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1

Functionalized nanospheres for targeted delivery of paclitaxel.  

PubMed

Targeted delivery of anti-cancer agents to cancer cells is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform with the future goal of merging two thus far parallel methods for selective elimination of cancer cells: targeted nanospheres and pretargeted radioimmunotherapy. Several clinical trials have shown the promise of pretargeted radioimmunotherapy, which leverages the specificity of antibodies for targeted cell populations and delivers a localized dose of a biotinylated radionuclide that is most often administered following binding of a biotinylated antibody and streptavidin (StA) to the target cells. The work presented here describes the development of biotinylated nanospheres based on an ABA-type copolymer comprised of a tyrosine-derived oligomer as the B-block and poly(ethylene glycol) (PEG) A-blocks. The biotinylated nanospheres encapsulate paclitaxel (PTX) to the same extent as unbiotinylated nanospheres. Efficacy of targeting was shown on CD44 positive cells in the SUM159 breast cancer cell line by incubating the cells sequentially with a biotinylated anti-CD44 antibody, StA and the biotinylated nanospheres encapsulating PTX. Targeted nanospheres achieved the half maximal inhibitory concentration of PTX on SUM159 cells at a 5-10 fold lower concentration than that of PTX applied in either non-targeted nanospheres or free drug approaches. Moreover, targeted nanospheres selectively eliminated CD44 positive SUM159 cells compared to free PTX and untargeted nanospheres. This new generation of nano-sized carrier offers a versatile platform that can be adopted for a wide variety of drug and target specific applications and has the potential to be combined with the clinically emerging method of pretargeted radioimmunotherapy. PMID:23792807

Bushman, Jared; Vaughan, Asa; Sheihet, Larisa; Zhang, Zheng; Costache, Marius; Kohn, Joachim

2013-11-10

2

Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers.  

PubMed

Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood-brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200?nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The P-gp ATPase assay suggested that the NP were not substrate for P-gp and would not be effluxed by P-gp present in the BBB. The in vitro release profile of the NP exhibited no initial burst release and showed sustained drug release. The proposed coated NP showed significantly higher cytotoxicity in RG2 cells compared with uncoated NP (p???0.05). Tubulin immunofluorescent study showed higher cell death by the NP due to increased microtubule stabilization. In vivo brain uptake study in mice showed higher brain uptake of the NP containing coumarin-6 compared with solution. The proposed brain-targeted NP delivery of paclitaxel could be an effective treatment for the brain cancers. PMID:21692650

Geldenhuys, Werner; Mbimba, Thomas; Bui, Thong; Harrison, Kimberly; Sutariya, Vijaykumar

2011-11-01

3

Encapsulation of paclitaxel into lauric acid-O-carboxymethyl chitosan-transferrin micelles for hydrophobic drug delivery and site-specific targeted delivery.  

PubMed

Transferrin/PEG/O-carboxymethyl chitosan/fatty acid/paclitaxel (TPOCFP) micelles were tested for suitability as a drug carrier characterized by low cytotoxicity, sustained release, high cellular uptake, and site-specific targeted delivery of hydrophobic drugs. Characterization, drug content, encapsulation efficiency, and in vitro drug release were investigated. When the feeding amount of paclitaxel (PTX) was increased, the drug content increased, but loading efficiency decreased. TPOCFP micelles had a spherical shape, with a particle size of approximately 140-649 nm. In vitro cell cytotoxicity and hemolysis assays were conducted to confirm the safety of the micelles. Anticancer activity and confocal laser scanning microscopy (CLSM) were used to confirm the targeting efficiency of target ligand-modified TPOCFP micelles. Anticancer activity and CLSM results clearly demonstrated that transferrin-modified TPOCFP micelles were quickly taken up by the cell. The endocytic pathway of TPOCFP micelles was analyzed by flow cytometry, revealing transfection via receptor-mediated endocytosis. These results suggest that PTX-encapsulated TPOCFP micelles may be used as an effective cancer-targeting drug delivery system for chemotherapy. PMID:24076228

Nam, Joung-Pyo; Park, Seong-Cheol; Kim, Tae-Hun; Jang, Jae-Yeang; Choi, Changyong; Jang, Mi-Kyeong; Nah, Jae-Woon

2013-11-30

4

Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery  

Microsoft Academic Search

Novel thermo-sensitive nanoparticles self-assembled from poly(N,N-diethylacrylamide- co-acrylamide)-block-poly(gamma-benzyl L-glutamate) were designed for targeted drug delivery in localized hyperthermia. The lower critical solution temperature (LCST) of nanoparticles was adjusted to a level between physiological body temperature (37 °C) and that used in local hyperthermia (about 43 °C). The temperature-dependent performances of the core-shell nanoparticles were systemically studied by nuclear magnetic resonance (NMR),

Yuanpei Li; Shirong Pan; Wei Zhang; Zhuo Du

2009-01-01

5

Development of EGFR-Targeted Polymer Blend Nanocarriers for Combination Paclitaxel/Lonidamine Delivery to Treat Multi-Drug Resistance in Human Breast and Ovarian Tumor Cells  

PubMed Central

Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, non-responsive disease. Targeted nanoparticles were made by synthesizing a poly(D,L-lactide-co-glycolide)/poly(ethylene glycol)/epidermal growth factor receptor targeting peptide (PLGA/PEG/EGFR-peptide) construct for incorporation in poly(epsilon-caprolactone) (PCL) nanoparticles. MDR was induced in a panel of nine human breast and ovarian cancer cell lines using hypoxia. EGFR-targeted polymer blend nanoparticles were shown to actively target EGFR over-expressing cell lines, especially upon induction of hypoxia. The nanoparticles were capable of sustained drug release. Combination therapy with lonidamine and paclitaxel significantly improved the therapeutic index of both drugs. Treatment with a nanoparticle dose of 1 ?M paclitaxel/10 ?M lonidamine resulted in less than 10% cell viability for all hypoxic/MDR cell lines and less than 5% cell viability for all normoxic cell lines. Comparatively, treatment with 1 ?M paclitaxel alone was the approximate IC50 value of the MDR cells while treatment with lonidamine alone had very little effect. PLGA/PEG/EGFR-peptide delivery system actively targets a MDR cell by exploiting the expression of EGFR. This system treats MDR by inhibiting the Warburg effect and promoting mitochondrial binding of pro-apoptotic Bcl-2 proteins (lonidamine), while hyperstabilizing microtubules (paclitaxel). This nanocarrier system actively targets a MDR associated phenotype (EGFR receptor over-expression), further enhancing the therapeutic index of both drugs and potentiating the use of lonidamine/paclitaxel combination therapy in the treatment of MDR cancer.

Milane, Lara; Duan, Zhenfeng; Amiji, Mansoor

2013-01-01

6

Engineering erythrocytes as a novel carrier for the targeted delivery of the anticancer drug paclitaxel  

PubMed Central

Paclitaxel (PTX) is formulated in a mixture of Cremophor EL and dehydrated alcohol. The intravenous administration of this formula is associated with a risk of infection and hypersensitivity reactions. The presence of Cremophor EL as a pharmaceutical vehicle contributes to these effects. Therefore, in this study, we used human erythrocytes, instead of Cremophor, as a pharmaceutical vehicle. PTX was loaded into erythrocytes using the preswelling method. Analysis of the obtained data indicates that 148.8 ?g of PTX was loaded/mL erythrocytes, with an entrapment efficiency of 46.36% and a cell recovery of 75.94%. Furthermore, we observed a significant increase in the mean cell volume values of the erythrocytes, whereas both the mean cell hemoglobin and the mean cell hemoglobin concentration decreased following the loading of PTX. The turbulence fragility index values for unloaded, sham-loaded and PTX-loaded erythrocytes were 3, 2, and 1 h, respectively. Additionally, the erythrocyte glutathione level decreased after PTX loading, whereas lipid peroxidation and protein oxidation increased. The release of PTX from loaded erythrocytes followed first-order kinetics, and about 81% of the loaded drug was released into the plasma after 48 h. The results of the present study revealed that PTX was loaded successfully into human erythrocytes with acceptable loading parameters and with some oxidative modification to the erythrocytes.

Harisa, Gamaleldin I.; Ibrahim, Mohamed F.; Alanazi, Fars; Shazly, Gamal A.

2013-01-01

7

Stabilized micelles as delivery vehicles for paclitaxel.  

PubMed

Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high encapsulation efficiency of approximately 70%. Gastrointestinal transit of the developed micelles was evaluated by oral administration of rhodamine-labeled micelles in rats. Our results showed prolonged gastrointestinal residence of the marker encapsulated into micelles, compared to a solution containing free marker. Further, the oral administration of micelles in mice showed high area under curve of micellar paclitaxel (similar to the area of i.v. Taxol(®)), longer mean residence time (9-times longer than i.v. Taxol(®)) and high distribution volume (2-fold higher than i.v. Taxol(®)) indicating an efficient oral absorption of paclitaxel delivered by micelles. Intravenous administration of micelles also showed a significant improvement of pharmacokinetic parameters of micellar paclitaxel vs. Taxol(®), in particular higher area under curve (1.2-fold), 5-times longer mean residence time and lower clearance, indicating longer systemic circulation of the micelles. PMID:22721848

Yoncheva, Krassimira; Calleja, Patricia; Agüeros, Maite; Petrov, Petar; Miladinova, Ivanka; Tsvetanov, Christo; Irache, Juan M

2012-10-15

8

Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel.  

PubMed

A targeted intracellular delivery system of paclitaxel (PTX) was successfully developed based on redox-sensitive hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates. The conjugates self-assembled into nano-size micelles in aqueous media and exhibited excellent drug-loading capacities (34.1%) and entrapment efficiency (93.2%) for PTX. HA-ss-DOCA micelles were sufficiently stable at simulated normal physiologic condition but fast disassembled in the presence of 20 mm reducing agent, glutathione. In vitro drug release studies showed that the PTX-loaded HA-ss-DOCA micelles accomplished rapid drug release under reducing condition. Intracellular release of fluorescent probe nile red indicated that HA-ss-DOCA micelles provide an effective approach for rapid transport of cargo into the cytoplasm. Enhanced cytotoxicity of PTX-loaded HA-ss-DOCA micelles further confirmed that the sensitive micelles are more potent for intracellular drug delivery as compared to the insensitive control. Based on flow cytometry and confocal microscopic analyses, observations revealed that HA-ss-DOCA micelles were taken up to human breast adenocarcinoma cells (MDA-MB-231) via HA-receptor mediated endocytosis. In vivo investigation of micelles in tumor-bearing mice confirmed that HA-ss-DOCA micelles possessed much higher tumor targeting capacity than the insensitive control. These results suggest that redox-sensitive HA-ss-DOCA micelles hold great potential as targeted intracellular delivery carriers of lipophilic anticancer drugs. PMID:22166223

Li, Jing; Huo, Meirong; Wang, Jing; Zhou, Jianping; Mohammad, Jumah M; Zhang, Yinlong; Zhu, Qinnv; Waddad, Ayman Y; Zhang, Qiang

2012-03-01

9

Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel.  

PubMed

New solubilizers, including Sorporol 230, Sorporol 120Ex, Aceporol 345-T, Aceporol 460 and Riciporol 335, as potential new delivery vehicles for paclitaxel were investigated, since recent studies have shown that the paclitaxel delivery vehicle Cremophor EL significantly alters the pharmacokinetics of paclitaxel. Cremophor EL and Tween 80 were used as a reference. As in the case of Cremophor EL, alteration of blood distribution of paclitaxel occurred in the presence of all tested vehicles. Also, no differences in the affinity of paclitaxel for the tested solubilizers was found during equilibrium dialysis experiments. The different vehicles could be distinguished by a different rate of esterase-mediated breakdown, which was correlated with the fatty acid content of the solubilizers. The activation of the complement cascade was less pronounced for all solubilizers, except Riciporol 335, compared to Cremophor EL. The strategies presented here provide the possibility to rapidly screen future candidate delivery vehicles with optimal characteristics for use as a solubilizer in clinical formulations of paclitaxel or other poorly water-soluble drugs. PMID:12187334

Loos, Walter J; Szebeni, Janos; ten Tije, Albert J; Verweij, Jaap; van Zomeren, Desirée M; Chung, Kyu-nung; Nooter, Kees; Stoter, Gerrit; Sparreboom, Alex

2002-08-01

10

Paclitaxel loaded PEG(5000)-DSPE micelles as pulmonary delivery platform: formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation.  

PubMed

The objective of the present study was to evaluate the potential of paclitaxel loaded micelles fabricated from PEG(5000)-DSPE as a sustained release system following pulmonary delivery. PEG(5000)-DSPE micelles containing paclitaxel were prepared by solvent evaporation technique followed by investigation of in vitro release of paclitaxel in lung simulated fluid. Tissue distribution and plasma pharmacokinetics of the PEG-lipid micelles after intratracheal and intravenous administrations were investigated in addition to intratracheally administered taxol. Finally, toxicological profile of PEG(5000)-DSPE was investigated. Paclitaxel was successfully formulated in PEG-lipid micelles with encapsulation efficiency of 95%. The PEG-lipid micelles exhibited a sustained release behavior in the simulated lung fluid. Intratracheally administered polymeric micellar paclitaxel showed highest accumulation of paclitaxel in the lungs with AUC(0-12) in lungs being 45-fold higher than intravenously administered formulation and 3-fold higher than intratracheally delivered taxol. Paclitaxel concentration in other non-targeted tissues and plasma were significantly lower as compared to other groups. Furthermore, toxicity studies showed no significant increase in levels of lung injury markers in PEG(5000)-DSPE treated group as compared to saline-treated group. PEG(5000)-DSPE micelles delivered intratracheally were able to sustain highest paclitaxel concentrations in lungs for long periods of time, thus apprehending their suitability as pulmonary drug carriers. PMID:21575719

Gill, Kanwaldeep K; Nazzal, Sami; Kaddoumi, Amal

2011-10-01

11

Nanoparticle Migration and Delivery of Paclitaxel to Regional Lymph Nodes in a Large Animal Model  

PubMed Central

Background To demonstrate feasibility of migration and in situ chemotherapy delivery to regional lymph nodes (LN) in a large animal model using an expansile polymer nanoparticle (eNP) delivery system. Study Design Dual-labeled 50 nm and 100 nm eNP were prepared by encapsulating an IR-813 near-infrared (NIR) fluorescent dye within coumarin-conjugated expansile polymer nanoparticles (NIR-C-eNP). NIR imaging and fluorescent microscopy were utilized to identify intralymphatic migration of NIR-nanoparticles to draining inguinal or mesenteric LN following injection in swine hindlegs or intestine. Nanoparticle-mediated intranodal delivery of chemotherapy was subsequently assessed with Oregon Green paclitaxel-loaded NIR-eNP (NIR-OGpax-eNP). Results NIR imaging demonstrated direct lymphatic migration of 50 nm, but not 100 nm, NIR-C-eNP and NIR-OGpax-eNP to the draining regional LNs following intradermal injection in the hindleg or subserosal injection in intestine. Fluorescent microscopy demonstrated that IR-813 used for NIR real-time trafficking colocalized with both the coumarin-labeled polymer and paclitaxel chemotherapy identified within the subcapsular spaces of the draining LNs. These studies verify nodal migration of both nanoparticle and encapsulated payload, and confirm the feasibility of focusing chemotherapy delivery directly to regional nodes. Conclusions Regionally-targeted intranodal chemotherapy can be delivered to draining LNs for both skin and solid organs using 50 nm paclitaxel-loaded eNP.

Khullar, Onkar V; Griset, Aaron P; Gibbs-Strauss, Summer L; Chirieac, Lucian R; Zubris, Kimberly AV; Frangioni, John V; Grinstaff, Mark W; Colson, Yolonda L

2012-01-01

12

Lyoprotected nanosphere formulations for paclitaxel controlled delivery.  

PubMed

The preparation and technological characterization of nanosphere formulations (NS) containing the anticancer drug paclitaxel (PTX) are reported. Poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) nanospheres (NS) were prepared by a solvent displacement method. They showed a mean particle size in the range 150-300 nm, with a high homogeneity (polydispersity index < 0.3). For long term stability, NS require additional procedures, such as freeze-drying. In this study, the effect on NS particle size and surface charge of different lyoprotectants (mono- and disaccharides, polyalcohols, and hydroxypropyl-beta-cyclodextrin) at various concentrations was tested by means of light scattering size analysis. The formulations freeze-dried with the addition of 10% glucose (w/v) showed interesting characteristics after freeze-drying. They were chosen for specific studies on drug encapsulation efficiency, in vitro drug release and biological activity on the human anaplastic thyroid carcinoma cell line 8305C. The PLGA NS, in particular, showed a cell growth inhibitory activity comparable to the free drug. PMID:17048526

Musumeci, T; Vicari, L; Ventura, C A; Gulisano, M; Pignatello, R; Puglisi, G

2006-01-01

13

Polymeric nanoparticles for the intracellular delivery of paclitaxel in lung and breast cancer  

NASA Astrophysics Data System (ADS)

Nanoparticles are useful for addressing many of the difficulties encountered when administering therapeutic compounds. Nanoparticles are able to increase the solubility of hydrophobic drugs, improve pharmacokinetics through sustained release, alter biodistribution, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues. The use of functional nanocarriers can also provide controlled intracellular delivery of a drug. To this end, we have developed functional pH-responsive expansile nanoparticles for the intracellular delivery of paclitaxel. The pH-responsiveness of these nanoparticles occurs due to a hydrophobic to hydrophilic transition of the polymer occurring under mildly acidic conditions. These polymeric nanoparticles were systematically evaluated for the delivery of paclitaxel in vitro and in vivo to improve local therapy for lung and breast cancers. Nanoparticles were synthesized using a miniemulsion polymerization process and were subsequently characterized and found to swell when exposed to acidic environments. Paclitaxel was successfully encapsulated within the nanoparticles, and the particles exhibited drug release at pH 5 but not at pH 7.4. In addition, the uptake of nanoparticles was observed using flow cytometry, and the anticancer efficacy of the paclitaxel-loaded nanoparticles was measured using cancer cell lines in vitro. The potency of the paclitaxel-loaded nanoparticles was close to that of free drug, demonstrating that the drug was effectively delivered by the particles and that the particles could act as an intracellular drug depot. Following in vitro characterization, murine in vivo studies demonstrated the ability of the paclitaxel-loaded responsive nanoparticles to delay recurrence of lung cancer and to prevent establishment of breast cancer in the mammary fat pads with higher efficacy than paclitaxel alone. In addition, the ability of nanoparticles to migrate up to 40 cm through lymphatic channels to local lymph nodes was demonstrated using near infrared imaging in a large animal model. Continued investigation of functional nanoparticles, like the system described here for lung and breast cancer, will facilitate the development of new materials that meet the varied and demanding needs in chemotherapy, and may afford new treatment options for the local and metastatic control of many forms of cancer.

Zubris, Kimberly Ann Veronica

14

Modulating paclitaxel bioavailability for targeting prostate cancer  

Microsoft Academic Search

Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between

Srinivas K. Kumar; Simon A. Williams; John T. Isaacs; Samuel R. Denmeade; Saeed R. Khan

2007-01-01

15

Modulating paclitaxel bioavailability for targeting prostate cancer.  

PubMed

Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between the peptide and paclitaxel in prodrugs 2-5 resulted in products with an increased rate of hydrolysis by PSA. The stability of prodrugs 2 and 3, with the PABA linker, was poor in the serum-containing medium because of the weak carbonate bond between the PABA and paclitaxel; however, this disadvantage was overcome by introducing a carbamate bond using an EDA linker in prodrugs 4 and 5. Thus, the incorporation of an EDA linker increased both the stability and PSA-mediated activation of these prodrugs. The cytotoxicity of each prodrug, as compared to paclitaxel, was determined against a variety of cell lines, including the PSA-secreting CWR22Rv1 prostate cancer cell line. The EDA-derived prodrug of paclitaxel 5 was stable and capable of being efficiently converted to an active drug that killed cells specifically in the presence of PSA, suggesting that this prodrug and similarly designed PSA-cleavable prodrugs may have potential as prostate cancer-specific therapeutic agents. PMID:17502149

Kumar, Srinivas K; Williams, Simon A; Isaacs, John T; Denmeade, Samuel R; Khan, Saeed R

2007-07-15

16

Nanoemulsions as Versatile Formulations for Paclitaxel Delivery: Peroral and Dermal Delivery Studies in Rats  

Microsoft Academic Search

Pathogenesis of psoriasis involves the keratinocytes in epidermis as well as the angiogenesis involving deeper skin layers. So, the drug delivery strategy should be customized to localize paclitaxel (PCL) inside both layers. In this investigation, in order to achieve penetration of PCL into deeper skin layers while minimizing the systemic escape, a nanoemulsion (NE) was formulated and evaluated its in

Sateesh Khandavilli; Ramesh Panchagnula

2007-01-01

17

Polymer-polymer conjugation to fabricate multi-block polymer as novel drug carriers: poly(lactic acid)-poly(ethylene glycol)-poly(L-lysine) to enhance paclitaxel target delivery.  

PubMed

Multifunctional nanoparticles assembled from multi-block polymers are now one of the most convenient and convincing carriers for target drug delivery. Multi-block polymers could provide multi-functions such as sufficient drug loading capability and efficient target ligand coupling potency. In this article, novel multi-block polymer poly(lactic acid)-poly(ethylene glycol)-poly(L-lysine) (PLA-PEG-PLL) with relatively precise block molecular weight were synthesized by new method which we called polymer-polymer conjugation. This method conjugated different polymer blocks by reactions between the terminal active groups of different blocks, thus simplified the synthesis procedure. The obtained PLA-PEG-PLL was characterized by 1H NMR and gel permeation chromatography. The controlled drug delivery capability and the target ligand coupling potency of PLA-PEG-PLL were verified using paclitaxel (PTX) as model drug and vascular endothelial growth factor (VEGF) antibody as target ligand. The PTX-loaded PLA-PEG-PLL nanoparticles (PNP) and VEGF antibody modified PTX-loaded PLA-PEG-PLL nanoparticles (VPNP) were prepared using solvent diffusion methods. The two nanoparticles showed spherical or ellipsoidal shapes with uniform particle size distribution (190.1 +/- 1.27 nm and 203.6 +/- 4.10 nm for PNP and VPNP, respectively) and positive zeta potential (23.76 +/- 0.72 mv and 20.76 +/- 0.34 mv for PNP and VPNP, respectively). The cellular cytotoxicity, cellular uptake, in vivo therapeutic effects of the two nanoparticles were investigated. Cytotoxicity of VPNP against HepG2 cells was superior to that of PNP and Taxol. The VPNP and PNP showed better antitumor efficacy in a murine model bearing H22 compared with Taxol and VPNP was the best. The study on cellular uptake indicated that the better antitumor efficacy of VPNP was attributed to the increased uptake of drug by tumor cells. These results demonstrated that PLA-PEG-PLL was a favorable multifunctional material for drug target delivery and polymer-polymer conjugation was a promising method to fabricate novel multi-block polymers. PMID:24749390

Liu, Yongjun; Liu, Chunxi; Li, Min; Liu, Fengxi; Feng, Lixia; Zhang, Li; Zhang, Na

2014-06-01

18

Carboxymethyl-chitosan-tethered lipid vesicles: hybrid nanoblanket for oral delivery of paclitaxel.  

