against squamous cell carcinoma of head and neck cells (SCCHN, Tu212).

Catechin prodrugs and analogs: a new array of chemical entities with improved pharmacological and pharmacokinetic properties.

PubMed

Bansal, Sumit; Vyas, Sandeep; Bhattacharya, Shoumyo; Sharma, Manu

2013-10-11

Extensive research on tea catechins, mainly (-)-epigallocatechin gallate, has shown numerous health promoting effects. However, various clinical studies demonstrated several issues associated with tea catechins which account for their poor systemic bioavailability. In order to improve pharmacological activity and bioavailability of natural tea catechins, two major strategies have been adopted to date which include synthesizing catechin analogs/prodrugs and the development of novel drug delivery systems. In this review, we provide a detailed account of novel synthetic analogs/prodrugs as well as novel drug delivery approaches used for natural tea catechins to make them therapeutically potent drug-like molecules.

Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

NASA Astrophysics Data System (ADS)

Zhang, Yumin; Yang, Cuihong; Wang, Weiwei; Liu, Jinjian; Liu, Qiang; Huang, Fan; Chu, Liping; Gao, Honglin; Li, Chen; Kong, Deling; Liu, Qian; Liu, Jianfeng

2016-02-01

Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

PubMed Central

Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

2011-01-01

Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

Synergistically enhanced selective intracellular uptake of anticancer drug carrier comprising folic acid-conjugated hydrogels containing magnetite nanoparticles

NASA Astrophysics Data System (ADS)

Kim, Haneul; Jo, Ara; Baek, Seulgi; Lim, Daeun; Park, Soon-Yong; Cho, Soo Kyung; Chung, Jin Woong; Yoon, Jinhwan

2017-01-01

Targeted drug delivery has long been extensively researched since drug delivery and release at the diseased site with minimum dosage realizes the effective therapy without adverse side effects. In this work, to achieve enhanced intracellular uptake of anticancer drug carriers for efficient chemo-therapy, we have designed targeted multifunctional anticancer drug carrier hydrogels. Temperature-responsive poly(N-isopropylacrylamide) (PNIPAm) hydrogel core containing superparamagnetic magnetite nanoparticles (MNP) were prepared using precipitation polymerization, and further polymerized with amine-functionalized copolymer shell to facilitate the conjugation of targeting ligand. Then, folic acid, specific targeting ligand for cervical cancer cell line (HeLa), was conjugated on the hydrogel surface, yielding the ligand conjugated hybrid hydrogels. We revealed that enhanced intracellular uptake by HeLa cells in vitro was enabled by both magnetic attraction and receptor-mediated endocytosis, which were contributed by MNP and folic acid, respectively. Furthermore, site-specific uptake of the developed carrier was confirmed by incubating with several other cell lines. Based on synergistically enhanced intracellular uptake, efficient cytotoxicity and apoptotic activity of HeLa cells incubated with anticancer drug loaded hybrid hydrogels were successfully achieved. The developed dual-targeted hybrid hydrogels are expected to provide a platform for the next generation intelligent drug delivery systems.

Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses

PubMed Central

Ocana, Alberto; Ethier, Josee-Lyne; Díez-González, Laura; Corrales-Sánchez, Verónica; Srikanthan, Amirrtha; Gascón-Escribano, María J.; Templeton, Arnoud J.; Vera-Badillo, Francisco; Seruga, Bostjan; Niraula, Saroj; Pandiella, Atanasio; Amir, Eitan

2015-01-01

Background Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents. Methods and findings Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 versus 1.65, p < 0.001) and grade 3/4 AEs (OR = 1.09 versus 2.10, p < 0.001), but no difference in risk of toxic death (OR = 1.40 versus 1.27, p = 0.69). Differences between agents with and without companion diagnostics were greatest for diarrhea (OR = 1.29 vs. 2.43, p < 0.001), vomiting (OR = 0.86 vs. 1.44, p = 0.005), cutaneous toxicity (OR = 1.82 vs. 3.88, p < 0.001) and neuropathy (OR = 0.64 vs. 1.60, p < 0.001). Conclusions Targeted drugs with companion diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity. PMID:26446908

Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses.

PubMed

Ocana, Alberto; Ethier, Josee-Lyne; Díez-González, Laura; Corrales-Sánchez, Verónica; Srikanthan, Amirrtha; Gascón-Escribano, María J; Templeton, Arnoud J; Vera-Badillo, Francisco; Seruga, Bostjan; Niraula, Saroj; Pandiella, Atanasio; Amir, Eitan

2015-11-24

Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents. Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 vs. 1.65, p < 0.001) and grade 3/4 AEs (OR = 1.09 vs. 2.10, p < 0.001), but no difference in risk of toxic death (OR = 1.40 vs. 1.27, p = 0.69). Differences between agents with and without companion diagnostics were greatest for diarrhea (OR = 1.29 vs. 2.43, p < 0.001), vomiting (OR = 0.86 vs. 1.44, p = 0.005), cutaneous toxicity (OR = 1.82 vs. 3.88, p < 0.001) and neuropathy (OR = 0.64 vs. 1.60, p < 0.001). Targeted drugs with companion diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity.

Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition.