PubMed

We describe the development and evaluation of a hybrid lipopolymeric system comprising carboxymethyl chitosan (CMC), covalently tethered to phosphatidylethanolamine units on the surface of lipid nanovesicles, for oral delivery of paclitaxel. The bioploymer is intended to act as a blanket, thereby shielding the drug from harsh gastrointestinal conditions, whereas the lipid nanovesicle ensures high encapsulation efficiency of paclitaxel and its passive targeting to tumor. CMC-tethered nanovesicles (LN-C-PTX) in the size range of 200-300 nm improved the gastrointestinal resistance and mucoadhesion properties as compared with unmodified lipid nanovesicles (LN-PTX). Conjugation of CMC did not compromise the cytotoxic potential of paclitaxel yet facilitated the interaction and uptake of the nanovesicles by murine melanoma (B16F10) cells through an ATP-dependent process. CMC-conjugated nanovesicles, upon oral administration in rats, improved the plasma concentration profile of paclitaxel, with 1.5 fold increase in its bioavailability and 5.5 folds increase in elimination half life in comparison with Taxol. We also found that CMC in addition to providing a gastric resistant coating also imparted stealth character to the nanovesicles, thereby reducing their reticuloendothelial system (RES)-mediated uptake by liver and spleen and bypassing the need for PEGylation. In vivo efficacy in subcutaneous model of B16F10 showed significantly improved tumor growth inhibition and survival with CMC-tethered nanovesicles as compared with unmodified nanovesicles, both administered orally. LN-C-PTX exhibited therapeutic efficacy comparable to Taxol and Abraxane and also showed reduced toxicity and improved survival. Overall, these results suggest the therapeutic potential of CMC tethered nanovesicles as a platform for oral administration of paclitaxel and also unravel the ability of CMC to impart stealth character to the nanoparticles, thereby preventing their RES clearance. PMID:23721348

Joshi, Nitin; Saha, Rama; Shanmugam, Thanigaivel; Balakrishnan, Biji; More, Prachi; Banerjee, Rinti

2013-07-01

19

Combined Delivery of Paclitaxel and Tanespimycin via Micellar Nanocarriers: Pharmacokinetics, Efficacy and Metabolomic Analysis  

PubMed Central

Background Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo. Methodology/Principal Findings Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles. Conclusions/Significance We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.

Wang, Yingzhe; Teng, Quincy; Tan, Chalet

2013-01-01

20

SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice  

PubMed Central

Design Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA). Results nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, KrasG12D;p53flox/?;p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response. Conclusions nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents.

Neesse, Albrecht; Frese, Kristopher K; Chan, Derek S; Bapiro, Tashinga E; Howat, William J; Richards, Frances M; Ellenrieder, Volker; Jodrell, Duncan I; Tuveson, David A

2014-01-01

21

Archaeosome: as new drug carrier for delivery of Paclitaxel to breast cancer.  

PubMed

In the present study, paclitaxel was archaeosomed to reduce side effects and improve its therapeutic index. Carriers have made a big evolution in treatment of many diseases in recent years. Lipid carriers are of special importance among carriers. Archaeosome is one of the lipid carriers. Paclitaxel is one of the drugs used to treat breast cancer which has some unwanted side effects despite its therapeutic effects. Archaeosomes were extracted from methanogenic archi bacteria and synthesized with a certain ratio of paclitaxel in PBS. The mean diameter of archaeosomal paclitaxel was measured by Zeta sizer instrument, Drug releasing of archaeosomal paclitaxel was examined within 26 h which results showed that the most drug releasing occurs during first 3 h. The cytotoxicity effect of archaeosomal paclitaxel on breast cancer's cell line was evaluated by MTT assay which results showed that the cytotoxicity effect of archaeosomal paclitaxel on breast cancer's cell line is more than that of the standard paclitaxel formulation. The results indicated that new drug delivery of paclitaxel using archaeosome, increases the therapeutic index of the drug. PMID:24757295

Alavi, Seyed Ebrahim; Mansouri, Hamidreza; Esfahani, Maedeh Koohi Moftakhari; Movahedi, Fatemeh; Akbarzadeh, Azim; Chiani, Mohsen

2014-04-01

22

A Novel Nanoparticle Formulation for Sustained Paclitaxel Delivery  

PubMed Central

Purpose To develop a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of a wide variety of therapeutics including paclitaxel. Methods Chitosan/GMO nanoparticles were prepared by multiple emulsion (o/w/o) solvent evaporation methods. Particle size and surface charge were determined. The morphological characteristics and cellular adhesion were evaluated with surface or transmission electron microscopy methods. The drug loading, encapsulation efficiency, in vitro release and cellular uptake were determined using HPLC methods. The safety and efficacy were evaluated by MTT cytotoxicity assay in human breast cancer cells (MDA-MB-231). Results These studies provide conceptual proof that chitosan/GMO can form polycationic nano-sized particles (400 to 700 nm). The formulation demonstrates high yields (98 to 100%) and similar entrapment efficiencies. The lyophilized powder can be stored and easily be resuspended in an aqueous matrix. The nanoparticles have a hydrophobic inner-core with a hydrophilic coating that exhibits a significant positive charge and sustained release characteristics. This novel nanoparticle formulation shows evidence of mucoadhesive properties; a fourfold increased cellular uptake and a 1000-fold reduction in the IC50 of PTX. Conclusion These advantages allow lower doses of PTX to achieve a therapeutic effect, thus presumably minimizing the adverse side effects.

Trickler, W. J.; Nagvekar, A. A.

2008-01-01

23

Targeting of albumin-embedded paclitaxel nanoparticles to tumors  

Microsoft Academic Search

We have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA and LyP-1 (CGNKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands

Priya Prakash Karmali; Venkata Ramana Kotamraju; Mark Kastantin; Matthew Black; Dimitris Missirlis; Matthew Tirrell; Erkki Ruoslahti

2009-01-01

24

Development of nonionic surfactant\\/phospholipid o\\/w emulsion as a paclitaxel delivery system  

Microsoft Academic Search

Paclitaxel is an anticancer agent with low aqueous solubility. More extensive clinical use of this drug is somewhat delayed due to lack of appropriate delivery vehicles. An attempt was made to adopt an o\\/w emulsion as the drug carrier which incorporated paclitaxel in the triacylglycerol stabilized by a mixed-emulsifier system. A suitable formulation was found in this study: 0.75 mg\\/ml

Pei Kan; Zhi-Beng Chen; Chau-Jen Lee; I-Ming Chu

1999-01-01

25

Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery.  

PubMed

The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and an aqueous polymer solution and subsequent heating of the resulting solution above the critical micelle temperature of the polymer. PTX could be almost quantitatively loaded in the micelles up to 2 mg/mL. By dynamic light scattering and cryo-transmission electron microscopy, it was shown that PTX-loaded micelles have a mean size around 60 nm with narrow size distribution. At pH 8.8 and 37 degrees C, PTX-loaded micelles destabilized within 10 h due to the hydrolysis of the lactic acid side group of the pHPMAmDL. Because the hydrolysis of the lactic acid side groups is first order in hydroxyl ion concentration, the micelles were stable for about 200 h at physiological conditions. The presence of serum proteins did not have an adverse effect on the stability of the micelles during at least 15 h. Interestingly, the dissolution kinetics of pHPMAmDL-b-PEG micelles was retarded by incorporation of PTX, indicating a strong interaction between PTX and the pHPMAmDL block. The PTX-loaded micelles showed a release of the incorporated 70% of PTX during 20 h at 37 degrees C and at pH 7.4. PTX-loaded pHPMAmDL-b-PEG micelles showed comparable in vitro cytotoxicity against B16F10 cells compared to the Taxol standard formulation containing Cremophor EL, while pHPMAmDL-b-PEG micelles without PTX were far less toxic than the Cremophor EL vehicle. Confocal laser-scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) analysis of fluorescently labelled micelles showed that pHPMAmDL-b-PEG micelles were internalized by the B16F10 cells. The present results suggest that pHPMAmDL-b-PEG block copolymer micelles are a promising delivery system for the parenteral administration of PTX. PMID:15763618

Soga, Osamu; van Nostrum, Cornelus F; Fens, Marcel; Rijcken, Cristianne J F; Schiffelers, Raymond M; Storm, Gert; Hennink, Wim E

2005-03-21

26

Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity  

PubMed Central

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

2014-01-01

27

Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity  

NASA Astrophysics Data System (ADS)

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R.; Ran, Yingqing; Wong, Harvey

2014-04-01

28

Aptamer conjugated paclitaxel and magnetic fluid loaded fluorescently tagged PLGA nanoparticles for targeted cancer therapy  

NASA Astrophysics Data System (ADS)

Controlled and targeted drug delivery is an essential criterion in cancer therapy to reduce the side effects caused by non-specific drug release and toxicity. Targeted chemotherapy, sustained drug release and optical imaging have been achieved using a multifunctional nanocarrier constructed from poly (D, L-lactide-co-glycolide) nanoparticles (PLGA NPs), an anticancer drug paclitaxel (PTX), a fluorescent dye Nile red (NR), magnetic fluid (MF) and aptamers (Apt, AS1411, anti-nucleolin aptamer). The magnetic fluid and paclitaxel loaded fluorescently labeled PLGA NPs (MF-PTX-NR-PLGA NPs) were synthesized by a single-emulsion technique/solvent evaporation method using a chemical cross linker bis (sulfosuccinimidyl) suberate (BS3) to enable binding of aptamer on to the surface of the nanoparticles. Targeting aptamers were then introduced to the particles through the reaction with the cross linker to target the nucleolin receptors over expressed on the cancer cell surface. Specific binding and uptake of the aptamer conjugated magnetic fluid loaded fluorescently tagged PLGA NPs (Apt-MF-NR-PLGA NPs) to the target cancer cells induced by aptamers was observed using confocal microscopy. Cytotoxicity assay conducted in two cell lines (L929 and MCF-7) confirmed that targeted MCF-7 cancer cells were killed while control cells were unharmed. In addition, aptamer mediated delivery resulting in enhanced binding and uptake to the target cancer cells exhibited increased therapeutic effect of the drug. Moreover, these aptamer conjugated magnetic polymer vehicles apart from actively transporting drugs into specifically targeted tumor regions can also be used to induce hyperthermia or for facilitating magnetic guiding of particles to the tumor regions.

Aravind, Athulya; Nair, Remya; Raveendran, Sreejith; Veeranarayanan, Srivani; Nagaoka, Yutaka; Fukuda, Takahiro; Hasumura, Takahashi; Morimoto, Hisao; Yoshida, Yasuhiko; Maekawa, Toru; Sakthi Kumar, D.

2013-10-01

29

Poly(ethylene glycol)-block-poly(?-caprolactone) Micelles for Combination Drug Delivery: Evaluation of Paclitaxel, Cyclopamine and Gossypol in Intraperitoneal Xenograft Models of Ovarian Cancer  

PubMed Central

Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(?-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3?-deoxy-3?-18F-fluorothymidine (18F-FLT) PET imaging, and overall survival. 18F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles.

Cho, Hyunah; Lai, Tsz Chung; Kwon, Glen S.

2012-01-01

30

Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery  

Microsoft Academic Search

The preparation, release and in vitro cytotoxicity of a novel polymeric micellar formulation of paclitaxel (PTX) were investigated. The micelles consisted of an AB block copolymer of poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol) (pHPMAmDL-b-PEG). Taking advantage of the thermosensitivity of pHPMAmDL-b-PEG, the loading was done by simply mixing of a small volume of a concentrated PTX solution in ethanol and

Osamu Soga; Cornelus F. van Nostrum; Marcel Fens; Cristianne J. F. Rijcken; Raymond M. Schiffelers; Gert Storm; Wim E. Hennink

2005-01-01

31

Characterization of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery.  

PubMed

Hyperthermia, the heating of tissue from 41 to 45?°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n?=?1000) methyl ether methacrylate and PEG (n?=?400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non-Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response. PMID:23683041

Meenach, Samantha A; Shapiro, Jenna M; Hilt, J Zach; Anderson, Kimberly W

2013-01-01

32

nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer.  

PubMed

Taxanes are highly active chemotherapeutic agents used in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-Paclitaxel is a biologically interactive, solvent-free, 130-nm-sized albumin-bound paclitaxel, developed to avoid the Cremophor vehicle used in solvent-based paclitaxel. Based on a pivotal phase 3 study, nab-paclitaxel was shown to be safely infused at a significantly higher dose of paclitaxel than the doses used with standard paclitaxel therapy, and had a shorter infusion time, no premedication, and higher response rates. It is now approved in the United States for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, and has demonstrated promising efficacy and favorable tolerability. Recently, several phase 2 and 3 studies have suggested a role for nab-paclitaxel in combination with biologically targeted agents for the treatment of early- and late-stage breast cancer. This review will discuss the findings of clinical trials evaluating nab-paclitaxel in combination with biologically targeted therapeutic agents for breast cancer in the neoadjuvant, adjuvant, and metastatic settings. PMID:24560997

Megerdichian, Christine; Olimpiadi, Yuliya; Hurvitz, Sara A

2014-06-01

33

Targeting of albumin-embedded paclitaxel nanoparticles to tumors  

PubMed Central

We have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA, and LyP-1 (CGQKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands expressing its receptor, p32. Self-assembled mixed micelles carrying the homing peptide and the label on different subunits accumulated in the same areas of tumors as LyP-1-abraxane, showing that Lyp-1 can deliver intact nanoparticles into extravascular sites. Untargeted, FAM-abraxane was detected in the form of a faint meshwork in tumor interstitium. LyP-1-abraxane produced a statistically highly significant inhibition of tumor growth compared to untargeted abraxane. These results show that nanoparticles can be effectively targeted into extravascular tumor tissue and that targeting can enhance the activity of a therapeutic nanoparticle.

Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Kastantin, Mark; Black, Matthew; Missirlis, Dimitris; Tirrell, Matthew; Ruoslahti, Erkki

2010-01-01

34

Low molecular weight chitosan-based conjugate: A new platform for oral delivery of paclitaxel  

Microsoft Academic Search

A new platform for oral delivery of paclitaxel (PTX) was developed using a chemical conjugate system between PTX and low molecular weight chitosan (LMWC) having a narrow range of molecular weight (Mw). Three different Mws of chitosan (3k, 6k, and 9k) were used to prepare the conjugates. LMWC-PTX conjugates were synthesized by two step reactions: i) modification of PTX with

Eunhye Lee; Jinju Lee; Sangvong Jon

2006-01-01

35

Preparation and in vitro properties of redox-responsive polymeric nanoparticles for paclitaxel delivery  

Microsoft Academic Search

Rice-like polymeric nanoparticles (NPs) composed of a new redox-responsive polymer, poly(ethylene glycol)-b-poly(lactic acid) (MPEG-SS-PLA), were prepared to carry paclitaxel (PTX) for glutathione (GSH)-regulated drug delivery. The PTX-loaded MPEG-SS-PLA NPs were fabricated using an optimized oil-in-water emulsion\\/solvent evaporation method. The size and morphology of the prepared NPs were characterized by scanning electron microscopy (SEM). The SEM results demonstrate that the NPs

Na Song; Wenming Liu; Qin Tu; Rui Liu; Yanrong Zhang; Jinyi Wang

2011-01-01

36

Paclitaxel targeting to lungs by way of liposomes prepared by the effervescent dispersion technique.  

PubMed

In order to develop a novel lung targeting drug delivery system (LTDDS) with large-sized liposomes containing paclitaxel (PTX), the liposomes composed of PTX, phosopholipon 90H and tween-80 were prepared by the effervescent dispersion technique with optimal formulation composition. The liposomes were found to be relatively uniform in particle size (8.166 ± 0.459 ?m) with a negative zeta-potential (-12.45 ± 1.34 mv), and high entrapment efficiency (92.20 ± 2.56 %). They kept stable for at least 3 months and exhibited a slow release behavior without any hemolysis reaction. Via intravenous administration in rabbits, the PTX liposomes presented a longer mean residence time and elimination half-life, and a much larger area under the plasma drug concentration-time curve compared with its injection; meanwhile, the liposomes altered its biodistribution and exhibited a significant lung targeting characteristic. For example, the relative intake rate (Re) and the ratio of peak concentration (Ce) of lung were 14.87 and 26.44, respectively. Compared with heart, liver, spleen and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 20.08, 11.10, 6.97 and 14.41, respectively. To sum up, the liposome could be a promising drug carrier for PTX as LTDDS for lung cancer treatment. PMID:23775475

Wei, Yumeng; Xue, Zhengkai; Ye, Yun; Huang, Yu; Zhao, Ling

2014-06-01

37

Poly(ester anhydride)/mPEG amphiphilic block co-polymer nanoparticles as delivery devices for paclitaxel.  

PubMed

This work focused on the preparation and characterization of a novel amphiphilic block co-polymer and paclitaxel-loaded co-polymer nanoparticles (NPs) and in vitro evaluation of the release of paclitaxel and cytotoxicity of NPs. mPEG-b-P(OA-DLLA)-b-mPEG was prepared via melt polycondensation of methoxy poly(ethylene glycol) (mPEG), octadecanedioic acid (OA) and D,L-lactic acid (DLLA) and characterized by FT-IR, (1)H-NMR, (13)C-NMR, GPC, DSC and XRD. The paclitaxel-loaded mPEG-b-P(OA-DLLA)-b-mPEG NPs were prepared by nanoprecipitation and then characterized by LPSA, TEM and (1)H-NMR. In vitro release behaviors of the paclitaxel-loaded NPs were investigated by HPLC. In vitro cytotoxicity of NPs was evaluated by MTT assay with normal mouse lung fibroblast cells (L929) as model cells. The composition of mPEG-b-P(OA-DLLA)-b-mPEG is consistent with that of the designed co-polymer. The paclitaxel-loaded NPs are of spherical shape with core/shell structure and size smaller than 300 nm. Paclitaxel can be continuously released from the paclitaxel-loaded NPs and the in vitro release rate of paclitaxel decreases with increasing the content of the P(OA-DLLA) segments in the co-polymer. The mPEG-b-P(OA-DLLA)-b-mPEG NPs are non-toxic to L929. The results suggest that mPEG-b-P(OA-DLLA)-b-mPEG NPs are a potential candidate carrier material for the controlled delivery of paclitaxel and other hydrophobic compounds. PMID:20566053

Liang, Yanqin; Xiao, Li; Li, Yimei; Zhai, Yinglei; Xie, Chaopeng; Deng, Liandong; Dong, Anjie

2011-01-01

38

COLON TARGETED DRUG DELIVERY SYSTEMS  

Microsoft Academic Search

Colon targeted drug delivery systems have the potential to deliver drugs for the treatment of a variety of colonic diseases and to deliver proteins and peptides to the colon for their systemic absorption. In recent years, various pharmaceutical approaches have been developed for targeting the drugs to the colon include, formation of prodrugs, coating of pH-sensitive polymers, use of colon

Ceyda Tuba

39

Improved Biochemical Strategies for Targeted Delivery of Taxoids  

PubMed Central

Paclitaxel (Taxol ®) and docetaxel (Taxotere ®) are very important anti-tumor drugs in clinical use for cancer. However, their clinical utility is limited due to systemic toxicity, low solubility and inactivity against drug resistant tumors. To improve chemotherapeutic levels of these drugs, it would be highly desirable to design strategies which bypass the above limitations. In this respect various prodrug and drug targeting strategies have been envisioned either to improve oral bioavailability or tumor specific delivery of taxoids. Abnormal properties of cancer cells with respect to normal cells have guided in designing of these protocols. This review article records the designed biochemical strategies and their biological efficacies as potential taxoid chemotherapeutics.

Ganesh, Thota

2008-01-01

40

Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles.  

PubMed

A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core-shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles would be a promising approach for tumor targeted therapy. PMID:24680191

Feng, Qiang; Yu, Min-Zhi; Wang, Jian-Cheng; Hou, Wen-Jie; Gao, Ling-Yan; Ma, Xiao-Fei; Pei, Xi-Wei; Niu, Yu-Jie; Liu, Xiao-Yan; Qiu, Chong; Pang, Wen-Hao; Du, Li-Li; Zhang, Qiang

2014-06-01

41

Local Intracerebral Administration of Paclitaxel with the Paclimer(R) Delivery System: Toxicity Study in a Canine Model  

PubMed Central

Introduction: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer®), and the efficacy of Paclimer® was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer® in a canine dose escalation toxicity study to prepare its translation into clinical scenarios. Methods: Twelve normal beagle dogs underwent a right parieto-occipital craniectomy and were randomized to receive either Paclimer® at 2-mg/kg (n=5), empty microspheres at 2-mg/kg (n=1), Paclimer® at 20-mg/kg (n=5), or empty microspheres at 20-mg/kg (n=1). Post-operatively, dogs were observed daily for signs of neurotoxicity. Complete blood counts and plasma levels of paclitaxel were obtained weekly. CSF levels and MRI scans were obtained on days14-120. Paclitaxel concentrations were quantified by LC-MS. Results: Animals treated with 20-mg/kg Paclimer® had minimal paclitaxel levels in plasma (range 0-7.84 ng/ml) and CSF (range 0-1.16 ng/ml). Animals treated with 2mg/kg Paclimer® had undetectable levels of paclitaxel in plasma, CSF was not obtained to minimize animal suffering. All animals exhibited normal behavior and weight gain, and were alive post-operatively through the last day of the study (day 60-120) without signs of neurological toxicity. There was no evidence of systemic toxicity or myelosuppression. MR imaging was comparable between Paclimer® animals and controls. Adverse effects included wound infections and a brain abscess, all of which responded to antibiotic therapy, and one ventriculomegaly due to communicating hydrocephalus. Conclusions: Paclimer®-based delivery of paclitaxel is safe for intraparenchymal delivery at the tested doses in normal dogs.

Pradilla, Gustavo; Wang, Paul P.; Gabikian, Patrik; Li, Khan; Magee, Carolyn A.; Walter, Kevin A.; Brem, Henry

2006-01-01

42

TARGETED DELIVERY OF INHALED PROTEINS  

EPA Science Inventory

ETD-02-047 (Martonen) GPRA # 10108 TARGETED DELIVERY OF INHALED PROTEINS T. B. Martonen1, J. Schroeter2, Z. Zhang3, D. Hwang4, and J. S. Fleming5 1Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Research Triangle Park...

43

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery  

PubMed Central

Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)0–? (20.343 ± 9.119 ?g · h · mL?1 vs 5.196 ± 1.426 ?g · h · mL?1), greater clearance (2.050 ± 0.616 L · kg?1 · h?1 vs 0.556 ± 0.190 L · kg?1 · h?1), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC0–? in liver, lung, and spleen (all P < 0.01), but not in heart or kidney.

Wang, Yonglu; Li, Xueming; Wang, Liyao; Xu, Yuanlong; Cheng, Xiaodan; Wei, Ping

2011-01-01

44

Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors  

Microsoft Academic Search

Purpose. The objective of this study was to evaluate the pharmacokinetics of paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration with or without P-glycoprotein (P-gp) inhibitors.

Shicheng Yang; R. Neslihan Gursoy; Gregory Lambert; Simon Benita

2004-01-01

45

Synthesis and biological evaluation (in vitro and in vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin ?V?3.  

PubMed

A small library of integrin ligand-paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified ?V?3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin ?V?3, making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used. PMID:23140358

Colombo, Raffaele; Mingozzi, Michele; Belvisi, Laura; Arosio, Daniela; Piarulli, Umberto; Carenini, Nives; Perego, Paola; Zaffaroni, Nadia; De Cesare, Michelandrea; Castiglioni, Vittoria; Scanziani, Eugenio; Gennari, Cesare

2012-12-13

46

Well-defined, size-tunable, multi-functional micelles for efficient paclitaxel delivery for cancer treatment  

PubMed Central

We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptakes of the smaller paclitaxel-loaded micelles (17–60 nm) by the tumor, and the larger micelles (150 nm) by the liver and lung. The toxicity and anti-tumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol® and Abraxane®.

Luo, Juntao; Xiao, Kai; Li, Yuanpei; Lee, Joyce S.; Shi, Lifang; Tan, Yih-Horng; Xing, Li; Cheng, R. Holland; Liu, Gang-Yu; Lam, Kit S.

2010-01-01

47

Dendritic poly(ethylene glycol) bearing paclitaxel and alendronate for targeting bone neoplasms.  

PubMed

Poly(ethylene glycol) (PEG) is the most popular polymer for protein conjugation, but its potential as carrier of low molecular weight drugs has been limited by the intrinsic low loading, owing to its chemical structure. In fact, only the two end chain groups of PEG can be modified and exploited for drug coupling. We have demonstrated that by synthesizing a dendrimer structure at the polymer end chains, it is possible to increase the drug payload and overcome this limitation. Furthermore, this approach can be improved by using heterobifunctional PEG. These polymers allow the precise linking of two different drugs, or a drug and a targeting agent, on the same polymeric chain. Heterobifunctional PEG-dendrimers have been obtained with defined chemical structures leading to their attractive use as drug delivery systems. In fact, they offer a double benefit; first, the possibility to choose the best drug/targeting agent ratio, and second, the separation of the two functions, activity and targeting, which are coupled at the opposite polymer end chains. In this study, we investigated the role of a PEG-dendrimer, H(2)N-PEG-dendrimer-(COOH)(4), as carrier for a combination of paclitaxel (PTX) and alendronate (ALN). PTX is a potent anticancer drug that is affected by severe side effects originating from both the drug itself and its solubilizing formulation, Cremophor EL. ALN is an aminobiphosphonate used for the treatment of osteoporosis and bone metastases as well as a bone-targeting moiety. The PTX-PEG-ALN conjugate was designed to exploit active targeting by the ALN molecule and passive targeting through the enhanced permeability and retention (EPR) effect. Our conjugate demonstrated a great binding affinity to the bone mineral hydroxyapatite in vitro and an IC(50) comparable to that of the free drugs combination in human adenocarcinoma of the prostate (PC3) cells. The PTX-PEG-ALN conjugate exhibited an improved pharmacokinetic profile compared with the free drugs owed to the marked increase in their half-life. In addition, PTX-PEG-ALN could be solubilized directly in physiological solutions without the need for Cremophor EL. The data presented in this manuscript encourage further investigations on the potential of PTX-PEG-ALN as treatment for cancer bone metastases. PMID:21608527

Clementi, Chiara; Miller, Keren; Mero, Anna; Satchi-Fainaro, Ronit; Pasut, Gianfranco

2011-08-01

48

Aptamers for Targeted Drug Delivery  

PubMed Central

Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

Ray, Partha; White, Rebekah R.

2010-01-01

49

Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.  

PubMed

Object The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. Methods The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. Results Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6-12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6-12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). Conclusions These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy. PMID:24605841

Gabikian, Patrik; Tyler, Betty M; Zhang, Irma; Li, Khan W; Brem, Henry; Walter, Kevin A

2014-05-01

50

Effective Drug Delivery, in vitro and in vivo, By Carbon-Based Nanovectors Non-Covalently Loaded With Unmodified Paclitaxel  

PubMed Central

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least twenty weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when non-covalently loaded with an unmodified drug.

Berlin, Jacob M.; Leonard, Ashley D.; Pham, Tam T.; Sano, Daisuke; Marcano, Daniela C.; Yan, Shayou; Fiorentino, Stefania; Milas, Zvonimir L.; Kosynkin, Dmitry V.; Katherine Price, B.; Lucente-Schultz, Rebecca M.; Wen, XiaoXia; Gabriela Raso, M.; Craig, Suzanne L.; Tran, Hai T.; Myers, Jeffrey N.; Tour, James M.

2010-01-01

51

Layer-by-layer assembly of chitosan stabilized multilayered liposomes for paclitaxel delivery.  

PubMed

Paclitaxel (PTX) loaded multilayered liposomes were prepared using layer-by-layer assembly in an effort to improve the stabilization of the liposomal compositions for PTX delivery. Stearyl amine was used to provide positive charge to the PTX-liposomes, and subsequently coated with anionic polyacrylic acid (PAA) followed by cationic chitosan. Various process variables were optimized and the optimum formulation was found to have particle size of 215±17nm, zeta potential of +27.9±3.4mV and encapsulation efficiency of 70.93±2.39%. The lyophilized chitosan-PAA-PTX-liposomes formulation was stable in simulated gastrointestinal fluids and at different environmental conditions (4°C and 25°C). In vitro drug release experiments demonstrated that chitosan-PAA-PTX-liposomes formulation exhibited obvious sustained release behaviors compared to PTX-liposomes. Furthermore, chitosan-PAA-PTX-liposomes formulation revealed enhanced PTX induced cytotoxicity in human cervical cancer cell culture experiments compared to PTX-liposomes. In conclusion, the approach presented herein will provide a promising solution for PTX delivery. PMID:25037355

Chen, Meng-Xia; Li, Bai-Kun; Yin, Deng-Ke; Liang, Jie; Li, Shan-Shan; Peng, Dai-Yin

2014-10-13

52

Poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) nanoparticles for local delivery of paclitaxel for restenosis treatment  

Microsoft Academic Search

Catheter-based local delivery of biodegradable nanoparticles (NP) with sustained release characteristics represents a therapeutic approach to reduce restenosis. Paclitaxel-loaded NP consisting of poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) (PVA-g-PLGA) with varying PLGA chain length as well as poly(lactide-co-glycolide) (PLGA), were prepared by a solvent evaporation technique. NP of <180 nm in diameter characterized by photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and atomic force

Ulrich Westedt; Marc Kalinowski; Matthias Wittmar; Thomas Merdan; Florian Unger; Jutta Fuchs; Susann Schäller; Udo Bakowsky; Thomas Kissel

2007-01-01

53

A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA–paclitaxel microspheres  

Microsoft Academic Search

A translymphatic drug delivery system which incorporates poly-lactide-co-glycolide–paclitaxel (PLGA–PTX) or PLGA–rhodamine microspheres into gelatin sponge matrix is described. The system combines the sustained release properties of PLGA–PTX with the structural advantages of gelatin matrix that can be implanted directly to the lymphatic site for both therapeutic and prophylactic purposes. The PLGA microspheres were prepared using spray drying technique. The particles

Jiang Liu; Dale Meisner; Elizabeth Kwong; Xiao Y. Wu; Michael R. Johnston

2007-01-01

54

Targeted Nanogels: A Versatile Platform for Drug Delivery to Tumors  

PubMed Central

While nanoparticle-based drug delivery formulations can improve the effectiveness and safety of certain anti-cancer drugs, many drugs, due to their chemical composition, are unsuitable for nanoparticle loading. Here, we describe a targeted nanogel drug delivery platform that can 1) encapsulate a wide range of drug chemotypes including: biological, small molecule, and cytotoxic agents 2) display targeting ligands and polymeric coatings on the surface, 3) enhance drug retention within the nanogel core after photo-crosslinking, and 4) retain therapeutic activity after lyophilization allowing for long term storage. For therapeutic studies, we utilized integrin ?v?3-targeted lipid-coated nanogels with crosslinked human serum albumin in the core for carrying therapeutic cargoes. These particles exhibited potent activity in tumor cell viability assays with drugs of distinct chemotype including: paclitaxel, docetaxel, bortezomib, 17-AAG, sorafenib, sunitinib, bosutinib, and dasatinib. Treatment of orthotopic breast and pancreas tumors in mice with taxane-loaded nanogels produced a 15-fold improvement in anti-tumor activity relative to Abraxane by blocking both primary tumor growth and spontaneous metastasis. With a modifiable surface and core, the lipid-coated nanogel represents a platform technology that can be easily adapted for specific drug delivery applications to treat a wide range of malignant diseases.

Murphy, Eric A.; Majeti, Bharat K.; Mukthavaram, Rajesh; Acevedo, Lisette M.; Barnes, Leo A.; Cheresh, David A.

2011-01-01

55

Efficacy of poly(sebacic acid-co-ricinoleic acid) biodegradable delivery system for intratumoral delivery of paclitaxel.  

PubMed

The effectiveness of an injectable polymeric formulation, based on poly(sebacic acid-co-ricinoleic acid) and paclitaxel against a heterotopic tumor model was studied. An injectable pasty polymer that releases an incorporated drug over a period of weeks was used. The degradation rate of formulations with paclitaxel was examined in vitro and in vivo. The effectiveness of the polymeric carrier of paclitaxel was investigated using a melanoma heterotopic model in C57BL/6 mice. Tumor bearing animals were injected intratumorally with 0.1 ml of formulations containing 5%, 10%, 15%, and 20% paclitaxel. Formulations with 5% and 10% paclitaxel content degraded faster in vivo then in vitro. Changes in tumor progression, survival time, and body weight were observed over a period of 77 days. The highest tumor size was reported for the control groups that did not receive paclitaxel in their treatment regiment: 3.6 g on day 20, while in all groups treated with polymer loaded with paclitaxel the tumor size was much smaller than that in the blank polymer or non treatment groups and ranged from 1.3 g to 0.3 g. Intratumoral injection of paclitaxel loaded in the polymer was found to be an effective treatment for localized tumors. PMID:19343769

Shikanov, Ariella; Vaisman, Boris; Shikanov, Sergey; Domb, Abraham J

2010-03-15

56

THE USE OF NANOPARTICLE-MEDIATED TARGETED GENE SILENCING AND DRUG DELIVERY TO OVERCOME TUMOR DRUG RESISTANCE  

PubMed Central

Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance.

Patil, Yogesh; Swaminathan, Suresh; Sadhukha, Tanmoy; Ma, Linan; Panyam, Jayanth

2009-01-01

57

Thermosensitive micelles-hydrogel hybrid system based on poloxamer 407 for localized delivery of paclitaxel.  

PubMed

A thermosensitive micelles-hydrogel hybrid system based on Poloxamer 407 (P407) was prepared to resolve the fast erosion and low loading capability of lipophilic drug of P407 gels for local chemotherapy. Different amounts of glutaraldehyde (GA) were applied to generate cross-linked networks with carboxymethyl chitosan (CMCS) interpenetrated in P407 gels, in which paclitaxel (PTX)-loaded N-octyl-O-sulfate chitosan micelles (PTX-M) were dispersed uniformly. The in vitro characteristics of CMCS-modified P407 gels (PTX-M-MG) were performed by examining the viscosity, swelling ratio, mechanical property, and drug release, while the in vivo evaluation included tissue distribution and anticancer efficacy through intratumoral administration in hepatoma solidity cell (Heps) tumor-bearing mice. The results showed that PTX-M-MG containing 0.05% (w/v) GA possessed lower viscosity, higher swelling ratio, stronger mechanical property, and longer term drug release, in which the loading efficiency of PTX was enlarged by the introduction of PTX-M. Moreover, PTX-M-MG revealed a prolonged retention at tumor sites, lasting for 20 days, and a superior tumor inhibition rate (64.27%) with reduced toxicity compared with Taxol(®) , PTX-M, and PTX-M loaded unmodified P407 gels (PTX-M-P407). It can be concluded that PTX-M-MG is a promising local delivery system for hydrophobic drug in cancer therapy, providing both improved efficacy and relieved side effects. PMID:23839931

Ju, Caoyun; Sun, Juan; Zi, Peng; Jin, Xiang; Zhang, Can

2013-08-01

58

Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel  

PubMed Central

Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)-N,N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50 % (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 ?g/mL to 86 ?g/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH-sensitivity, which was clearly observed at relatively high AA contents and pH > 6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH=6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH=1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery.

Kim, Sungwon; Kim, Ji Young; Huh, Kang Moo; Acharya, Ghanshyam; Park, Kinam

2008-01-01

59

Targeting Paclitaxel-Loaded Nanoparticles to Ovarian Cancer.  

National Technical Information Service (NTIS)

The specific aims of this project are to: (1) determine the efficacy, pharmacokinetics, toxicology and imaging capacity of RGD-targeted Nexil; and, (2) determine the ability of other ovarian cancer-specific targeting ligands to enhance the efficacy of Nex...

S. Howell

2011-01-01

60

Aptamer-targeted Antigen Delivery  

PubMed Central

Effective therapeutic vaccines often require activation of T cell-mediated immunity. Robust T cell activation, including CD8 T cell responses, can be achieved using antibodies or antibody fragments to direct antigens of interest to professional antigen presenting cells. This approach represents an important advance in enhancing vaccine efficacy. Nucleic acid aptamers present a promising alternative to protein-based targeting approaches. We have selected aptamers that specifically bind the murine receptor, DEC205, a C-type lectin expressed predominantly on the surface of CD8?+ dendritic cells (DCs) that has been shown to be efficient at facilitating antigen crosspresentation and subsequent CD8+ T cell activation. Using a minimized aptamer conjugated to the model antigen ovalbumin (OVA), DEC205-targeted antigen crosspresentation was verified in vitro and in vivo by proliferation and cytokine production by primary murine CD8+ T cells expressing a T cell receptor specific for the major histocompatibility complex (MHC) I-restricted OVA257–264 peptide SIINFEKL. Compared with a nonspecific ribonucleic acid (RNA) of similar length, DEC205 aptamer-OVA-mediated antigen delivery stimulated strong proliferation and production of interferon (IFN)-? and interleukin (IL)-2. The immune responses elicited by aptamer-OVA conjugates were sufficient to inhibit the growth of established OVA-expressing B16 tumor cells. Our results demonstrate a new application of aptamer technology for the development of effective T cell-mediated vaccines.

Wengerter, Brian C; Katakowski, Joseph A; Rosenberg, Jacob M; Park, Chae Gyu; Almo, Steven C; Palliser, Deborah; Levy, Matthew

2014-01-01

61

Specific tumor delivery of paclitaxel using glycolipid-like polymer micelles containing gold nanospheres.  

PubMed

It is difficult for most of the drug delivery systems to really display a temporal and spatial release of entrapped drug once the systems are iv administrated. We hypothesized that the photothermal effect, mediated by a near-infrared (NIR) laser and hollow gold nanospheres (HAuNS), can modulate paclitaxel (PTX) release from polymer micelles, and further result in the enhanced antitumor activity of the micelles. We loaded PTX and HAuNS, which display strong plasmon absorption in the NIR region, into glycolipid-like polymer micelles with an excellent cell internalization capability. The surface of the micelles was conjugated successfully with a peptide, which has the specific-binding with EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on cell membrane of numerous tumors, to increase the delivery of PTX into tumor cells. Rapid and repetitive drug release from our polymer (HP-TCS) micelles could be readily achieved upon NIR laser irradiation. Our data demonstrated the specific delivery of HP-TCS micelles into positive-EphB4 tumors using a duel-tumor model after iv administration during the whole experiment process (1-48 h). Interestingly, significantly higher uptake of the micelles by SKOV3 tumors (positive-EphB4) than A549 tumors (negtive-EphB4) was observed, with increased ratio on experiment time. However, the specific cell uptake was observed only during the short incubation time (1-4 h) in vitro. Our data also indicated the treatment of tumor cells with the micelles followed by NIR laser irradiation showed significantly greater toxicity activity than the treatment with the micelles alone, free PTX and the micelles (without PTX loading) plus NIR laser irradiation. The enhanced toxicity activity to tumor cells should be attributed to the enhanced drug cellular uptake mediated by the glycolipid-like micelles, chemical toxicity of the released drug from the micelles due to the trigger of NIR laser, and the photothermal ablation under NIR laser irradiation. PMID:23510855

You, Jian; Wang, Zuhua; Du, Yongzhong; Yuan, Hong; Zhang, Peizun; Zhou, Jialin; Liu, Fei; Li, Chun; Hu, Fuqiang

2013-06-01

62

Specific tumor delivery of paclitaxel using glycolipid-like polymer micelles containing gold nanospheres  

PubMed Central

It is difficult for most of drug delivery system to really display a temporal and spatial release of entrapped drug once the systems are iv administrated. We hypothesized that the photothermal effect, mediated by a near-infrared (NIR) laser and hollow gold nanospheres (HAuNS), can modulate paclitaxel (PTX) release from polymer micelles, and further result in the enhanced antitumor activity of the micelles. We loaded PTX and HAuNS, which display strong plasmon absorption in the NIR region, into glycolipid-like polymer micelles with an excellent cell internalization capability. The surface of the micelles was conjugated successfully with a peptide, which has the specific-binding with EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on cell membrane of numerous tumors, to increase the delivery of PTX into tumor cells. Rapid and repetitive drug release from our polymer (HP-TCS) micelles could be readily achieved upon NIR laser irradiation. Our data demonstrated the specific-delivery of HPTCS micelles into positive-EphB4 tumors using a duel-tumor model after iv administration during the whole experiment process (1-48h). Interestingly, significantly higher uptake of the micelles by SKOV3 tumors (positive-EphB4) than A549 tumors (negtive-EphB4) was observed, with increased ratio on experiment time. However, the specific cell uptake was observed only during the short incubation time (1-4h) in vitro. Our data also indicated the treatment of tumor cells with the micelles followed by NIR laser irradiation showed significantly greater toxicity activity than the treatment with the micelles alone, free PTX and the micelles (without PTX loading) plus NIR laser irradiation. The enhanced toxicity activity to tumor cells should be attributed to the enhanced drug cellular uptake mediated by the glycolipid-like micelles, chemical toxicity of the released drug from the micelles due to the trigger of NIR laser, and the photothermal ablation under NIR laser irradiation.

You, Jian; Wang, Zuhua; Du, Yongzhong; Yuan, Hong; Zhang, Peizun; Zhou, Jialin; Liu, Fei; Li, Chun; Hu, Fuqiang

2014-01-01

63

Nonviral approach for targeted nucleic acid delivery.  

PubMed

Despite their relatively lower efficiency, nonviral approaches are emerging as safer alternatives in gene therapy to viral vectors. Delivery of nucleic acids to the target site is an important factor for effective gene expression (plasmid DNA) or knockdown (siRNA) with minimal side effects. Direct deposition at the target site by physical methods, including ultrasound, electroporation and gene gun, is one approach for local delivery. For less accessible sites, the development of carriers that can home into the target tissue is required. Cationic peptides, lipoplexes, polyplexes and nanoplexes have been used as carriers for delivery of nucleic acids. Targeting ligands, such as cell targeting peptides, have also been applied to decorate delivery vehicles in order to enhance their efficacy. This review focuses on delivery strategies and recent progress in non-viral carriers and their modifications to improve their performance in targeting and transfection. PMID:22320298

Jafari, M; Soltani, M; Naahidi, S; Karunaratne, D N; Chen, P

2012-01-01

64

Multifunctional hierarchically assembled nanostructures as complex stage-wise dual-delivery systems for coincidental yet differential trafficking of siRNA and paclitaxel.  

PubMed

Development of multifunctional nanostructures that can be tuned to codeliver multiple drugs and diagnostic agents to diseased tissues is of great importance. Hierarchically assembled theranostic (HAT) nanostructures based on anionic cylindrical shell cross-linked nanoparticles and cationic shell cross-linked knedel-like nanoparticles (cSCKs) have recently been developed by our group to deliver siRNA intracellularly and to undergo radiolabeling. In the current study, paclitaxel, a hydrophobic anticancer drug, and siRNA have been successfully loaded into the cylindrical and spherical components of the hierarchical assemblies, respectively. Cytotoxicity, immunotoxicity, and intracellular delivery mechanism of the HAT nanostructures and their individual components have been investigated. Decoration of nanoparticles with F3-tumor homing peptide was shown to enhance the selective cellular uptake of the spherical particles, whereas the HAT nanoassemblies underwent an interesting disassembly process in contact with either OVCAR-3 or RAW 264.7 cell lines. The HAT nanostructures were found to "stick" to the cell membrane and "trigger" the release of spherical cSCKs templated onto their surfaces intracellularly, while retaining the cylindrical part on the cell surface. Combination of paclitaxel and cell-death siRNA (siRNA that induces cell death) into the HAT nanostructures resulted in greater reduction in cell viability than siRNA complexed with Lipofectamine and the assemblies loaded with the individual drugs. In addition, a shape-dependent immunotoxicity was observed for both spherical and cylindrical nanoparticles with the latter being highly immunotoxic. Supramolecular assembly of the two nanoparticles into the HAT nanostructures significantly reduced the immunotoxicity of both cSCKs and cylinders. HAT nanostructures decorated with targeting moieties, loaded with nucleic acids, hydrophobic drugs, radiolabels, and fluorophores, with control over their toxicity, immunotoxicity, and intracellular delivery might have great potential for biomedical delivery applications. PMID:23574430

Elsabahy, Mahmoud; Shrestha, Ritu; Clark, Corrie; Taylor, Sara; Leonard, Jeffrey; Wooley, Karen L

2013-05-01

65

Multifunctional hierarchically-assembled nanostructures as complex stage-wise dual-delivery systems for coincidental yet differential trafficking of siRNA and paclitaxel  

PubMed Central

Development of multifunctional nanostructures that can be tuned to co-deliver multiple drugs and diagnostic agents to diseased tissues is of great importance. Hierarchically-assembled theranostic (HAT) nanostructures based on anionic cylindrical shell crosslinked nanoparticles and cationic shell crosslinked knedel-like nanoparticles (cSCKs) have recently been developed by our group to deliver siRNA intracellularly, and to undergo radiolabeling. In the current study, paclitaxel, a hydrophobic anticancer drug, and siRNA have been successfully loaded into the cylindrical and spherical components of the hierarchical assemblies, respectively. Cytotoxicity, immunotoxicity and intracellular delivery mechanism of the HAT nanostructures and their individual components have been investigated. Decoration of nanoparticles with F3-tumor homing peptide was shown to enhance the selective cellular uptake of the spherical particles, whereas the HAT nanoassemblies underwent an interesting disassembly process in contact with either OVCAR-3 or RAW 264.7 cell lines. The HAT nanostructures were found to “stick” to the cell membrane and “trigger” the release of spherical cSCKs templated onto their surfaces intracellularly, while retaining the cylindrical part on the cell surface. Combination of paclitaxel and cell-death siRNA (siRNA that induces cell death) into the HAT nanostructures resulted in greater reduction in cell viability than siRNA complexed with Lipofectamine and the assemblies loaded with the individual drugs. In addition, a shape-dependent immunotoxicity was observed for both spherical and cylindrical nanoparticles, with the latter being highly immunotoxic. Supramolecular assembly of the two nanoparticles into the HAT nanostructures significantly reduced the immunotoxicity of both cSCKs and cylinders. HAT nanostructures decorated with targeting moieties, loaded with nucleic acids, hydrophobic drugs, radiolabels, fluorophores, with control over their toxicity, immunotoxicity and intracellular delivery might have great potential for biomedical delivery applications.