PubMed

Yamazaki, Hiroki; Lai, Yu-Chang; Tateno, Morihiro; Setoguchi, Asuka; Goto-Koshino, Yuko; Endo, Yasuyuki; Nakaichi, Munekazu; Tsujimoto, Hajime; Miura, Naoki

2017-01-01

We tested the hypotheses that hypoxic stimulation enhances growth potentials of canine lymphoma cells by activating hypoxia-inducible factor 1α (HIF-1α), and that the hypoxia-activated prodrug (TH-302) inhibits growth potentials in the cells. We investigated how hypoxic culture affects the growth rate, chemoresistance, and invasiveness of canine lymphoma cells and doxorubicin (DOX)-resistant lymphoma cells, and influences of TH-302 on survival rate of the cells under hypoxic conditions. Our results demonstrated that hypoxic culture upregulated the expression of HIF-1α and its target genes, including ATP-binding cassette transporter B1 (ABCB1), ATP-binding cassette transporter G2 (ABCG2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and survivin, and enhanced the growth rate, DOX resistance, and invasiveness of the cells. Additionally, TH-302 decreased the survival rate of the cells under hypoxic condition. Our studies suggest that hypoxic stimulation may advance the tumorigenicity of canine lymphoma cells, favoring malignant transformation. Therefore, the data presented may contribute to the development of TH-302-based hypoxia-targeting therapies for canine lymphoma.

Corrosion-Activated Chemotherapeutic Function of Nanoparticulate Platinum as a Cisplatin Resistance-Overcoming Prodrug with Limited Autophagy Induction.

PubMed

Cheng, Hsien-Jen; Wu, Te-Haw; Chien, Chih-Te; Tu, Hai-Wei; Cha, Ting-Shan; Lin, Shu-Yi

2016-11-01

Despite nanoparticulate platinum (nano-Pt) has been validated to be acting as a platinum-based prodrug for anticancer therapy, the key factor in controlling its cytotoxicity remains to be clarified. In this study, it is found that the corrosion susceptibility of nano-Pt can be triggered by inducing the oxidization of superficial Pt atoms, which can kill both cisplatin-sensitive/resistance cancer cells. Direct evidence in the oxidization of superficial Pt atoms is validated to observe the formation of platinum oxides by X-ray absorption spectroscopy. The cytotoxicity is originated from the dissolution of nano-Pt followed by the release of highly toxic Pt ions during the corrosion process. Additionally, the limiting autophagy induction by nano-Pt might prevent cancer cells from acquiring autophagy-related drug resistance. With such advantages, the possibility of further autophagy-related drug resistance could be substantially reduced or even eliminated in cancer cells treated with nano-Pt. Moreover, nano-Pt is demonstrated to kill cisplatin-resistant cancer cells not only by inducing apoptosis but also by inducing necrosis for pro-inflammatory/inflammatory responses. Thus, nano-Pt treatment might bring additional therapeutic benefits by regulating immunological responses in tumor microenvironment. These findings support the idea that utilizing nano-Pt for its cytotoxic effects might potentially benefit patients with cisplatin resistance in clinical chemotherapy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Self-Delivery Nanoparticles of Amphiphilic Methotrexate-Gemcitabine Prodrug for Synergistic Combination Chemotherapy via Effect of Deoxyribonucleotide Pools.

PubMed

Wang, Yao; Huang, Ping; Hu, Minxi; Huang, Wei; Zhu, Xinyuan; Yan, Deyue

2016-11-16

The distinct and complementary biochemical mechanisms of folic acid analog methotrexate (MTX) and cytidine analog gemcitabine (GEM) make their synergistic combination effective. Unfortunately, such a combination faces severe pharmacokinetic problems and several transportation barriers. To overcome these problems, a new strategy of amphiphilic small molecule prodrug (ASMP) is developed to improve their synergistic combination effect. The ASMP was prepared by the amidation of the hydrophilic GEM with the hydrophobic MTX at a fixed ratio. Owing to its inherent amphiphilicity, the MTX-GEM ASMP self-assembled into stable nanoparticles (ASMP-NPs) with high drug loading capacity (100%), in which the MTX and GEM could self-deliver without any carriers and release synchronously in cancer cells. In vitro studies showed that the MTX-GEM ASMP-NPs could greatly improve the synergistic combination effects by the reason of arresting more S phase of the cell cycle and reducing levels of deoxythymidine triphosphate (dTTP), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP). The stronger synergistic effects caused the higher cell cytotoxicity and apoptotic ratio, and circumvented the multidrug resistance (MDR) of tumor cells. Additionally, MTX-GEM ASMP-NPs could achieve the same anticancer effect with the greatly reduced dosage compared with the free drugs according to the dose-reduction index (DRI) values of MTX and GEM in MTX-GEM ASMP-NPs, which may be beneficial for reducing the side effects.

Syntheses of prodrug-type phosphotriester oligonucleotides responsive to intracellular reducing environment for improvement of cell membrane permeability and nuclease resistance.

PubMed

Hayashi, Junsuke; Samezawa, Yusuke; Ochi, Yosuke; Wada, Shun-Ichi; Urata, Hidehito

2017-07-15