Elsabahy, Mahmoud; Shrestha, Ritu; Clark, Corrie; Taylor, Sara; Leonard, Jeffrey; Wooley, Karen L.

2013-01-01

66

Membranes and Barriers: Targeted Drug Delivery.  

National Technical Information Service (NTIS)

Contents: Retrometabolic Approaches to Drug Targeting; Vector-Mediated Delivery of Opioid Peptides to the Brain; Conformationally Constrained Peptide Drugs Targeted at the Blood-Brain Barrier; Passive and Facilitative Transport of Nucleobases, Nucleosides...

R. S. Rapaka

1995-01-01

67

Paclitaxel delivery from cobalt-chromium alloy surfaces using self-assembled monolayers.  

PubMed

Polymer-based platforms in drug-eluting stents (DESs) can cause adverse reactions in patients. Hence, the development of a polymer-free drug delivery platform may reduce adverse reactions to DES. In this study, the use of a polymer-free platform, self-assembled monolayers (SAMs), is explored for delivering an antiproliferative drug [paclitaxel (PAT)] from a stent material [cobalt-chromium ((Co-Cr) alloy]. Initially, carboxylic acid terminated phosphonic acid SAMs were coated on Co-Cr alloy. Two different doses (25 and 100 ?g/cm²) of PAT were coated on SAM coated Co-Cr surfaces using a microdrop deposition method. Also, control experiments were carried out to coat PAT directly on Co-Cr surfaces with no SAM modification. The PAT coated specimens were characterized using the Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). FTIR spectra showed the successful deposition of PAT on SAM coated and control-Co-Cr surfaces. SEM images showed islands of high density PAT crystals on SAM coated surfaces, while low density PAT crystals were observed on control-Co-Cr alloy. AFM images showed molecular distribution of PAT on SAM coated as well as control-Co-Cr alloy surfaces. In vitro drug release studies showed that PAT was released from SAM coated Co-Cr surfaces in a biphasic manner (an initial burst release in first 7 days was followed by a slow release for up to 35 days), while the PAT was burst released from control-Co-Cr surfaces within 1-3 days. Thus, this study demonstrated the use of SAMs for delivering PAT from Co-Cr alloy surfaces for potential use in drug-eluting stents. PMID:21721838

Mani, Gopinath; Torres, Nelson; Oh, Sunho

2011-06-01

68

Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel  

PubMed Central

Introduction Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-R?, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen.

Jilaveanu, Lucia B.; Zhao, Fengmin; Zito, Christopher R.; Kirkwood, John M.; Nathanson, Katherine L.; D'Andrea, Kurt; Wilson, Melissa; Rimm, David L.; Flaherty, Keith T.; Lee, Sandra J.; Kluger, Harriet M.

2013-01-01

69

Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy  

NASA Astrophysics Data System (ADS)

Effective anticancer therapy can be achieved by designing a targeted drug-delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug-delivery system, formed by multivalent host–guest interactions between a polymer–cyclodextrin conjugate and a polymer–paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery.

Namgung, Ran; Mi Lee, Yeong; Kim, Jihoon; Jang, Yuna; Lee, Byung-Heon; Kim, In-San; Sokkar, Pandian; Rhee, Young Min; Hoffman, Allan S.; Kim, Won Jong

2014-05-01

70

pH and glutathion-responsive hydrogel for localized delivery of paclitaxel.  

PubMed

pH and glutathion (GSH)- responsive nanogels (NGs) based on poly-N-isopropylacrilamide (NIPA), N-hydroxyethyl acrylamide (HEAA) and tert-butyl 2-acrylamidoethyl carbamate (2AAECM) were synthesized by a microemulsion polymerization method using N, N'-cystaminebisacrylamide (CBA) as a crosslinking agent and evaluated for passive targeting of paclitaxel (PTX). Physicochemical characterizations of unloaded and PTX-loaded NGs, such as particle size, morphology, encapsulation efficiency and in vitro PTX release were also assessed. Electron microscopy techniques (SEM and TEM) as well as dynamic light scattering (DLS) analysis showed nanosized spherical hydrogels. FTIR spectra confirmed the synthesis of nanogels by free radical polymerization among vinyl groups of monomers. In vitro release was analyzed by high-performance liquid chromatography (HPLC) and differences between two NG formulations were obtained. Nanogels released almost 64% of PTX after 50h at GSH concentrations equivalent to that in the cellular cytosol, whereas less PTX was released from NGs at pH and GSH levels similar to plasma. Cellular uptake and cytotoxicity were also demonstrated by using coumarin-6 and MTT assays, respectively, for three tumor cell lines (MCF7, HeLa and T47D). Cellular uptake assays revealed rapid uptake within 2h and intracellular accumulation of coumarin-6-loaded nanogels after 48h incubation. MTT assays showed changes in cell viability at different concentrations of PTX formulations, as well as pure PTX (10?M, 20?M and 30?M). To investigate PTX effect on cell viability, changes in cell cycle were examined by flow cytometry and a G2/M cell arrest was demonstrated. Overall, synthesized nanogels may be used as potential carriers for hydrophobic anticancer drugs. PMID:24491841

Pérez, Elena; Fernández, Ana; Olmo, Rosa; Teijón, Jose M; Blanco, M Dolores

2014-04-01

71

Polymers for colon targeted drug delivery.  

PubMed

The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems. PMID:21969739

Rajpurohit, H; Sharma, P; Sharma, S; Bhandari, A

2010-11-01

72

Polymers for Colon Targeted Drug Delivery  

PubMed Central

The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems.

Rajpurohit, H.; Sharma, P.; Sharma, S.; Bhandari, A.

2010-01-01

73

Non-Covalent Functionalization of Carbon Nanovectors with an Antibody Enables Targeted Drug Delivery  

PubMed Central

Current chemotherapeutics are characterized by efficient tumor cell-killing and severe side effects mostly derived from off target toxicity. Hence targeted delivery of these drugs to tumor cells is actively sought. We previously demonstrated that poly(ethylene glycol)-functionalized carbon nanovectors are able to sequester paclitaxel, a widely used hydrophobic cancer drug, by simple physisorption and deliver the drug for killing of cancer cells. The cell-killing when these drug-loaded carbon nanoparticles were used was equivalent to when a commercial formulation of paclitaxel was used. Here we show that by further mixing the drug-loaded nanoparticles with Cetuximab, a monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR), paclitaxel is preferentially targeted to EGFR+ tumor cells in vitro. This supports progressing to in vivo studies. Moreover, the construct is unusual in that all three components are assembled through non-covalent interactions. Such non-covalent assembly could enable high-throughput screening of drug/antibody combinations.

Berlin, Jacob M.; Pham, Tam T.; Sano, Daisuke; Mohamedali, Khalid A.; Marcano, Daniela C.; Myers, Jeffrey N.; Tour, James M.

2011-01-01

74

Successful revascularization of re-stenosis of lower extremity arteries with localized delivery of paclitaxel.  

PubMed

Restenosis after percutaneous revascularization techniques is a challenging issue in patients with severe peripheral arterial disease. We report two cases where multiple revascularization techniques had been used previously, but restenosis occurred. We used an irrigation balloon to deliver paclitaxel locally into the tissues to obtain better results. PMID:18655111

Latif, Faisal; Hennebry, Thomas A

2008-08-01

75

Effect of Paclitaxel Local Delivery on Neointimal Formation after Endothelial Denudation of the Rat Carotid Artery  

Microsoft Academic Search

Background and Objectives:Mechanisms of restenosis following successful coronary angioplasty (PTCA are known as vascular smooth muscle cells (VSMCs proliferation and migration, elastic recoil or vascular wall remodeling. Paclitaxel whose effect on the stabilization of microtubles leads to cell death is highly lipophilic, permitting easy pass through cell membrane, and has a long-term antiproliferative effect. This study was performed to evaluate

Myeong-Chan Cho; Nam Joo Kwak; Hainan Piao; Tae Jin Youn

76

Folate-targeted paclitaxel-conjugated polymeric micelles inhibits pulmonary metastatic hepatoma in experimental murine H22 metastasis models  

PubMed Central

Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA) and paclitaxel (PTX) containing composite micelles (FA-M[PTX]) were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX) on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22) on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain), followed by survival analysis. The results indicated that FA-M(PTX) prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA-M(PTX) group gained significantly prolonged survival time when compared with others given equivalent doses of PTX of 30 mg/kg. The enhanced efficacy of FA-M(PTX) is theoretically ascribed to the target effect of FA; moreover, the extensive pulmonary capillary networks may play a role. In conclusion, FA-M(PTX) displayed great potential as a promising antimetastatic agent, and the FA-conjugated micelles is a preferential targeted delivery system when compared to micelles without FA.

Zhang, Yan; Zhang, Hui; Wu, Wenbin; Zhang, Fuhong; Liu, Shi; Wang, Rui; Sun, Yingchun; Tong, Ti; Jing, Xiabin

2014-01-01

77

Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer.  

PubMed

Despite progress, combination therapy of different functional drugs to increase the efficiency of anticancer treatment still remains challenges. An amphiphilic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-lysine) triblock copolymer decorated with deoxycholate (mPEsG-b-PLG-b-PLL/DOCA) was synthesized and developed as a nanovehicle for the co-delivery of anticancer drugs: doxorubicin (DOX) and paclitaxel (PTX). The amphiphilic copolymer spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and the blank nanoparticles possessed excellent stability. Three different domains of the copolymer performed distinct functions: PEG outer corona provided prolonged circulation, middle biodegradable and hydrophilic PLG shell was designed for DOX loading through electrostatic interactions, and hydrophobic deoxycholate modified PLL served as the container for PTX. In vitro cytotoxicity assays against A549 human lung adenocarcinoma cell line demonstrated that the DOX + PTX co-delivered nanoparticles (Co-NPs) exhibited synergistic effect in inducing cancer cell apoptosis. Ex vivo DOX fluorescence imaging revealed that Co-NPs had highly efficient targeting and accumulation at the implanted site of A549 xenograft tumor in vivo. Co-NPs exhibited significantly higher antitumor efficiency in reducing tumor size compared to free drug combination or single drug-loaded nanoparticles, while no obvious side effects were observed during the treatment, indicating this co-delivery system with different functional antitumor drugs provides the clinical potential in cancer therapy. PMID:24794923

Lv, Shixian; Tang, Zhaohui; Li, Mingqiang; Lin, Jian; Song, Wantong; Liu, Huaiyu; Huang, Yubin; Zhang, Yuanyuan; Chen, Xuesi

2014-07-01

78

ENDOCYTIC MECHANISMS FOR TARGETED DRUG DELIVERY  

PubMed Central

Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway have serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer’s disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules.

Bareford, Lisa M.; Swaan, Peter W.

2007-01-01

79

Nanoparticles for intracellular-targeted drug delivery  

NASA Astrophysics Data System (ADS)

Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

Paulo, Cristiana S. O.; Pires das Neves, Ricardo; Ferreira, Lino S.

2011-12-01

80

A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer.  

PubMed

Paclitaxel (PTX) is one of the most effective chemotherapeutic drugs for the treatment of a variety of cancers. However, it is associated with serious side effects caused by PTX itself and the Cremophor EL emulsifier. In the present study, we report the development of a well-defined amphiphilic linear-dendritic copolymer (named as telodendrimer) composed of polyethylene glycol (PEG), cholic acid (CA, a facial amphiphilic molecule) and lysine, which can form drug-loaded core/shell micelles when mixed with hydrophobic drug, such as PTX, under aqueous condition. We have used PEG(5k)-CA(8), a representive telodendrimer, to prepare paclitaxel-loaded nanoparticles (PTX-PEG(5k)-CA(8) NPs) with high loading capacity (7.3 mg PTX/mL) and a size of 20-60 nm. This novel nanoformulation of PTX was found to exhibit similar in vitro cytotoxic activity against ovarian cancer cells as the free drug (Taxol) or paclitaxel/human serum albumin nanoaggregate (Abraxane). The maximum tolerated doses (MTDs) of PTX-PEG(5k)-CA(8) NPs after single dose and five consecutive daily doses in mice were approximately 75 and 45 mg PTX/kg, respectively, which were 2.5-fold higher than those of Taxol. In both subcutaneous and orthotopic intraperitoneal murine models of ovarian cancer, PTX-PEG(5k)-CA(8) NPs achieved superior toxicity profiles and anti-tumor effects compared to Taxol and Abraxane at equivalent PTX doses, which were attributed to their preferential tumor accumulation, and deep penetration into tumor tissue, as confirmed by near infrared fluorescence (NIRF) imaging. PMID:19660809

Xiao, Kai; Luo, Juntao; Fowler, Wiley L; Li, Yuanpei; Lee, Joyce S; Xing, Li; Cheng, R Holland; Wang, Li; Lam, Kit S

2009-10-01

81

Tumor’host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds  

Microsoft Academic Search

Targeting of the tumor stroma, including the tumor vasculature, represents a new frontier in the treatment of malignancy.\\u000a Preclinical studies and clinical experiences have established that stroma-directed novel agents must be combined with conventional\\u000a therapies in order to achieve relevant therapeutic efficacy. Here we review our preclinical experience on combinations of\\u000a paclitaxel with a tyrosine kinase receptor inhibitor of angiogenesis

Raffaella Giavazzi; Maria Rosa Bani; Giulia Taraboletti

2007-01-01

82

Targeted prodrug design to optimize drug delivery  

Microsoft Academic Search

Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited\\u000a bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents\\u000a a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific\\u000a membrane transporter, or both, has potential as

Hyo-Kyung Han; Gordon L. Amidon

2000-01-01

83

A Dicarboxylic Fatty Acid Derivative of Paclitaxel for Albumin Assisted Drug Delivery  

PubMed Central

Paclitaxel is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize paclitaxel (PTX) by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (~5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor bearing mice, [3H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 hours. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23-h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics.

Hackett, Michael J.; Joolakanti, Shyamsunder; Hartranft, Megan E.; Guley, Patrick C.; Cho, Moo J.

2013-01-01

84

Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel.  

PubMed

Paclitaxel and poly (L-Lactic acid) (PLA) were co-precipitated to form micro and submicron particles in a manner similar to that used in the supercritical antisolvent with enhanced mass transfer (SAS-EM) process. As compared with conventional processes, a major advantage of supercritical CO(2) as an antisolvent in the SAS-EM process is the effective removal of residual organic solvents. In this work, the organic phase was sprayed into supercritical CO(2) (for CO(2), Tc=31.1 degrees C, Pc=73.8 bar) from a 500 microm ID capillary nozzle. Ultrasonic vibration with an amplitude of 0 to 120 microm (from a 3/8'' tip diameter titanium probe) was employed in the high pressure vessel during the antisolvent process to provide enhanced mixing between the solvent and antisolvent phases. The role and effects of ultrasonication on the properties of the resulting particles were studied. When no ultrasonication was applied, micrometer-sized particles were obtained. When ultrasonication was applied, more uniform particles in the submicron size range were obtained. The size of the particles was found to vary with the ultrasonic vibration amplitude. Encapsulation efficiencies up to 83.5% and controlled release of paclitaxel for more than 30 days were achieved with the particles fabricated in this study. PMID:18054107

Lee, Lai Yeng; Wang, Chi Hwa; Smith, Kenneth A

2008-01-22

85

Targeted gene delivery to dendritic cells  

US Patent & Trademark Office Database

Methods and compositions are provided for delivery of a polynucleotide encoding a gene of interest, typically an antigen, to a dendritic cell (DC). The virus envelope comprises a DC-SIGN specific targeting molecule. The methods and related compositions can be used to treat patients suffering from a wide range of conditions, including infection, such as HIV/AIDS, and various types of cancers.

2012-09-25

86

Targeted drug delivery via the folate receptor  

Microsoft Academic Search

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including

Jennifer Sudimack; Robert J Lee

2000-01-01

87

Amphiphilic carboxymethyl chitosan-quercetin conjugate with P-gp inhibitory properties for oral delivery of paclitaxel.  

PubMed

An amphiphilic carboxymethyl chitosan-quercetin (CQ) conjugate was designed and synthesized for oral delivery of paclitaxel (PTX) to improve its oral bioavailability by increasing its water solubility and bypassing the P-gp drug efflux pumps. CQ conjugate had low critical micelle concentration (55.14 ?g/mL), and could self assemble in aqueous condition to form polymeric micelles (PMs). PTX-loaded CQ PMs displayed a particle size of 185.8 ± 4.6 nm and polydispersity index (PDI) of 0.134 ± 0.056. The drug-loading content (DL) and entrapment efficiency (EE) were 33.62 ± 1.34% and 85.63 ± 1.26%, respectively. Moreover, PTX-loaded CQ PMs displayed similar sustained-release profile in simulated gastrointestinal fluids (pH 1.2/pH 6.8) and PBS (pH 7.4). In situ intestinal absorption experiment showed that PTX-loaded CQ PMs significantly improved the effective permeability of PTX as compared to verapamil (P < 0.01). Likewise, PTX-loaded CQ PMs significantly enhanced the oral bioavailability of PTX, resulting in strong antitumor efficacy against tumor xenograft models with better safety profile as compared to Taxol(®) and Taxol(®) with verapamil. Overall, the results implicate that CQ PMs are promising vehicles for the oral delivery of water-insoluble anticancer drugs. PMID:24927684

Wang, Xiaoying; Chen, Yihang; Dahmani, Fatima Zohra; Yin, Lifang; Zhou, Jianping; Yao, Jing

2014-08-01

88

Paclitaxel combined with siRNA targeting HPV16 oncogenes improves cytotoxicity for cervical carcinoma  

Microsoft Academic Search

Cervical cancer is attributable to continuous expression of the E6 and E7 oncoproteins of the high-risk human papillomaviruses. These proteins target p53 and members of the retinoblastoma cellular regulatory protein family respectively for degradation, disrupting cellular control over apoptosis, senescence and the cell cycle. Delivery of short interfering RNAs (siRNAs) targeting mRNA from the HPV16 E6\\/E7 open reading frame to

W-l Liu; N Green; L W Seymour; M Stevenson

2009-01-01

89

Delivery of paclitaxel from cobalt-chromium alloy surfaces without polymeric carriers  

PubMed Central

Polymer-based carriers are commonly used to deliver drugs from stents. However, adverse responses to polymer coatings have raised serious concerns. This research is focused on delivering drugs from stents without using polymers or any carriers. Paclitaxel (PAT), an anti-restenotic drug, has strong adhesion towards a variety of material surfaces. In this study, we have utilized such natural adhesion property of PAT to attach these molecules directly to cobalt–chromium (Co–Cr) alloy, an ultra-thin stent strut material. Four different groups of drug coated specimens were prepared by directly adding PAT to Co–Cr alloy surfaces: Group-A (PAT coated, unheated, and ethanol cleaned); Group-B (PAT coated, heat treated, and ethanol cleaned); Group-C (PAT coated, unheated, and not ethanol cleaned); and Group-D (PAT coated, heat treated and not ethanol cleaned). In vitro drug release of these specimens was investigated using high performance liquid chromatography. Groups A and B showed sustained PAT release for up to 56 days. A simple ethanol cleaning procedure after PAT deposition can remove the loosely bound drug crystals from the alloy surfaces and thereby allowing the remaining strongly bound drug molecules to be released at a sustained rate. The heat treatment after PAT coating further improved the stability of PAT on Co–Cr alloy and allowed the drug to be delivered at a much slower rate, especially during the initial 7 days. The specimens which were not cleaned in ethanol, Groups C and D, showed burst release. PAT coated Co–Cr alloy specimens were thoroughly characterized using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. These techniques were collectively useful in studying the morphology, distribution, and attachment of PAT molecules on Co–Cr alloy surfaces. Thus, this study suggests the potential for delivering paclitaxel from Co–Cr alloy surfaces without using any carriers.

Mani, Gopinath; Macias, Celia E.; Feldman, Marc D.; Marton, Denes; Oh, Sunho; Agrawal, C. Mauli

2014-01-01

90

Liposomes loaded with paclitaxel and modified with novel triphenylphosphonium-PEG-PE conjugate possess low toxicity, target mitochondria and demonstrate enhanced antitumor effects in vitro and in vivo.  

PubMed

Previously, stearyl triphenylphosphonium (STPP)-modified liposomes (STPP-L) were reported to target mitochondria. To overcome a non-specific cytotoxicity of STPP-L, we synthesized a novel polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate with the TPP group attached to the distal end of the PEG block (TPP-PEG-PE). This conjugate was incorporated into the liposomal lipid bilayer, and the modified liposomes were studied for their toxicity, mitochondrial targeting, and efficacy in delivering paclitaxel (PTX) to cancer cells in vitro and in vivo. These TPP-PEG-PE-modified liposomes (TPP-PEG-L), surface grafted with as high as 8 mol% of the conjugate, were less cytotoxic compared to STPP-L or PEGylated STPP-L. At the same time, TPP-PEG-L demonstrated efficient mitochondrial targeting in cancer cells as shown by confocal microscopy in co-localization experiments with stained mitochondria. PTX-loaded TPP-PEG-L demonstrated enhanced PTX-induced cytotoxicity and anti-tumor efficacy in cell culture and mouse experiments compared to PTX-loaded unmodified plain liposomes (PL). Thus, TPP-PEG-PE can serve as a targeting ligand to prepare non-toxic liposomes as mitochondria-targeted drug delivery systems (DDS). PMID:22286008

Biswas, Swati; Dodwadkar, Namita S; Deshpande, Pranali P; Torchilin, Vladimir P

2012-05-10

91

Integrin Targeted Delivery of Gene Therapeutics  

PubMed Central

Integrins have become key targets for molecular imaging and for selective delivery of anti-cancer agents. Here we review recent work concerning the targeted delivery of antisense and siRNA oligonucleotides via integrins. A variety of approaches have been used to link oligonucleotides to ligands capable of binding integrins with high specificity and affinity. This includes direct chemical conjugation, incorporating oligonucleotides into lipoplexes, and use of various polymeric nanocarriers including dendrimers. The ligand-oligonucleotide conjugate or complex associates selectively with the integrin, followed by internalization into endosomes and trafficking through subcellular compartments. Escape of antisense or siRNA from the endosome to the cytosol and nucleus may come about through endogenous trafficking mechanisms, or because of membrane disrupting capabilities built into the conjugate or complex. Thus a variety of useful strategies are available for using integrins to enhance the pharmacological efficacy of therapeutic oligonucleotides.

Juliano, Rudy L; Ming, Xin; Nakagawa, Osamu; Xu, Rongzuo; Yoo, Hoon

2011-01-01

92

Chitosan\\/pshRNA plasmid nanoparticles targeting MDR1 gene reverse paclitaxel resistance in ovarian cancer cells  

Microsoft Academic Search

Summary  In order to investigate the effect of chitosan\\/pshRNA plasmid nanoparticles targeting MDR1 genes on the resistance of A2780\\/TS\\u000a cells to paclitaxel, chitosan\\/pshRNA plasmid nanoparticles were synthesized by means of a complex coacervation technique and\\u000a transfected into A2780\\/TS cells. The cells transfected with MDR1-targeted chitosan\\/pshRNA plasmid nanoparticles were experimental\\u000a cells and the cells transfected with chitosan\\/pGPU6\\/GFP\\/Neo no-load plasmid nanoparticles served as

Yan Yang; Zehua Wang; Minfang Li; Shi Lu

2009-01-01

93

miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6.  

PubMed

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1. PMID:24510775

Zhu, Xiaolan; Li, Yuefeng; Xie, Chanjuan; Yin, Xinming; Liu, Yueqin; Cao, Yuan; Fang, Yue; Lin, Xin; Xu, Yao; Xu, Wenlin; Shen, Huiling; Wen, Jian

2014-09-15

94

Synthesis and biological evaluation of a peptide-paclitaxel conjugate which targets the integrin ?v??.  

PubMed

The integrin ?(v)?(6) is an emergent biomarker for non-small cell lung cancer (NSCLC) as well as other carcinomas. We previously developed a tetrameric peptide, referred to as H2009.1, which binds ?(v)?(6) and displays minimal affinity for other RGD-binding integrins. Here we report the use of this peptide to actively deliver paclitaxel to ?(v)?(6)-positive cells. We synthesized a water soluble paclitaxel-H2009.1 peptide conjugate in which the 2'-position of paclitaxel is attached to the tetrameric peptide via an ester linkage. The conjugate maintains its specificity for ?(v)?(6)-expressing NSCLC cells, resulting in selective cytotoxicity. Treatment of ?(v)?(6)-positive cells with the conjugate results in cell cycle arrest followed by induction of apoptosis in the same manner as free paclitaxel. However, initiation of apoptosis and the resultant cell death is delayed compared to free drug. The conjugate demonstrates anti-tumor activity in a H2009 xenograft model of NSCLC with efficacy comparable to treatment with free paclitaxel. PMID:21868241

Li, Shunzi; Gray, Bethany Powell; McGuire, Michael J; Brown, Kathlynn C

2011-09-15

95

Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors  

PubMed Central

Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100 ?m) and release the drug over 10 days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14 days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability.

Bajaj, Gaurav; Kim, Mi Ran; Mohammed, Sulma I.; Yeo, Yoon

2012-01-01

96

Delivery of paclitaxel by physically loading onto poly(ethylene glycol) (PEG)-graftcarbon nanotubes for potent cancer therapeutics  

NASA Astrophysics Data System (ADS)

Physically loading of paclitaxel (PTX) onto carbon nanotubes (CNTs) is achieved through immersion of poly(ethylene glycol) (PEG)-graft-single walled CNTs (PEG-g-SWNTs) or PEG-graft-multi-walled CNTs (PEG-g-MWNTs) in a saturated solution of PTX in methanol. After loading once the loading capacity (LD%) is 26% (w/w) and 36% (w/w) for PEG-g-SWNTs or PEG-g-MWNTs, respectively. With these PTX contents, PTX loaded PEG-g-SWNTs and PTX loaded PEG-g-MWNTs still have good dispersity in aqueous solution and individual CNTs can be observed in TEM images. PTX can be released from PEG-g-CNTs several times faster than from free PTX but still in a sustained profile with less than 40% of PTX being released in 40 days at pH 7 or 5. In vitro cytotoxicity of samples is evaluated in HeLa cells and MCF-7 cells. PEG-g-SWNTs and PEG-g-MWNTs show low cytotoxicity in both cells with insignificant effects on the cell proliferation rates. However, both PTX loaded PEG-g-SWNTs and PTX loaded PEG-g-MWNTs show high efficacy to kill HeLa cells and MCF-7 cells, as reflected by IC50 lower than free PTX. Therefore, PTX loaded PEG-g-CNTs are promising for cancer therapeutics. Keywords: carbon nanotubes, poly(ethylene glycol), drug delivery, cancer therapy, nanomedicine.

Leng Lay, Chee; Liu, Hui Qi; Tan, Hui Ru; Liu, Ye

2010-02-01

97

Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer  

PubMed Central

Introduction Elevated expression of erbB3 rendered erbB2-overexpressing breast cancer cells resistant to paclitaxel via PI-3 K/Akt-dependent upregulation of Survivin. It is unclear whether an erbB3-targeted therapy may abrogate erbB2-mediated paclitaxel resistance in breast cancer. Here, we study the antitumor activity of an anti-erbB3 antibody MM-121/SAR256212 in combination with paclitaxel against erbB2-overexpressing breast cancer. Methods Cell growth assays were used to determine cell viability. Cells undergoing apoptosis were quantified by a specific apoptotic ELISA. Western blot analyses were performed to assess the protein expression and activation. Lentiviral vector containing shRNA was used to specifically knockdown Survivin. Tumor xenografts were established by inoculation of BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with paclitaxel and/or MM-121/SAR256212 to determine whether the antibody (Ab) enhances paclitaxel’s antitumor activity. Immunohistochemistry was carried out to study the combinatorial effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly facilitated paclitaxel-mediated anti-proliferative/anti-survival effects on SKBR3 cells transfected with a control vector or erbB3 cDNA. It specifically downregulated Survivin associated with inactivation of erbB2, erbB3, and Akt. MM-121 enhances paclitaxel-induced poly(ADP-ribose) polymerase (PARP) cleavage, activation of caspase-8 and -3, and apoptosis in both paclitaxel-sensitive and -resistant cells. Specific knockdown of Survivin in the trastuzumab-resistant BT474-HR20 cells dramatically enhanced paclitaxel-induced apoptosis, suggesting that increased Survivin caused a cross-resistance to paclitaxel. Furthermore, the studies using a tumor xenograft model-established from BT474-HR20 cells revealed that either MM-121 (10 mg/kg) or low-dose (7.5 mg/kg) paclitaxel had no effect on tumor growth, their combinations significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed that the combinations of MM-121 and paclitaxel significantly reduced the cells with positive staining for Ki-67 and Survivin, and increased the cells with cleaved caspase-3. Conclusions The combinations of MM-121 and paclitaxel not only inhibit tumor cell proliferation, but also promote erbB2-overexpressing breast cancer cells to undergo apoptosis via downregulation of Survivin in vitro and in vivo, suggesting that inactivation of erbB3 with MM-121 enhances paclitaxel-mediated antitumor activity against erbB2-overexpressing breast cancers. Our data supports further exploration of the combinatorial regimens consisting of MM-121 and paclitaxel in breast cancer patients with erbB2-overexpressing tumors, particularly those resistant to paclitaxel.

2013-01-01

98

New Approaches to Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

For targeted drug delivery, one of the primary drawbacks lies with the inability to design a delivery system that can be loaded with a variety of drugs and biomolecules. Motivated by this challenge, we will present data showing 400 nm liposomes loaded via the novel method of lysenin pores. These pores are approximately 3 nm in diameter and can be closed with divalent and trivalent ions in addition to charged polymers. This new method allows for the controllable passage of large biomolecules such as DNA and protein without the inherent problems common to active and passive loading methods. We will show proof-of-concept results of this method using fluorescent calcein as a drug simulator. Furthermore, data demonstrating current attempts at loading DNA will also be presented.

Cooper, James; Oliver, William; Fologea, Daniel

2013-03-01

99

Paclitaxel-Loaded Poly(n-butylcyanoacrylate) Nanoparticle Delivery System to Overcome Multidrug Resistance in Ovarian Cancer  

Microsoft Academic Search

Purpose  The aim of this study was to test the ability of paclitaxel-loaded poly(butylcyanoacrylate) (PBCA) nanoparticles to overcome\\u000a multidrug resistance (MDR) in human ovarian resistant cells (A2780\\/T) and investigate its possible mechanism.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We prepared paclitaxel-loaded PBCA nanoparticles by interfacial polymerization method. The physicochemistry of the nanoparticles\\u000a was characterized. The cytotoxicity of paclitaxel-loaded PBCA nanoparticles was measured by MTT assay. Calcein-AM assay

Fei Ren; Ruda Chen; Ying Wang; Yabin Sun; Yaodong Jiang; Guofeng Li

2011-01-01

100

Well-defined, Reversible Disulfide Cross-linked Micelles for On-demand Paclitaxel Delivery  

PubMed Central

To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross-linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti-tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N-acetylcysteine, after PTX-DCMs have reached the tumor site.

Li, Yuanpei; Xiao, Kai; Luo, Juntao; Xiao, Wenwu; Lee, Joyce S.; Gonik, Abby M.; Kato, Jason; Dong, Tiffany; Lam, Kit S.

2011-01-01

101

The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Hyaluronic Acid as Drug Delivery System: Synthesis, Self-Assembled Property, Drug Release, and In Vitro Efficiency  

Microsoft Academic Search

Purpose  A cell-targeted prodrug with good self-assembly properties in aqueous solution was prepared for the anti-cancer drug paclitaxel,\\u000a offering great potential for further investigation.\\u000a \\u000a \\u000a \\u000a Methods  We synthesized hyaluronic acid (HA) with a specific targeting property as a carrier to conjugate with paclitaxel by inserting\\u000a different amino acids as spacers, including valine, leucine, and phenylalanine, respectively. The structure of HA-amino acid-paclitaxel\\u000a conjugates was

Dingcheng Xin; Ying Wang; Jiannan Xiang

2010-01-01

102

Synthesis and Evaluation of a Backbone Biodegradable Multiblock HPMA Copolymer Nanocarrier for the Systemic Delivery of Paclitaxel  

PubMed Central

The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer- PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents.

Zhang, Rui; Luo, Kui; Yang, Jiyuan; Sima, Monika; Sun, Yongen; Janat-Amsbury, Margit M.; Kopecek, Jindrich

2012-01-01

103

Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.  

PubMed

The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents. PMID:23262201

Zhang, Rui; Luo, Kui; Yang, Jiyuan; Sima, Monika; Sun, Yongen; Janát-Amsbury, Margit M; Kope?ek, Jind?ich

2013-02-28

104

PEG-PE-based micelles co-loaded with paclitaxel and cyclosporine A or loaded with paclitaxel and targeted by anticancer antibody overcome drug resistance in cancer cells.  

PubMed

The over-expression of the P-glycoprotein (P-gp) in cancer cells is one of the main reasons of the acquired Multidrug Resistance (MDR). Combined treatment of MDR cancer cells with P-gp inhibitors and chemotherapeutic agents could result in reversal of resistance in P-gp-expressing cells. In this study, paclitaxel (PTX) was co-encapsulated in actively targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles with Cyclosporine A (CycA), which is one of the most effective first generation P-gp inhibitors. Cell culture studies performed using MDCKII (parental and MDR1) cell lines to investigate the potential MDR reversal effect of the formulations. The average size of both empty and loaded PEG????-PE/Vitamin E mixed micelles was found between 10 and 25 nm. Zeta potentials of the formulations were found between -7 and -35 mV. The percentage of PTX in the micelles was found higher than 3% for both formulations and cumulative PTX release of about 70% was demonstrated. P-gp inhibition with CycA caused an increase in the cytotoxicity of PTX. Dual-loaded micelles demonstrated significantly higher cytotoxicity in the resistant MDCKII-MDR1 cells than micelles loaded with PTX alone. Micelle modification with mAb 2C5 results in the highest cytotoxicity against resistant cells, with or without P-gp modulator, probably because of better internalization bypassing the P-gp mechanism. Our results suggest that micelles delivering a combination of P-gp modulator and anticancer drug or micelles loaded with only PTX, but targeted with mAb 2C5 represent a promising approach to overcome drug resistance in cancer cells. PMID:22506922

Sarisozen, Can; Vural, Imran; Levchenko, Tatyana; Hincal, A Atilla; Torchilin, Vladimir P

2012-05-01

105

Self-Assembled Biodegradable Nanoparticles Developed by Direct Dialysis for the Delivery of Paclitaxel  

Microsoft Academic Search

Purpose. The main objective of this study was to obtain self-assembled biodegradable nanoparticles by a direct dialysis method for the delivery of anticancer drug. The in vitro cellular particle uptake and cytotoxicity to C6 glioma cell line were investigated. Methods. Self-assembled anticancer drugsVpaclitaxel-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid) (PLA) nanoparticlesVwere achieved by direct dialysis. The physical and chemical properties

Jingwei Xie; Chi-Hwa Wang

2005-01-01

106

Targeted delivery of colloids by swimming bacteria  

PubMed Central

The possibility of exploiting motile microorganisms as tiny propellers represents a fascinating strategy for the transport of colloidal cargoes. However, delivery on target sites usually requires external control fields to steer propellers and trigger cargo release. The need for a constant feedback mechanism prevents the design of compact devices where biopropellers could perform their tasks autonomously. Here we show that properly designed three-dimensional microstructures can define accumulation areas where bacteria spontaneously and efficiently store colloidal beads. The process is stochastic in nature and results from the rectifying action of an asymmetric energy landscape over the fluctuating forces arising from collisions with swimming bacteria. As a result, the concentration of colloids over target areas can be strongly increased or depleted according to the topography of the underlying structures. Besides the significance to technological applications, our experiments pose some important questions regarding the structure of stationary probability distributions in non-equilibrium systems.

Koumakis, N.; Lepore, A.; Maggi, C.; Di Leonardo, R.

2014-01-01

107

Targeted delivery of colloids by swimming bacteria  

NASA Astrophysics Data System (ADS)

The possibility of exploiting motile microorganisms as tiny propellers represents a fascinating strategy for the transport of colloidal cargoes. However, delivery on target sites usually requires external control fields to steer propellers and trigger cargo release. The need for a constant feedback mechanism prevents the design of compact devices where biopropellers could perform their tasks autonomously. Here we show that properly designed three-dimensional (3D) microstructures can define accumulation areas where bacteria spontaneously and efficiently store colloidal beads. The process is stochastic in nature and results from the rectifying action of an asymmetric energy landscape over the fluctuating forces arising from collisions with swimming bacteria. As a result, the concentration of colloids over target areas can be strongly increased or depleted according to the topography of the underlying structures. Besides the significance to technological applications, our experiments pose some important questions regarding the structure of stationary probability distributions in non-equilibrium systems.

Koumakis, N.; Lepore, A.; Maggi, C.; di Leonardo, R.

2013-10-01

108

Sustained delivery of paclitaxel using thermogelling poly(PEG/PPG/PCL urethane)s for enhanced toxicity against cancer cells.  

PubMed

A multiblock poly(ether ester urethane)s comprising poly(?-caprolactone), poly(ethylene glycol), and poly(propylene glycol) segments was synthesized. The aqueous copolymer solution exhibited thermogelling behavior at a critical gelation concentration of 3 wt %. The chemical structure and molecular characteristic of the copolymers were studied by gel permeation chromatography, NMR, and fourier transform infrared spectroscopy (FTIR). Rheological characterizations on the thermogel were carried out. Drug release studies using paclitaxel showed that sustained drug release of more than 2 weeks can be achieved with this system. The paclitaxel-loaded gels showed efficiency in the control of the growth of HeLa cells when compared with the paclitaxel dissolved in solution or paclitaxel encapsulated in Pluronics F127. The results demonstrated that the copolymers could be potentially used in chemotherapeutic applications. PMID:22619090

Loh, Xian Jun; Yee, Benjamin Jia Han; Chia, Fu Siong

2012-10-01

109

d-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified poly(l-lactide) (PLLA) films for localized delivery of paclitaxel.  

PubMed

d-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) was used as a novel additive to the poly(l-lactide) (PLLA) films for local drug delivery with paclitaxel as a prototype therapeutic agent. Paclitaxel-loaded PLLA/TPGS films were prepared by the solvent casting technique with dichloromethane as the solvent. Effects of TPGS component on the films' physicomechanical properties and the drug release profile were investigated. It was found by field emission scanning microscopy (FESEM) that a biphasic honeycomb surface was formed for the PLLA/TPGS films, while the PLLA film exhibited a smooth and homogeneous surface. There was no significant effect of the drug loading on the morphological structure of the PLLA/TPGS films. Differential scanning calorimetry (DSC) demonstrated that the PLLA/TPGS films was a phase-separated system. Tensile testing showed that the flexibility of the PLLA/TPGS films was much higher than that of the PLLA film. The elongation at break for the PLLA/TPGS film of 5%, 10% and 15% TPGS content was 6.8, 8.9 and 19.4 times of that for the PLLA film, respectively. In vitro drug release studies found that incorporation of TPGS considerably facilitated paclitaxel release. PMID:17920218

Dong, Yuancai; Zhang, Zhiping; Feng, Si-Shen

2008-02-28

110

Development and characterization of stabilized double loaded mPEG-PDLLA micelles for simultaneous delivery of paclitaxel and docetaxel.  

PubMed

Abstract Objective: Double loaded micelles (DLM) in which paclitaxel (PTX) and docetaxel (DTX) were co-solubilized with monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PLA) copolymer were prepared and evaluated in an aim to investigate the effect of a combination of PTX and DTX on the stability of mPEG-PLA micelles compared to single drug-loaded micelles (SDM), especially that recent clinical anticancer formulations are limited by the existence of toxic excipients and stability issues. Materials and methods: The SDM and DLM of PTX and DTX were prepared by a solvent evaporation method. Micellar size, size distribution, drug loading content and drug release were investigated. Transmission electron microscopy was used to investigate the stabilization mechanism. Results: The drug loading efficiency of both PTX and DTX in DLM and SDM were 25% and 10%, respectively. (1)H NMR showed a successful encapsulation of both drugs in the polymeric micelle. DLM showed better physical stability at drug concentrations higher than 1?mg/mL compared to SDM. Moreover, DLM, SDM-PTX and SDM-DTX were stable for 24, 9 and 1?h, respectively. The stabilization mechanism of DLM was investigated, a network structure of DLM was observed in TEM graphs. Furthermore, DLM showed complete and faster drug release compared to SDM. mPEG-PLA double loaded micelles can deliver two poorly water soluble anticancer drugs at clinically relevant doses. The obtained results offer a promising alternative for double drug therapy without any formulation associated undesirable effects and encourage further in vivo development and optimization of the DLM as a drug delivery system for anticancer drugs. PMID:23600653

Ouahab, Ammar; Shao, Chengyi; Shen, Yan; Tu, Jiasheng

2014-07-01

111

Prophylactic cannabinoid administration blocks the development of paclitaxel-induced neuropathic nociception during analgesic treatment and following cessation of drug delivery  

PubMed Central

Background Chemotherapeutic treatment results in chronic pain in an estimated 30-40 percent of patients. Limited and often ineffective treatments make the need for new therapeutics an urgent one. We compared the effects of prophylactic cannabinoids as a preventative strategy for suppressing development of paclitaxel-induced nociception. The mixed CB1/CB2 agonist WIN55,212-2 was compared with the cannabilactone CB2-selective agonist AM1710, administered subcutaneously (s.c.), via osmotic mini pumps before, during, and after paclitaxel treatment. Pharmacological specificity was assessed using CB1 (AM251) and CB2 (AM630) antagonists. The impact of chronic drug infusion on transcriptional regulation of mRNA markers of astrocytes (GFAP), microglia (CD11b) and cannabinoid receptors (CB1, CB2) was assessed in lumbar spinal cords of paclitaxel and vehicle-treated rats. Results Both WIN55,212-2 and AM1710 blocked the development of paclitaxel-induced mechanical and cold allodynia; anti-allodynic efficacy persisted for approximately two to three weeks following cessation of drug delivery. WIN55,212-2 (0.1 and 0.5 mg/kg/day s.c.) suppressed the development of both paclitaxel-induced mechanical and cold allodynia. WIN55,212-2-mediated suppression of mechanical hypersensitivity was dominated by CB1 activation whereas suppression of cold allodynia was relatively insensitive to blockade by either CB1 (AM251; 3 mg/kg/day s.c.) or CB2 (AM630; 3 mg/kg/day s.c.) antagonists. AM1710 (0.032 and 3.2 mg/kg /day) suppressed development of mechanical allodynia whereas only the highest dose (3.2 mg/kg/day s.c.) suppressed cold allodynia. Anti-allodynic effects of AM1710 (3.2 mg/kg/day s.c.) were mediated by CB2. Anti-allodynic efficacy of AM1710 outlasted that produced by chronic WIN55,212-2 infusion. mRNA expression levels of the astrocytic marker GFAP was marginally increased by paclitaxel treatment whereas expression of the microglial marker CD11b was unchanged. Both WIN55,212-2 (0.5 mg/kg/day s.c.) and AM1710 (3.2 mg/kg/day s.c.) increased CB1 and CB2 mRNA expression in lumbar spinal cord of paclitaxel-treated rats in a manner blocked by AM630. Conclusions and implications Cannabinoids block development of paclitaxel-induced neuropathy and protect against neuropathic allodynia following cessation of drug delivery. Chronic treatment with both mixed CB1/CB2 and CB2 selective cannabinoids increased mRNA expression of cannabinoid receptors (CB1, CB2) in a CB2-dependent fashion. Our results support the therapeutic potential of cannabinoids for suppressing chemotherapy-induced neuropathy in humans.

2014-01-01

112

Preparation and characterization of polymeric pH-sensitive STEALTH® nanoparticles for tumor delivery of a lipophilic prodrug of paclitaxel.  

PubMed

Paclitaxel is an effective and widely used anti-cancer agent. However, the drug is difficult to formulate for parenteral administration because of its low water solubility and Cremophor EL, the expient used for its formulation, has been shown to cause serious side effects. The present study reports an alternative administration vehicle involving a lipophilic paclitaxel prodrug, paclitaxel oleate, incorporated in the core of a nanoparticle-based dosage form. A hydrophobic poly (?-amino ester) (PbAE) was used to formulate the nanoparticles, which were stabilized with a mixture of phosphatidylcholine, Synperonic® F 108, and poly(ethylene glycol)-dipalmitoyl phosphatidyl ethanolamine. PbAE undergoes rapid dissolution when the pH of the medium is less than 6.5 and is expected to rapidly release its content within the acidic tumor microenvironment and endo/lysosome compartments of cancer cells. PbAE nanoparticles were prepared by an ultrasonication method and characterized for particle size and physical stability. The nanoparticles obtained had a diameter of about 70 nm and a good physical stability when stored at 4 °C. In vitro cellular uptake and release of paclitaxel oleate PbAE nanoparticles were studied in Jurkat acute lymphoblastic leukemia cells. The results were compared with pclitaxel oleate in poly(?-caprolactone) (PCL) particles, that do not display pH-sensitive release behavior, and paclitaxel in PbAE particles. Both uptake and release of the prodrug were faster when administered in PbAE than in PCL, but much slower than those of the free drug in PbAE. Cytotoxicity assay was performed on the formulations at different doses. Paclitaxel and paclitaxel oleate showed almost identical activity, IC50 123 and 128 nM, respectively, while that of the prodrug in PCL was much lower with IC50 at 2.5 ?M. Thus, PbAE nanoparticles with the incorporated paclitaxel prodrug paclitaxel oleate may prove useful for replacement of the toxic Cremophor EL and also by improving the distribution of the drug to the tumor. PMID:21296135

Lundberg, B B

2011-04-15

113

Supramolecular micellar nanoaggregates based on a novel chitosan/vitamin E succinate copolymer for paclitaxel selective delivery  

PubMed Central

Background Nowadays, many cytotoxic anticancer drugs exhibit low solubility and poor tumor selectivity, which means that the drug formulation is very important. For example, in the case of paclitaxel (PTX), Cremophor EL® (BASF, Ludwigshafen, Germany) needs to be used as a solubilizer in its clinical formulation (Taxol®, Bristol-Myers Squibb, New York, NY), although it can cause serious side effects. Nanomicellar systems are promising carriers to resolve the above problems, and the polymer chosen is the key element. Methods In this study, a novel amphiphilic chitosan/vitamin E succinate (CS-VES) copolymer was successfully synthesized for self-assembling polymeric micelles. Proton nuclear magnetic resonance spectroscopy and infrared were used to characterize the molecular structure of the copolymer. The PTX-loaded CS-VES polymeric micelles (PTX-micelles) were characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, and differential scanning calorimetry. Results The critical micelle concentration of CS-VES was about 12.6 ?g/mL, with the degree of amino group substitution being 20.4%. PTX-micelles were prepared by a nanoprecipitation/dispersion technique without any surfactant being involved. PTX-micelles exhibited a drug loading as high as 21.37% and an encapsulation efficiency of 81.12%, with a particle size ranging from 326.3 to 380.8 nm and a zeta potential of +20 mV. In vitro release study showed a near zero-order sustained release, with 51.06%, 50.88%, and 44.35% of the PTX in the micelles being released up to 168 hours at three drug loadings of 7.52%, 14.09%, and 21.37%, respectively. The cellular uptake experiments, conducted by confocal laser scanning microscopy, showed an enhanced cellular uptake efficiency of the CS-VES micelles in MCF-7 cells compared with Taxol. The PTX-micelles exhibited a comparable but delayed cytotoxic effect compared with Taxol against MCF-7 cells, due to the sustained-release characteristics of the nanomicelles. More interestingly, blank nanomicelles based on CS-VES copolymer demonstrated significant cytotoxicity against MCF-7 cells. Conclusion The supramolecular micellar aggregates based on CS-VES copolymer is a promising nanocarrier and efficacy enhancer when used as an anticancer drug-delivery system.

Lian, He; Sun, Jin; Yu, Yan Ping; Liu, Yan Hua; Cao, Wen; Wang, Yong Jun; Sun, Ying Hua; Wang, Si Ling; He, Zhong Gui

2011-01-01

114

Hyaluronic acid-coated nanostructured lipid carriers for targeting paclitaxel to cancer.  

PubMed

The aim of our study was to develop hyaluronic acid-coated, paclitaxel-loaded, nanostructured lipid carriers (HA-NLCs) prepared via electrostatic attraction for delivering paclitaxel (PTX) to tumors overexpressing CD44. First, cationic PTX-NLC was prepared by melt emulsion technology. Then, PTX-NLC were coated with hyaluronic acid (HA). The in vitro release of PTX was evaluated by the dialysis method. This analysis showed that PTX was released more slowly from HA-NLC than from Taxol®. The in vitro cytotoxicity of HA-NLC was investigated using the MTT method in B16, CT26 and HCT116 cell lines. The results showed that the cytotoxicity of HA-NLC against these three cancer cell lines was superior to that of Taxol®. The in vivo antitumor effect, the pharmacokinetics and the tissue distribution of HA-NLC were all evaluated in B16-bearing Kunming mice. The results showed that HA-NLC was better tolerated and had increased antitumor activity in B16-bearing Kunming mice compared with Taxol®. Furthermore, HA-NLC could prolong the circulation time of PTX in blood and increase the accumulation of PTX in the tumor. Therefore, HA-NLC prepared via electrostatic attraction was an effective carrier for delivering PTX to tumors overexpressing CD44. PMID:22776563

Yang, Xiao-Yan; Li, Yun-Xia; Li, Min; Zhang, Li; Feng, Li-Xia; Zhang, Na

2013-07-01

115

Giant Fullerenes for Target Specific Drug Delivery  

NASA Astrophysics Data System (ADS)

Carbon nano-structures, such as giant fullerenes, have a great potential for biological and medical applications. Most of the previous research is dedicated to investigate the use of fullerenes as vehicles for carrying medication which is chemisorbed on the outside surface of the fullerenes. In contrast, using fullerenes as an enclosure was largely abandoned due to the high strength of the carbon-carbon bonds which has been perceived to prevent the rupturing of the fullerene to release their cargo. We performed atomistic computations based on classical force fields that will address this perception. Specifically we explore the physics and chemistry of OH functionalized carbon based giant fullerenes with diameters from 0.72 nm (60 atoms) to 5.7 nm (3840 atoms). The preliminary results show that OH functionalization on these fullerenes is not only viable but also provides a pH sensitive release mechanism. Furthermore our current results show that carbon-carbon bonds can be broken in low energy biological environments in the presence of a flow induced strain field. These insights may have implications for target specific drug delivery in general and cancer treatment in particular.

Courtney, Robert; Kiefer, Boris

2013-03-01

116

Paclitaxel Injection  

MedlinePLUS

Paclitaxel injection manufactured with human albumin is used to treat breast cancer that has not improved or that has come back after ... doctor and pharmacist if you are allergic to paclitaxel, any other ... polyoxyethylated castor oil, or medications that contain polyoxyethylated ...

117

Strategies for combination of aptamer and targeted drug delivery.  

PubMed

Cell-specific delivery of active agents for treatment of human disease is a long cherished object for scientific researchers. Nanoscience generated nanosized carriers, such as liposome, micelle and nanoparticle, provides potential to realize such purpose based on the nanometer size effect (< 1000 nm), however, the sole nanocarrier with no specific ligands are not sufficient to deliver drugs to target sites. Aptamers are single-stranded oligonucleotides which can specifically recognize and bind to target cells by distinct secondary and tertiary structures even without knowledge of characteristic protein profiles on cell surface. Thus, aptamer, as a target moiety, provides a potential approach to realize pathological site-specific delivery of active agents. This review highlighted the strategies for combination of aptamer and targeted drug delivery, further summarized their preparation methods, strengths and weaknesses to facilitate the development of targeted drug delivery system. PMID:24730278

Wang, Cheng; Liu, Biao; Lu, Jun; Zhang, Ge; Lu, Aiping

2014-01-01

118

The class I HDAC inhibitor Romidepsin targets inflammatory breast cancer tumor emboli and synergizes with paclitaxel to inhibit metastasis.  

PubMed

Inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer. IBC has distinctive characteristics including invasion of tumor emboli into the skin and rapid disease progression. Given our previous studies suggesting that HDAC inhibitors have promise in targeting IBC, the present study revealed that the class I HDAC inhibitor Romidepsin (FK-288, Istodax; Celgene Corporation, Summit, NJ) potently induced destruction of IBC tumor emboli and lymphatic vascular architecture. associated with inhibition of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha, (HIF1alpha) proteins in the Mary-X pre-clinical model of IBC. Romidepsin treatment induced clinically relevant biomarkers in including induction of acetylated Histone 3 (Ac-H3) proteins, apoptosis, and increased p21WAF1/CIP1. Romidepsin, alone and synergistically when combined with Paclitaxel, effectively eliminated both primary tumors and metastatic lesions at multiple sites formed by the SUM149 IBC cell line. This is the first report of the ability of an HDAC inhibitor to eradicate IBC tumor emboli, to destroy the integrity of lymphatic vessel architecture and to target metastasis. Furthermore, Romidepsin, in combination with a taxane, warrants evaluation as a therapeutic strategy that may effectively target the skin involvement and rapid metastasis that are hallmarks of IBC. PMID:24416998

Robertson, Fredika M; Chu, Khoi; Boley, Kimberly M; Ye, Zaiming; Liu, Hui; Wright, Moishia C; Moraes, Ricardo; Zhang, Xuejun; Green, Tessa L; Barsky, Sanford H; Heise, Carla; Cristofanilli, Massimo

2013-01-01

119

Poly(ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases.  

PubMed

Paclitaxel (PTX) and alendronate (ALN) are effective drugs used for the treatment of breast cancer bone metastases. Growing evidence suggests that low-dose taxanes and bisphosphonates possess anti-angiogenic properties. However, PTX is water-insoluble and toxic, even if administered at anti-angiogenic dosing schedule. Polymer conjugation of PTX will increase water-solubility and improve its pharmacokinetic profile directing it to the tumor site. We further propose to combine it with ALN for active bone targeting. We conjugated ALN and PTX with poly(ethylene glycol) (PEG) forming self-assembled micelles where PTX molecules are located at the inner core and the water-soluble ALN molecules at the outer shell. PTX-PEG-ALN micelles exhibited similar in vitro cytotoxic and anti-angiogenic activity as the free drugs. Biodistribution analysis demonstrated preferential tumor accumulation of FITC-labeled PTX-PEG-ALN micelles. Pharmacokinetic studies revealed longer t1/2 of the conjugate than free PTX. PTX-PEG-ALN micelles achieved improved efficacy and safety profiles over free PTX in syngeneic and xenogeneic mouse models of mCherry-infected mammary adenocarcinoma in the tibia, as monitored intravitally non-invasively by a fluorescence imaging system. The described data warrants the potential use of PTX-PEG-ALN as bone-targeted anticancer and anti-angiogenic therapy for breast cancer bone metastases. PMID:23434349

Miller, Keren; Clementi, Chiara; Polyak, Dina; Eldar-Boock, Anat; Benayoun, Liat; Barshack, Iris; Shaked, Yuval; Pasut, Gianfranco; Satchi-Fainaro, Ronit

2013-05-01

120

A novel lanreotide-encoded micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors.  

PubMed

Many tumor cells specifically overexpress somatostatin receptors, in particular, subtype 2 (SSTR2). Lanreotide, a somatostatin analogue with high affinity for SSTR2, can be exploited as a ligand for tumor targeted therapy. In this study, lanreotide was first conjugated to poly(ethylene glycol)-b-poly(?-caprolactone) (PEG-b-PCL) copolymer, and the active targeting micelles with paclitaxel (lanreotide-PM-PTX) or fluorescent agent were constructed and characterized with various analytical methods. Lanreotide-PM-PTX micelles were spherical in shape with a hydrodynamic diameter of 43.2 ± 0.4 nm, high drug encapsulation (87.1 ± 2.8%) and slow drug release rate. Two cancer cell lines (human lung cancer H446 and human breast cancer MCF-7 cells) with different expression levels of SSTR2 were used in this study. As observed by flow cytometry, confocal microscopy and cytotoxicity studies, lanreotide-encoded PEG-b-PCL micelles demonstrated more specific cell uptake and cytotoxicity in SSTR2-positive tumor cells via a receptor-mediated mechanism over the passive targeting micelles. The active targeting micelles showed higher accumulation in tumor tissue and tumor cells in tumor-bearing mice in vivo by near-infrared fluorescence (NIRF) imaging, high-performance liquid chromatography and confocal microscopy, respectively. Furthermore, treatment with lanreotide-PM-PTX micelles resulted in stronger tumor inhibition, increased life span and enhanced tumor cell apoptosis in SSTR2-overexpressing tumor model in athymic nude mice. The in vivo efficacy test with both H446 and MCF-7 tumor models further demonstrated the involvement of receptor-mediated interaction. Finally, the active targeting micelles exhibited less body weight loss, lower hemolysis and lower myelosuppression, as compared with the control groups. In conclusion, lanreotide can serve as an effective homing peptide, and the lanreotide-modified PEG-b-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors. PMID:22435704

Zheng, Nan; Dai, Wenbing; Du, Wenwen; Zhang, Haoran; Lei, Liandi; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Gao, Jinming; Zhang, Qiang

2012-05-01

121

Decoration of polymeric micelles with cancer-specific peptide ligands for active targeting of paclitaxel.  

PubMed

Polymeric micelles based on poly(ethylene oxide)-b-poly(?-caprolactone) PEO-b-PCL or poly(ethylene oxide)-b-poly(?-benzyl carboxylate-?-caprolactone) PEO-b-PBCL block copolymers were prepared and decorated with either c(RGDfK) or p160, a cancer cell-specific peptide ligand, on their surface. The cellular uptake of p160-decorated PEO-b-PBCL micelles containing DiI fluorescent label by MDA-MB-435 cancer cells was assessed and compared to that for c(RGDfK)-decorated micelles. The hydrophobic anticancer drug paclitaxel (PTX) was physically encapsulated into PEO-b-PCL or PEO-b-PBCL micelles (with and without peptide ligands) using a dialysis technique. The effect of the micellar formulation on the specificity of encapsulated PTX against cancer cells was assessed by investigating the in vitro cytotoxicity of free and encapsulated PTX against MDA-MB-435 cancer cell line versus two normal cells, Human Umbilical Vein Endothelial Cells (HUVEC) and MCF10A cells, using the MTT assay. Our results showed both peptide ligands to facilitate the association of micelles with MDA-MB-435 cells. The p160-micelles, however showed better binding and internalizing in MDA-MB-435 cells than c(RGDfK)-micelles. In general, peptide decoration enhanced the selective cytotoxicity of encapsulated PTX against MDA-MB-435 cells over normal HUVEC and MCF10A cells. The extent of this increase in cancer cell specificity for encapsulated PTX was more for p160-decorated micelles than c(RGDfK)-decorated ones. PMID:21501865

Shahin, Mostafa; Ahmed, Sahar; Kaur, Kamaljit; Lavasanifar, Afsaneh

2011-08-01

122

Metronomic Activity of CD44-Targeted Hyaluronic Acid-Paclitaxel in Ovarian Carcinoma  

PubMed Central

Purpose Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid (HA). Metronomic (MET) dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize “off-treatment” exposure resulting in an improved therapeutic ratio. Experimental Design We tested the hypothesis that HA conjugates of paclitaxel (TXL; HA-TXL) would exert strong anti-tumor effects with MET dosing and induce anti-angiogenic effects superior to those achieved with MTD administration or with free TXL. Female nude mice bearing SKOV3ip1 or HeyA8 ovarian cancer cells were treated intraperitoneally (ip) with MET HA-TXL regimens (or MTD administration to determine therapeutic and biological effects. Results All MET HA-TXL-treated mice and the MTD group revealed significantly reduced tumor weights and nodules compared to controls (all p values < 0.05) in the chemotherapy-sensitive models. However, the MTD HA-TXL-treated mice showed significant weight loss compared to control mice, whereas body weights were not affected in the MET groups in HeyA8-MDR model, reflecting reduced toxicity. In the taxane-resistant HeyA8-MDR model, significant reduction in tumor weight and nodule counts was noted in the MET groups, whereas the response of the MTD group did not achieve significance. While both MTD and MET regimens reduced proliferation (Ki-67) and increased apoptosis (TUNEL), only MET treatment resulted in significant reductions in angiogenesis (CD31, microvessel density). Moreover, MET treatment resulted in substantial increases in thrombospondin-1 (Tsp-1), an inhibitor of angiogenesis. Conclusions This study demonstrated that MET HA-TXL regimens have substantial antitumor activity in ovarian carcinoma, likely via a predominant anti-angiogenic mechanism.

Lee, Sun Joo; Ghosh, Sukhen C.; Han, Hee Dong; Stone, Rebecca L.; Bottsford-Miller, Justin; Shen, De Yue; Auzenne, Edmond J.; Lopez-Araujo, Alejandro; Lu, Chunhua; Nishimura, Masato; Pecot, Chad V.; Zand, Behrouz; Thanapprapasr, Duangmani; Jennings, Nicholas B; Kang, Yu; Huang, Jie; Hu, Wei; Klostergaard, Jim; Sood, Anil K.

2013-01-01

123

Nanocarriers targeting dendritic cells for pulmonary vaccine delivery.  

PubMed

Pulmonary vaccine delivery has gained significant attention as an alternate route for vaccination without the use of needles. Immunization through the pulmonary route induces both mucosal and systemic immunity, and the delivery of antigens in a dry powder state can overcome some challenges such as cold-chain and availability of medical personnel compared to traditional liquid-based vaccines. Antigens formulated as nanoparticles (NPs) reach the respiratory airways of the lungs providing greater chance of uptake by relevant immune cells. In addition, effective targeting of antigens to the most 'professional' antigen presenting cells (APCs), the dendritic cells (DCs) yields an enhanced immune response and the use of an adjuvant further augments the generated immune response thus requiring less antigen/dosage to achieve vaccination. This review discusses the pulmonary delivery of vaccines, methods of preparing NPs for antigen delivery and targeting, the importance of targeting DCs and different techniques involved in formulating dry powders suitable for inhalation. PMID:23054093

Kunda, Nitesh K; Somavarapu, Satyanarayana; Gordon, Stephen B; Hutcheon, Gillian A; Saleem, Imran Y

2013-02-01

124

Targeted drug delivery by thermally responsive polymers  

Microsoft Academic Search

This review article summarizes recent results on the development of macromolecular carriers for thermal targeting of therapeutics to solid tumors. This approach employs thermally responsive polymers in conjunction with targeted heating of the tumor. The two thermally responsive polymers that are discussed in this article, poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAAm)) and an artificial elastin-like polypeptide (ELP), were designed to exhibit a soluble–insoluble lower

Ashutosh Chilkoti; Matthew R Dreher; Dan E Meyer; Drazen Raucher

2002-01-01

125

Nanoparticles for oral delivery: Targeted nanoparticles with peptidic ligands for oral protein delivery  

PubMed Central

As the field of biotechnology has advanced, oral protein delivery has also made significant progress. Oral delivery is the most common method of drug administration with high levels of patient acceptance. Despite the preference of oral delivery, administration of therapeutic proteins has been extremely difficult. Increasing the bioavailability of oral protein drugs to the therapeutically acceptable level is still a challenging goal. Poor membrane permeability, high molecular weight, and enzymatic degradation of protein drugs have remained unsolved issues. Among diverse strategies, nanotechnology has provided a glimpse of hope in oral delivery of protein drugs. Nanoparticles have advantages, such as small size, high surface area, and modification using functional groups for high capacity or selectivity. Nanoparticles with peptidic ligands are especially worthy of notice because they can be used for specific targeting in the gastrointestinal (GI) tract. This article reviews the transport mechanism of the GI tract, barriers to protein absorption, current status and limitations of nanotechnology for oral protein delivery system.

Yun, Yeonhee; Cho, Yong Woo; Park, Kinam

2012-01-01

126

[Hyaluronic acid-based carriers for tumor targeted delivery system].  

PubMed

Hyaluronic acid (HA) as anticancer drug carrier has become the new hot point in the field of tumor-targeted drugs delivery system in recent years. Tumor therapeutic agents could be transmitted into cells because of hyaluronic acid innate ability to recognize specific cellular receptors that overexpressed on tumor cells surface. This review introduces the basic properties and physiology foundation of hyaluronic acid. Recent research developments based on different forms of HA tumor-targeted drugs delivery systems are reviewed in particular. PMID:24358769

Qiu, Li-peng; Long, Miao-miao; Chen, Da-wei

2013-09-01

127

Cell-Specific Aptamer-Mediated Targeted Drug Delivery  

PubMed Central

Nucleic acid aptamers are in vitro-selected small, single-stranded DNA or RNA oligonucleotides that can specifically recognize their target on the basis of their unique 3-dimensional structures. Recent advances in the development of escort aptamers to deliver and enhance the efficacy of other therapeutic agents have drawn enthusiasm in exploiting cell-type-specific aptamers as drug delivery vehicles. This review mainly focuses on the recent developments of aptamer-mediated targeted delivery systems. We also place particular emphasis on aptamers evolved against cell membrane receptors and possibilities for translation to clinical applications.

Zhou, Jiehua

2011-01-01

128

Colon Targeted Delivery Systems: Review of Polysaccharides for Encapsulation and Delivery  

Microsoft Academic Search

Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon-based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. Recent research into the utilization of the metabolic activity and the colonic microenvironment in the lower gastrointestinal tract has attained great value in

Shantha L. Kosaraju

2005-01-01

129

Design of a Paclitaxel prodrug conjugate for active targeting of an enzyme upregulated in breast cancer cells.  

PubMed

Breast cancer is the second most common cause of cancer-related deaths in women. Chemotherapy is an important treatment modality, and paclitaxel (PTX) is often the first-line therapy for its metastatic form. The two most notable limitations related to PTX-based treatment are the poor hydrophilicity of the drug and the systemic toxicity due to the drug's nonspecific and indiscriminate distribution among the tissues. The present work describes an approach to counter both challenges by designing a conjugate of PTX with a hydrophilic macromolecule that is coupled through a biocleavable linker, thereby allowing for active targeting to an enzyme significantly upregulated in cancer cells. The resultant strategy would allow for the release of the active ingredient preferentially at the site of action in related cancer cells and spare normal tissue. Thus, PTX was conjugated to the hydrophilic poly(amdioamine) [PAMAM] dendrimer through the cathepsin B-cleavable tetrapeptide Gly-Phe-Leu-Gly. The PTX prodrug conjugate (PGD) was compared to unbound PTX through in vitro evaluations against breast cancer cells and normal kidney cells as well as through in vivo evaluations using xenograft mice models. As compared to PTX, PGD demonstrated a higher cytotoxicity specific to cell lines with moderate-to-high cathepsin B activity; cells with comparatively lower cathepsin B activity demonstrated an inverse of this relationship. Regression analysis between the magnitude of PGD-induced cytotoxic increase over PTX and cathepsin B expression showed a strong, statistically significant correlation (r(2) = 0.652, p < 0.05). The PGD conjugate also demonstrated a markedly higher tumor reduction as compared to PTX treatment alone in MDA-MB-231 tumor xenograft models, with PGD-treated tumor volumes being 48% and 34% smaller than PTX-treated volumes at weeks 2 and 3 after treatment initiation. PMID:24847940

Satsangi, Arpan; Roy, Sudipa S; Satsangi, Rajiv K; Vadlamudi, Ratna K; Ong, Joo L

2014-06-01

130

Preparation of nano-emulsified paclitaxel using MPEG–PLGA diblock copolymers  

Microsoft Academic Search

In this work, we prepared nano-emulsified paclitaxel using administration form of the self-microemulsifying drug delivery systems (SMEDDS) in order to increase efficacy of paclitaxel. As paclitaxel delivery carrier, we chose MPEG–PLGA diblock copolymers with different hydrophilic and hydrophobic balances (HLB) by changing PLGA segments under constant MPEG segment. Paclitaxel and MPEG–PLGA diblock copolymers were dissolved by solubilizer such as tetraglycol,

Soo Young Lee; Hoon Hyun; Ju Yong Youn; Byung Soo Kim; In Beum Song; Moon Suk Kim; Bong Lee; Gilson Khang; Hai Bang Lee

2008-01-01

131

[Antigenicity study of paclitaxel].  

PubMed

The antigenic property of paclitaxel was examined using its protein mixtures (paclitaxel + OVA, paclitaxel + GSA, paclitaxel + RSA) in guinea pigs and mice in comparison with ovalbumin (OVA) and the protein conjugate of 4-aminoantipriyne (AAP). The following results were obtained: 1. When guinea pigs were sensitized with paclitaxel or paclitaxel + OVA emulsified with Freund's complete adjuvant, none of active systemic anaphylaxis (ASA), passive cutaneous anaphylaxis (PCA) and Schultz-Dale reaction were induced by challenge with paclitaxel or paclitaxel + GSA (guinea pig serum albumin). In the observation of active cutaneous anaphylaxis (ACA), no changes were observed in animals treated with paclitaxel alone as a sensitizing and/or a challenging antigen under the condition where slight delayed type hypersensitivity was elicited in animals sensitized with paclitaxel + OVA and challenged with paclitaxel + GSA. 2. When mice were sensitized with paclitaxel or paclitaxel + OVA adsorbed to alum. sera of these animals revealed a negative reaction in PCA using rats by challenge with paclitaxel or paclitaxel + RSA (rat serum albumin). 3. Protein bindings of paclitaxel with the above albumins were more than 40%. As shown above, paclitaxel was considered not to possess antigenic property under the experimental condition. In addition, the dose levels of paclitaxel employed in the present experiment were confirmed not to suppress the immune response to OVA. PMID:7966458

Kawano, S; Ishikawa, K; Kohmura, H; Kadota, T; Takahashi, N

1994-08-01

132

Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: Preparation, characterization and antitumor activity.  

PubMed

Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53m(2)/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group. PMID:24954663

Patel, Ketan; Patil, Anand; Mehta, Miten; Gota, Vikram; Vavia, Pradeep

2014-09-10

133

A co-delivery system based on paclitaxel grafted mPEG-b-PLG loaded with doxorubicin: Preparation, in vitro and in vivo evaluation.  

PubMed

Herein, we develop a co-delivery system of paclitaxel (PTX) and doxorubicin hydrochloride (DOX·HCl) based on methoxypoly(ethylene glycol)-block-poly(l-glutamic acid) (mPEG-b-PLG) for cancer treatment. PTX was grafted to the mPEG-b-PLG by esterification to give mPEG-b-PLG-g-PTX. DOX·HCl was encapsulated via electrostatic interaction and hydrophobic stack between the DOX·HCl and mPEG-b-PLG-g-PTX in aqueous solution. The release rate of DOX·HCl from the drug-loaded nanoparticles (mPEG-b-PLG-g-PTX-DOX) was slow at blood pH (pH 7.4), but obviously increased at endosome pH (pH 5.4). The mPEG-b-PLG-g-PTX-DOX exhibited slight synergistic effect in inhibition of proliferation of A549 and MCF-7 human cancer cells. For in vivo treatment of xenograft human breast tumor (MCF-7), the mPEG-b-PLG-g-PTX-DOX nanoparticles exhibited remarkable tumor inhibition effect with a 95.5% tumor-suppression-rate which was significantly higher than those of related single anticancer agents such as free DOX·HCl and mPEG-b-PLG-g-PTX. These results indicated that the mPEG-b-PLG-g-PTX-DOX would have great potential in cancer therapy. PMID:24905776

Li, Qian; Lv, Shixian; Tang, Zhaohui; Liu, Muhua; Zhang, Dawei; Yang, Yan; Chen, Xuesi

2014-08-25

134

Antitumor drug Paclitaxel-loaded pH-sensitive nanoparticles targeting tumor extracellular pH  

Microsoft Academic Search

Research efforts have been devoted to demonstrating that the pH-sensitive characteristics of poly NIPAAm\\/chitosan nanoparticles can be applied to targeting tumors. A copolymer of (NIPAAm) and chitosan (4:1, m\\/m) was synthesized, and its drug release characteristics investigated. The results revealed that drug-loaded nanoparticles which encapsulation and loading efficiencies were 85.7% and 9.6%, respectively, exhibited pH-sensitive responses to tumor pH. The

Fan Li; Hong Wu; Hui Zhang; Fei Li; Chun-hu Gu; Qian Yang

2009-01-01

135

Targeted Delivery of Drugs to Brain Tumors  

SciTech Connect

Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs. Her talk was presented June 27, 2007.

Trudy Forte

2008-03-03

136

Targeted Delivery of Drugs to Brain Tumors  

SciTech Connect

Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering... Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs. Her talk was presented June 27, 2007.

LBNL

2008-03-03

137

Targeted Delivery of Drugs to Brain Tumors  

ScienceCinema

Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering... Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs. Her talk was presented June 27, 2007.

LBNL

2009-09-01

138

Targeted Delivery of Drugs to Brain Tumors  

ScienceCinema

Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs. Her talk was presented June 27, 2007.

Trudy Forte

2013-06-10

139

Development of colon targeted drug delivery systems for mebendazole  

Microsoft Academic Search

The objective of the present study is to develop colon targeted drug delivery systems for mebendazole using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for drug content uniformity, and were subjected to in vitro drug release studies. The

Y. S. R Krishnaiah; P Veer Raju; B Dinesh Kumar; P Bhaskar; V Satyanarayana

2001-01-01

140

The preparation and characterization of anti-VEGFR2 conjugated, paclitaxel-loaded PLLA or PLGA microspheres for the systemic targeting of human prostate tumors  

Microsoft Academic Search

Purpose  The objective of this study was to manufacture paclitaxel (PTX) loaded polymeric microspheres, that were surface conjugated\\u000a with antibodies to vascular endothelial growth factor receptor 2 (anti-VEGFR2), for systemic targeting to angiogenic sites\\u000a in prostate tumors.\\u000a \\u000a \\u000a \\u000a Methods  Microspheres were manufactured in the 1–3 ?m size range from poly (l-lactic acid) (PLLA) or poly (lactide-co-glycolide) (PLGA)\\u000a by a modified solvent evaporation method using

Jianjun Lu; John K. Jackson; Martin E. Gleave; Helen M. Burt

2008-01-01

141

Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

The systemic delivery of therapeutics is currently limited by off-target side effects and poor drug uptake into the cells that need to be treated. One way to circumvent these issues is to target the delivery and release of therapeutics to the desired location while limiting systemic toxicity. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures for the development of targeted therapies. Specifically, the research has focused on the interrelationships between presentation of targeting moeities and the control of nanostructure morphology in the context of systemic delivery for targeting cancer and vascular injuries. The self-assembly region of the PA was systematically altered to achieve control of nanostructure widths, from 100 nm to 10 nm, by the addition of valine-glutamic acid dimers into the chemical structure, subsequently increasing the degree of nanostructure twist. For the targeting of tumors, a homing PA was synthesized to include a dimeric, cyclic peptide sequence known to target the cancer-specific, death receptor 5 (DR5) and initiate apoptosis through the oligomerization of DR5. This PA presented a multivalent display of DR5-binding peptides, resulting in improved binding affinity measured by surface plasmon resonance. The DR5-targeting PA also showed enhanced efficacy in both in vitro and in vivo tumor models relative to non-targeted controls. Alternative modifications to the PA-based antitumor therapies included the use of a cytotoxic, membrane-lytic PA coassembled with a pegylated PA, which showed enhanced biodistribution and in vivo activity after coassembly. The functionalization of the hydrophobic core was also accomplished through the encapsulation of the chemotherapy camptothecin, which was shown to be an effective treatment in vivo. Additionally, a targeted PA nanostructure was designed to bind to the site of vascular intervention by targeting collagen IV. Following balloon angioplasty, targeted PA nanofibers showed enhanced binding by fluorescence relative to spherical micelles with the same targeting sequence, demonstrating the importance of nanostructure shape for vascular binding. Nitric oxide was functionalized onto the PA nanostructure through the S-nitrosylation (SNO) of a cysteine residue. Two weeks after vascular injury, the SNO-functionalized, targeted nanofibers showed significantly decreased levels of restenosis. In all treatment methods described, the control of multivalency through the tuning of supramolecular structure was essential to achieve optimal binding. Understanding the role of dynamic, supramolecular structures for the systemic delivery of peptide therapeutics should be an important focus of future work.

Moyer, Tyson

142

Clinical implementation of target tracking by breathing synchronized delivery  

SciTech Connect

Target-tracking techniques can be categorized based on the mechanism of the feedback loop. In real time tracking, breathing-delivery phase correlation is provided to the treatment delivery hardware. Clinical implementation of target tracking in real time requires major hardware modifications. In breathing synchronized delivery (BSD), the patient is guided to breathe in accordance with target motion derived from four-dimensional computed tomography (4D-CT). Violations of mechanical limitations of hardware are to be avoided at the treatment planning stage. Hardware modifications are not required. In this article, using sliding window IMRT delivery as an example, we have described step-by-step the implementation of target tracking by the BSD technique: (1) A breathing guide is developed from patient's normal breathing pattern. The patient tries to reproduce this guiding cycle by following the display in the goggles; (2) 4D-CT scans are acquired at all the phases of the breathing cycle; (3) The average tumor trajectory is obtained by deformable image registration of 4D-CT datasets and is smoothed by Fourier filtering; (4) Conventional IMRT planning is performed using the images at reference phase (full exhalation phase) and a leaf sequence based on optimized fluence map is generated; (5) Assuming the patient breathes with a reproducible breathing pattern and the machine maintains a constant dose rate, the treatment process is correlated with the breathing phase; (6) The instantaneous average tumor displacement is overlaid on the dMLC position at corresponding phase; and (7) DMLC leaf speed and acceleration are evaluated to ensure treatment delivery. A custom-built mobile phantom driven by a computer-controlled stepper motor was used in the dosimetry verification. A stepper motor was programmed such that the phantom moved according to the linear component of tumor motion used in BSD treatment planning. A conventional plan was delivered on the phantom with and without motion. The BSD plan was also delivered on the phantom that moved with the prescheduled pattern and synchronized with the delivery of each beam. Film dosimetry showed underdose and overdose in the superior and inferior regions of the target, respectively, if the tumor motion is not compensated during the delivery. BSD delivery resulted in a dose distribution very similar to the planned treatments.

Tewatia, Dinesh; Zhang Tiezhi; Tome, Wolfgang; Paliwal, Bhudatt; Metha, Minesh [Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53705 (United States); Department of Radiation Oncology, William Beaumant Hospital, Royal Oak, Michigan 48073 (United States); Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53705 (United States)

2006-11-15

143

Tetraspecific ligand for tumor-targeted delivery of nanomaterials.  

PubMed

The polygenetic nature of most cancers emphasizes the necessity of cancer therapies that target multiple essential signaling pathways. However, there is a significant paucity of targeting ligands with multi-specificities for targeted delivery of biomaterials. To address this unmet need, we generated a tetraspecific targeting ligand that recognizes four different cancer biomarkers, including VEGFR2, ?v?3 integrin, EGFR, and HER2 receptors, which have been implicated in numerous malignant tumors. The tetraspecific targeting ligand was constructed by sequentially connecting four targeting ligand subunits via flexible linkers, yielding a fusion protein that can be highly expressed in Escherichia coli and readily purified to near homogeneity. Surface Plasmon Resonance (SPR), Bio-Layer Interferometry (BLI) studies and extensive cellular binding analyses indicated that all the targeting ligand subunits in the tetraspecific fusion protein recognized their target receptors proximately to the corresponding monospecific ligands. The resulting tetraspecific targeting ligand was applied for the delivery of nanomaterials such as gold nanoparticles (AuNPs) for targeted hyperthermic killing of various cancer cell lines with biomarkers of interest expressed. We demonstrate that the tetraspecific ligand can be facilely introduced on the surface of AuNPs and efficient target-dependent killing of cancer cells can be achieved only when the AuNPs are conjugated with the tetraspecific ligand. Significantly, the tetraspecific ligand simultaneously interacts with more than one receptors, such as EGFR and HER2 receptors, when they are expressed on the surface of the same cell, as demonstrated by in vitro binding assays and cell binding analyses. Our results demonstrate that the tetraspecific ligand, through multivalency and synergistic binding, can be readily used to generate various 'smart' biomaterials with greatly broadened tumor targeting range for simultaneous targeting of multiple signaling pathways on many different cancer types. PMID:24786763

Kim, Dongwook; Friedman, Adam D; Liu, Rihe

2014-07-01

144

Development of a Thermally Responsive Nanogel Based on Chitosan-Poly(N-Isopropylacrylamide-co-Acrylamide) for Paclitaxel Delivery.  

PubMed

A thermally responsive nanogel was developed through the radical polymerization based on chitosan (CTS) and N-isopropylacrylamide (NIPAAm) with acrylamide (AAm) blended to explore the possibility of increasing the volume phase transition temperature (VPTT). The thermally sensitive features of resultant nanogels were studied by determining variance of transmittance and changeable size. The VPTT of the CTS-poly(NIPAAm-co-AAm5.5) nanogel, coplymerized with 5.5% wt. AAm /wt. NIPAAm, was 38°C in contrast to 32°C of the CTS-poly(NIPAAm) polymer and the former was studied thereafter. The critical aggregation concentration of CTS-poly(NIPAAm-co-AAm5.5) nanogels was 1.11 ?g/mL, much smaller than CTS-poly(NIPAAm) nanogels (5.00 ?g/mL). Paclitaxel (PTX) was encapsulated in CTS-poly(NIPAAm-co-AAm5.5) nanogels with loading efficiency of about 9.06 ± 0.195% (n = 3). Thermally responsive PTX in vitro release fromPTX-loaded nanogels was verified. Coumarin-6-loaded nanogels showed thermally responsive cellular uptake because of electrostatic absorptive endocytosis. Furthermore, the half maximal inhibitory concentration of PTX-loaded nanogels was about 2.025 nmol/L, 10-fold improved relative to PTX solutions against SMMC 7721 cells. In vivo, PTX-loaded nanogels presented remarkably higher antitumor efficacy against human colon carcinoma cells HT-29 xenograft nude mice model after intravenous administration. Accordingly, our results reinforced the potential means of CTS-poly(NIPAAm-co-AAm5.5) nanogels for the combination of thermal therapy and chemotherapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2012-2021, 2014. PMID:24823900

Wang, Yajing; Xu, Hongjiang; Wang, Jiu; Ge, Liang; Zhu, Jiabi

2014-07-01

145

CYCLOSTREPTIN DERIVATIVES SPECIFICALLY TARGET CELLULAR TUBULIN AND FURTHER MAP THE PACLITAXEL SITE†  

PubMed Central

Cyclostreptin is the first microtubule stabilizing agent whose mechanism of action was discovered to involve formation of a covalent bond with tubulin. Treatment of cells with cyclostreptin irreversibly stabilizes their microtubules because cyclostreptin forms a covalent bond to ?-tubulin at either the T220 or the N228 residue, located, respectively, at the microtubule pore and luminal taxoid binding sites. Due to its unique mechanism of action, cyclostreptin overcomes P-glycoprotein-mediated multidrug resistance in tumor cells. We used a series of reactive cyclostreptin analogues, 6-chloroacetyl-cyclostreptin, 8-chloroacetyl-cyclostreptin, and [14C-acetyl]-8-acetyl-cyclostreptin, to characterize the cellular target of the compound and to map the binding site. The three analogues were cytotoxic and stabilized microtubules in both sensitive and multidrug resistant tumor cells. In both types of cells, we identified ?-tubulin as the only or the predominantly labeled cellular protein, indicating that a covalent binding to microtubules is sufficient to prevent drug efflux mediated by P-glycoprotein. 6-chloroacetyl-cyclostreptin, 8-chloroacetyl-cyclostreptin, and 8-acetyl-cyclostreptin labeled both microtubules and unassembled tubulin at a single residue of the same tryptic peptide of ?-tubulin as was labeled by cyclostreptin (219-LTTPTYGDLNHLVSATMSGVTTCLR-243), but labeling with the analogues occurred at different positions of the peptide. 8-Acetyl-cyclostreptin reacted either with T220 or N228, as did the natural product, while 8-chloroacetyl-cyclostreptin formed a cross link to C241. Finally 6-chloroacetyl-cyclostreptin reacted with any one of the three residues, thus labeling the pathway for cyclostreptin-like compounds, leading from the pore where these compounds enter the microtubule to the luminal binding pocket.

Calvo, Enrique; Barasoain, Isabel; Matesanz, Ruth; Pera, Benet; Camafeita, Emilio; Pineda, Oriol; Hamel, Ernest; Vanderwal, Christopher D.; Andreu, Jose Manuel; Lopez, Juan A.; Diaz, Jose Fernando

2012-01-01

146

Targeted Delivery of Gemcitabine to Pancreatic Adenocarcinoma Using Cetuximab as a Targeting Agent  

Microsoft Academic Search

One of the key challenges in anticancer therapy is the toxicity and poor bioavailability of the anticancer drugs. Nanotech- nology can play a pivotal role by delivering drugs in a targeted fashion to the malignant cells that will reduce the systemic toxicity of the anticancer drug. In this report, we show a stepwise development of a nanoparticle-based targeted delivery system

Chitta Ranjan Patra; Resham Bhattacharya; Enfeng Wang; Julie S. Lau; Shamit Dutta; Michael Muders; Shanfeng Wang; Sarah A. Buhrow; Stephanie L. Safgren; Michael J. Yaszemski; Joel M. Reid; Matthew M. Ames; Priyabrata Mukherjee; Debabrata Mukhopadhyay

147

Targeted Disruption of the JAK2/STAT3 Pathway in Combination with Systemic Administration of Paclitaxel Inhibits the Priming of Ovarian Cancer Stem Cells Leading to a Reduced Tumor Burden  

PubMed Central

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo, we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7?days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4?weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients.

Abubaker, Khalid; Luwor, Rodney B.; Escalona, Ruth; McNally, Orla; Quinn, Michael A.; Thompson, Erik W.; Findlay, Jock K.; Ahmed, Nuzhat

2014-01-01

148

Carbon nanotube lipid drug approach for targeted delivery of a chemotherapy drug in a human breast cancer xenograft animal model.  

PubMed

Carbon nanotube (CNT) possesses excellent properties as a drug carrier. To overcome the challenge of drug functionalization with CNT, we have developed a lipid-drug approach for efficient drug loading onto CNT, in which a long chain lipid molecule is conjugated to the drug molecule so that the lipid-drug can be loaded directly onto CNT through binding of the lipid 'tail' in the drug molecule to CNT surfaces via hydrophobic interactions. In a proof-of-concept study, drug paclitaxel (PTX) was conjugated with a non-toxic lipid molecule docosanol for functionalization with CNT. Folic acid was also conjugated to CNT for targeted drug delivery. High level of drug loading onto SWNT could be achieved by lipid-drug approach. Conjugation of FA to SWNT-lipid-PTX led to an increase in cell penetration capacity, and the targeted SWNT-lipid-PTX showed much improved drug efficacy in vitro in comparison to free drug Taxol and non-targeted SWNT-lipid-PTX at 48 h (78.5% vs. 31.6% and 59.1% in cytotoxicity respectively, p < 0.01). In vivo analysis using a human breast cancer xenograft mice model also confirmed the improved drug efficacy. The targeted SWNT-lipid-PTX was found non-toxic as evaluated by biochemical analysis using blood samples, and by histological analysis of major organs. PMID:24060420

Shao, Wei; Paul, Arghya; Zhao, Bin; Lee, Crystal; Rodes, Laetitia; Prakash, Satya

2013-12-01

149

Diphtheria toxin receptor-targeted brain drug delivery  

Microsoft Academic Search

Brain drug delivery is limited by the blood–brain barrier (BBB). We have newly identified the membrane-bound precursor of heparin-binding epidermal growth factor (HB-EGF), which is also known as the diphtheria toxin receptor (DTR), as a well characterized internalizing transport receptor on the BBB for the targeting of drugs to the brain. This transport receptor has several unique advantages. It makes

Pieter J. Gaillard; Arjen Brink; Albertus G. de Boer

2005-01-01

150

New targets and delivery systems for antifungal therapy.  

PubMed

Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium. PMID:11204162

Walsh, T J; Viviani, M A; Arathoon, E; Chiou, C; Ghannoum, M; Groll, A H; Odds, F C

2000-01-01

151

Advances in polymeric micelles for drug delivery and tumor targeting.  

PubMed

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, ?(2)-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs. PMID:20542144

Kedar, Uttam; Phutane, Prasanna; Shidhaye, Supriya; Kadam, Vilasrao

2010-12-01

152

Magnetic nanoparticles as targeted delivery systems in oncology  

PubMed Central

Background Many different types of nanoparticles, magnetic nanoparticles being just a category among them, offer exciting opportunities for technologies at the interfaces between chemistry, physics and biology. Some magnetic nanoparticles have already been utilized in clinical practice as contrast enhancing agents for magnetic resonance imaging (MRI). However, their physicochemical properties are constantly being improved upon also for other biological applications, such as magnetically-guided delivery systems for different therapeutics. By exposure of magnetic nanoparticles with attached therapeutics to an external magnetic field with appropriate characteristics, they are concentrated and retained at the preferred site which enables the targeted delivery of therapeutics to the desired spot. Conclusions The idea of binding chemotherapeutics to magnetic nanoparticles has been around for 30 years, however, no magnetic nanoparticles as delivery systems have yet been approved for clinical practice. Recently, binding of nucleic acids to magnetic nanoparticles has been demonstrated as a successful non-viral transfection method of different cell lines in vitro. With the optimization of this method called magnetofection, it will hopefully become another form of gene delivery for the treatment of cancer.

Prijic, Sara; Sersa, Gregor

2011-01-01

153

Microfluidics: a focus on improved cancer targeted drug delivery systems.  

PubMed

Pharmaceutical science aims to localize the pharmacological activity of the drug at the site of action. Targeted drug delivery systems can directly deliver the payload to the desired site of action without undesired interaction with normal cells. This is especially important for anticancer drugs to avoid side effects and improve therapeutic response and patient compliance. Number of targeted drug delivery systems for anticancer drugs are in market and many more are in research phase. Most of the methods so far used suffer from poor drug loading, variation in composition, attachment of targeting ligands to carriers, and in vivo and in vitro cellular uptake in cancer cell. Recently microfluidic techniques are gaining attention from researchers and formulation scientists due to the ability of having a better control over the above said parameters not to mention saving cost, material, time and the possibility offered to synthesize different system morphologies from nano to microscale. This article reviews the recent advances in the design of various targeted systems obtained through microfluidics and to some extent addresses challenges and hurdles faced during cancer cell treatment. PMID:23933524

Khan, Ikram Ullah; Serra, Christophe A; Anton, Nicolas; Vandamme, Thierry

2013-12-28

154

Chlorotoxin Labeled Magnetic Nanovectors for Targeted Gene Delivery to Glioma  

PubMed Central

Glioma accounts for 80% of brain tumors, and currently remains one of the most lethal forms of cancers. Gene therapy could potentially improve the dismal prognosis of patients with glioma, but this treatment modality has not yet reached the bedside from the laboratory due to the lack of safe and effective gene delivery vehicles. In this study we investigate targeted gene delivery to C6 glioma cells in a xenograft mouse model using chlorotoxin (CTX) labeled nanoparticles. The developed nanovector consists of an iron oxide nanoparticle core, coated with a copolymer of chitosan, polyethylene glycol (PEG) and polyethylenimine (PEI). Green fluorescent protein (GFP) encoding DNA was bound to these nanoparticles, and CTX was then attached using a short PEG linker. Nanoparticles without CTX were also prepared as a control. Mice bearing C6 xenograft tumors were injected intravenously with the DNA bound nanoparticles. Nanoparticle accumulation in the tumor site was monitored using magnetic resonance imaging and analyzed by histology, and GFP gene expression was monitored through Xenogen IVIS fluorescence imaging and confocal fluorescence microscopy. Interestingly, the CTX did not affect the accumulation of nanoparticles at the tumor site, but specifically enhanced their uptake into cancer cells as evidenced by higher gene expression. These results indicate that this targeted gene delivery system may potentially improve treatment outcome of gene therapy for glioma and other deadly cancers.

Kievit, Forrest M.; Veiseh, Omid; Fang, Chen; Bhattarai, Narayan; Lee, Donghoon; Ellenbogen, Richard G.; Zhang, Miqin

2010-01-01

155

Delivery of substances and their target-specific topical activation.  

PubMed

Goal in pharmaceutical research is achievement of necessary drug concentrations in the target organ, effective treatment with safe delivery of genetic agents, while sparing normal tissue and minimizing side effects. A new "BioShuttle"-delivery system harbouring a cathepsin B cutting site, a nuclear address sequence and a functional peptide was developed and tumor cells were treated. Transport and subcellular activation were determined by confocal laser scanning microscopy permitting the conclusion: BioShuttle-conjugates prove as efficient tools for genetic interventions by selective and topical activation of therapeutic peptide precursors by enzymatic cleavage. As shown here for glioma cells and the cathepsin B cleavable site, living cells can be treated with high specificity and selectivity for diagnostic and therapeutic purposes. PMID:16730647

Pipkorn, Rüdiger; Waldeck, Waldemar; Spring, Herbert; Jenne, Jürgen W; Braun, Klaus

2006-05-01

156

Multifunctional Particles for Melanoma-Targeted Drug Delivery  

PubMed Central

New magnetic-based core-shell particles (MBCSP) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSP consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSP were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the ?5?3+ receptor of melanoma cell. MBCSP consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSP has an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 ?g ml?1. Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSP were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in presence of a magnet. Results indicate great potential of MBCSP as a platform technology to target, treat, and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents.

Wadajkar, Aniket S.; Bhavsar, Zarna; Ko, Cheng-Yu; Koppolu, Bhanuprasanth; Cui, Weina; Tang, Liping; Nguyen, Kytai T.

2012-01-01

157

"Nanotheranostics" for tumor imaging and targeted drug delivery  

NASA Astrophysics Data System (ADS)

The magnetic resonance imaging (MRI) technique is a promising tool that improves cancer detection, facilitates diagnosis and monitors therapeutic effects. Superparamagnetic iron oxide nanoparticles (SPIOs) have emerged as MRI contrast agents for tumor imaging and as potential vectors for targeted anti-cancer drug delivery; nevertheless, the application of SPIOs has been hampered due to a lack of specificity to tumor tissues and premature drug release. This project aims at developing multifunctional SPIOs for both cancer imaging and targeted drug delivery via conjugation of tumor specific antibodies with SPIOs. The application of anti-TAG-72 antibodies as tumor targeting modalities was evaluated in cultured colorectal cancer cells and in xenograft models by using fluorescent imaging and positron emission tomography (PET) imaging. It was demonstrated that antibody-labeled SPIOs were superior imaging agents and drug carriers for increased tumor specificity. The regulation and kinetics of intracellular drug release from SPIOs were explored by means of fluorescence imaging. In vitro and in vivo fluorescence resonance energy transfer (FRET) imaging was employed to investigate the mechanisms of premature drug release from nanocarriers. The large volume and high hydrophobicity of cell membranes were found to play an important role in premature drug release. The encapsulation of SPIOs into nanocarriers decreased drug release in a dose-dependent mode. This study provided future opportunities to improve the efficiency of nanocarriers by exploring the mechanism of drug release and disassembly of SPIO-loaded polymeric nanoparticles.

Zou, Peng

158

Integrated nanoplasmonic-nanofluidic biosensors with targeted delivery of analytes  

NASA Astrophysics Data System (ADS)

Performances of the biosensors are often limited by the depletion zones created around the sensing area which impede the effective analyte transport. To overcome this limitation, we propose and demonstrate a nanoplasmonic-nanofluidic sensor enabling targeted delivery of analytes to the sensor surface with dramatic improvements in mass transport efficiency. Our sensing platform is based on extraordinary light transmission effect in suspended plasmonic nanoholes. This scheme allows three-dimensional control of the fluidic flow by connecting separate layers of microfluidic channels through plasmonic/nanofluidic holes. To implement the proposed sensor platform, we also introduce a lift-off free nanofabrication method.

Yanik, Ahmet Ali; Huang, Min; Artar, Alp; Chang, Tsung-Yao; Altug, Hatice

2010-01-01

159

A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments.  

PubMed

ErbB2 is frequently activated in tumors, and influences a wide array of cellular functions, including proliferation, apoptosis, cell motility and adhesion. HKI-272 (neratinib) is a small molecule pan-kinase inhibitor of the ErbB family of receptor tyrosine kinases, and shows strong antiproliferative activity in ErbB2-overexpressing breast cancer cells. We undertook a genome-wide pooled lentiviral RNAi screen to identify synthetic lethal or enhancer (synthetic modulator screen) genes that interact with neratinib in a human breast cancer cell line (SKBR-3). These genes upon knockdown would modulate cell viability in the presence of subeffective concentrations of neratinib. We discovered a diverse set of genes whose depletion selectively impaired or enhanced the viability of SKBR-3 cells in the presence of neratinib. We observed diverse pathways including EGFR, hypoxia, cAMP, and protein ubiquitination that, when co-treated with RNAi and neratinib, resulted in arrest of cell proliferation. Examining the changes of these genes and their protein products also led to a rationale for clinically relevant drug combination treatments. Treatment of cells with either paclitaxel or cytarabine in combination with neratinib resulted in a strong antiproliferative effect. The identification of novel mediators of cellular response to neratinib and the development of potential drug combination treatments have expanded our understanding of neratinib's mode-of-action for the development of more effective therapeutic regimens. Notably, our findings support a paclitaxel and neratinib phase III clinical trial in breast cancer patients. PMID:21487605

Seyhan, Attila A; Varadarajan, Usha; Choe, Sung; Liu, Yan; McGraw, John; Woods, Matthew; Murray, Stuart; Eckert, Amy; Liu, Wei; Ryan, Terence E

2011-06-01

160

Development, characterization and in vitro assessement of stearylamine-based lipid nanoparticles of paclitaxel.  

PubMed

The objective of the study was to design and evaluate a solid lipid nanoparticle (SLN) drug delivery system for delivery of paclitaxel. Components of the SLN were lipid (stearylamine) and surfactants (Pluronic F68 and Soya lecithin). The paclitaxel loaded nanoparticles were prepared by a modified solvent injection method. Experiments were carried out with excipients, where surfactants, lipid and drug molar ratios were varied to optimize the formulation characteristics. The in vitro drug release profile from the nanoparticles followed a diffusion controlled mechanism. The modified solvent injection method ensured high entrapment efficiency (approximately 75%), produced smaller, stable nanoparticles with a narrow size distribution and proved to be a reproducible and fast production method. The present study describes the feasibility and suitability of stearylamine based SLN produced using a mixture of surfactants to develop a clinically useful system with targeting potential for poorly soluble antineoplastic drugs. PMID:21553646

Pandita, D; Ahuja, A; Lather, V; Dutta, T; Velpandian, T; Khar, R K

2011-03-01

161

Pharmaceutical approaches to colon targeted drug delivery systems  

Microsoft Academic Search

Purpose. Although oral delivery has become a widely accepted route of administration of therapeutic drugs, the gastrointestinal tract presents several formidable barriers to drug delivery. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon but also for its potential for the delivery of proteins

M. K. Chourasia; S. K. Jain

162

Targeted electrohydrodynamic printing for micro-reservoir drug delivery systems  

NASA Astrophysics Data System (ADS)

Microfluidic drug delivery systems consisting of a drug reservoir and microfluidic channels have shown the possibility of simple and robust modulation of drug release rate. However, the difficulty of loading a small quantity of drug into drug reservoirs at a micro-scale limited further development of such systems. Electrohydrodynamic (EHD) printing was employed to fill micro-reservoirs with controlled amount of drugs in the range of a few hundreds of picograms to tens of micrograms with spatial resolution of as small as 20 µm. Unlike most EHD systems, this system was configured in combination with an inverted microscope that allows in situ targeting of drug loading at micrometer scale accuracy. Methylene blue and rhodamine B were used as model drugs in distilled water, isopropanol and a polymer solution of a biodegradable polymer and dimethyl sulfoxide (DMSO). Also tetracycline-HCl/DI water was used as actual drug ink. The optimal parameters of EHD printing to load an extremely small quantity of drug into microscale drug reservoirs were investigated by changing pumping rates, the strength of an electric field and drug concentration. This targeted EHD technique was used to load drugs into the microreservoirs of PDMS microfluidic drug delivery devices and their drug release performance was demonstrated in vitro.

Hwang, Tae Heon; Kim, Jin Bum; Som Yang, Da; Park, Yong-il; Ryu, WonHyoung

2013-03-01

163

Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy.  

National Technical Information Service (NTIS)

The endocytic trafficking pathway is the site of action for receptor- targeted drug-delivery strategies, including Antibody-Drug- Conjugates (ADCs) and nanoparticle drug-delivery systems. Effective drug-release requires trafficking of the endocytosed rece...

H. Band S. Raja T. Bronich

2013-01-01

164

Potential of magnetic nanoparticles for targeted drug delivery  

PubMed Central

Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications.

Yang, Hung-Wei; Hua, Mu-Yi; Liu, Hao-Li; Huang, Chiung-Yin; Wei, Kuo-Chen

2012-01-01

165

Targeted drug delivery and enhanced intracellular release using functionalized liposomes  

NASA Astrophysics Data System (ADS)

The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin alpha5beta1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin alpha 5beta1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin alpha5beta1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin alpha5beta1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through alpha 5beta1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin alpha5beta 1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5-fluorouracil (5-FU) show significantly higher cytotoxicity than the PR_b-targeted inert stealth liposomes and the non-targeted stealth liposomes (both pH-sensitive and inert). The studies demonstrated that optimized PR_b functionalized pH sensitive liposomes have the potential to deliver a payload, such as chemotherapeutic agents, directly to colon cancer cells in an efficient and specific manner.

Garg, Ashish

166

Zein-based oral drug delivery system targeting activated macrophages.  

PubMed

Reactive oxygen species (ROS) play an important role in the pathogenesis of rheumatoid arthritis (RA). ROS such as hydrogen peroxide and superoxide are overproduced by activated macrophages in RA. As scavengers of ROS, enzymatic proteins such as catalase and superoxide dismutase (SOD) have a great therapeutic potential; however, in vivo application is limited especially when they are orally administered. Although, the oral route is the most convenient for drug administration, therapeutic proteins are easily degraded in vivo by the harsh conditions of gastrointestinal (GI) tract. Here, we introduce a novel drug delivery system composed of zein, a plant storage protein derived from maize. We demonstrate that zein nanoparticles can protect therapeutic proteins, catalase and SOD, from the harsh conditions of GI tract. Folate-conjugated catalase or SOD in zein nanoparticles can target the activated macrophages and scavenge the ROS generated by macrophages in vitro. This novel drug delivery system will be applicable to other orally administered treatments based on the protective property in the harsh conditions of GI tract. PMID:23876501

Lee, Sungmun; Alwahab, Noaf Salah Ali; Moazzam, Zainab Muhammad

2013-09-15

167

Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma  

PubMed Central

Background N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE) was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin. Methods Lactosylated liposomes encapsulating calcein (Lac-L-calcein) or doxorubicin (Lac-L-DOX) composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol) were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L-DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts. Results The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L-calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L-DOX), and its pharmacokinetic parameters indicate that Lac-L-DOX has a long blood circulation time (t1/2 8.73 hours). Tissue distribution and therapeutic efficacy studies in nude mice bearing HepG2 xenografts show that Lac-L-DOX had significantly stronger tumor inhibitory activity compared with L-DOX and free doxorubicin, along with a higher accumulation of drug within the tumor site and greater cellular uptake by tumor cells. Conclusion These data suggest that lactosylated liposomes are promising drug delivery vehicles for hepatocellular carcinoma.

Zhou, Xiaoju; Zhang, Mengzi; Yung, Bryant; Li, Hong; Zhou, Chenguang; Lee, L James; Lee, Robert J

2012-01-01

168

Physical blends of starch graft copolymers as matrices for colon targeting drug delivery systems  

Microsoft Academic Search

Colon targeting drug delivery systems have attracted many researchers due to the distinct advantages they present such as near neutral pH, longer transit time and reduced enzymatic activity. Moreover, in recent studies, colon specific drug delivery systems are gaining importance for use in the treatment of local pathologies of the colon and also for the systemic delivery of protein and

I. Silva; M. Gurruchaga; I. Goñi

2009-01-01

169

Targeted Spinal Cord Therapeutics Delivery: Stabilized Platform and Microelectrode Recording Guidance Validation  

Microsoft Academic Search

Background\\/Aims: No validated delivery technique exists for accurate, reproducible delivery of biological therapies to discrete spinal cord targets. To address this unmet need, we have constructed a stabilized platform capable of supporting physiologic mapping, through microelectrode recording, and cellular or viral payload delivery to the ventral horn. Methods: A porcine animal model (n = 7) has been chosen based upon

Jonathan Riley; John Butler; Kenneth B. Baker; Shearwood McClelland III; Qingshan Teng; Jun Yang; Mary Garrity-Moses; Thais Federici; Nicholas M. Boulis

2008-01-01

170

Transcranial Route of Brain Targeted Delivery of Methadone in Oil  

PubMed Central

The unique anatomical arrangement of blood vessels and sinuses in the human skull and the brain, the prevalence of a high density of skin appendages in the scalp, extracranial vessels of the scalp communicating with the brain via emissary veins and most importantly, the way that the scalp is used in Ayurvedic medical system in treating diseases associated with the brain show that a drug could be transcranially delivered and targeted to the brain through the scalp. The present study was to investigate by measuring the antinociceptive effect on rats whether the opioid analgesic methadone could be delivered and targeted to the brain by transcranial delivery route. A non aqueous solution of methadone base in sesame oil was used for the application on the scalp. Animal studies were carried out using six groups of male rats consisting of group 1, the oral control treated with distilled water 1 ml; group 2, the oral positive control treated with methadone hydrochloride solution 316.5 ?g/ml; group 3, the negative control treated transcranially with the blank sesame oil 0.2 ml and three test groups 4, 5 and 6 treated with three different dose levels of the transcranial oil formulation of methadone base, 41.6 ?g/0.2 ml, 104 ?g/0.2 ml and 208 ?g/0.2 ml, respectively. The antinociceptive effects were examined by subjecting the rats to the hot plate and tail flick tests. The two higher concentrations of the three transcranial methadone formulations yielded response vs time curves showing nearly equal maximum antinociceptive effects similar to that of the oral positive control. Maximum analgesic effect after transcranial administration was observed between 1st and 2nd h and declined up to 6th hour. The results indicate that the transcranial brain targeted delivery of methadone base in the form of an oil based non aqueous solution results in statistically significant antinociceptive effects under experimental conditions. Therefore, it is possible to deliver central nervous system drugs through the proposed transcranial route when suitably formulated.

Pathirana, W.; Abhayawardhana, P.; Kariyawasam, H.; Ratnasooriya, W. D.

2009-01-01

171

Magnetically responsive microparticles for targeted drug and radionuclide delivery.  

SciTech Connect

We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 {micro}m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 {micro}m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 {micro}m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial system (RES) prefer to associate with hydrophobic surfaces. Accordingly, we will tackle this challenge by modifying the particles with hydrophilic coatings such as PEG or poloxamer (co-polymers containing hydrophobic polyoxypropylene segments and repetitive polyoxyethylene hydrophilic groups), which have a proven ability to mask recognition by the RES. Modeling is needed to help optimize the performance of targeted magnetic-particle delivery, enhance its medicinal value, and expedite its medical application. To this end, scientists at Argonne National Laboratory, working with The University of Chicago and Cleveland Clinic Hospital, are working on an effective magnetic drug targeting system based on custom magnetic field designs coupled to a three-dimensional imaging platform that addresses all associated physical and theoretical problems. Furthermore, while our clinical trial results are encouraging with regard to the tolerance and applicability of the system, more improvements must be made with respect to future study designs and systems being used. Given the technical hurdles in developing this potentially important technology, we believe we have made great progress and that we have a strong developmental plan.

Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

2004-02-16

172

Chimeric aptamers in cancer cell-targeted drug delivery.  

PubMed

Aptamers are single-stranded structured oligonucleotides (DNA or RNA) that can bind to a wide range of targets ("apatopes") with high affinity and specificity. These nucleic acid ligands, generated from pools of random-sequence by an in vitro selection process referred to as systematic evolution of ligands by exponential enrichment (SELEX), have now been identified as excellent tools for chemical biology, therapeutic delivery, diagnosis, research, and monitoring therapy in real-time imaging. Today, aptamers represent an interesting class of modern pharmaceuticals which with their low immunogenic potential mimic extend many of the properties of monoclonal antibodies in diagnostics, research, and therapeutics. More recently, chimeric aptamer approach employing many different possible types of chimerization strategies has generated more stable and efficient chimeric aptamers with aptamer-aptamer, aptamer-nonaptamer biomacromolecules (siRNAs, proteins) and aptamer-nanoparticle chimeras. These chimeric aptamers when conjugated with various biomacromolecules like locked nucleic acid (LNA) to potentiate their stability, biodistribution, and targeting efficiency, have facilitated the accurate targeting in preclinical trials. We developed LNA-aptamer (anti-nucleolin and EpCAM) complexes which were loaded in iron-saturated bovine lactofeerin (Fe-blf)-coated dopamine modified surface of superparamagnetic iron oxide (Fe(3)O(4)) nanoparticles (SPIONs). This complex was used to deliver the specific aptamers in tumor cells in a co-culture model of normal and cancer cells. This review focuses on the chimeric aptamers, currently in development that are likely to find future practical applications in concert with other therapeutic molecules and modalities. PMID:21955150

Kanwar, Jagat R; Roy, Kislay; Kanwar, Rupinder K

2011-12-01

173

Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

Guar galactomannan is a biodegradable polysaccharide used widely in the food industry but also in the cosmetics, pharmaceutical, oil drilling, textile and paper industries. Guar consists of a mannose backbone and galactose side groups that are both susceptible to enzyme degradation, a unique property that can be explored for targeted drug delivery especially since those enzymes are naturally secreted by the microflora in human colon. The present study can be divided into three parts. In the first part, we discuss ways to modify guar to produce nanofibers by electrospinning, a process that involves the application of an electric field to a polymer solution or melt to facilitate production of fibers in the sub-micron range. Nanofibers are currently being explored as the next generation of drug carriers due to its many advantages, none more important than the fact that nanofibers are on a size scale that is a fraction of a hair's width and have large surface-to-volume ratio. The incorporation and controlled release of nano-sized drugs is one way in which nanofibers are being utilized in drug delivery. In the second part of the study, we explore various methods to crosslink guar nanofibers as a means to promote water-resistance in a potential drug carrier. The scope and utility of water-resistant guar nanofibers can only be fully appreciated when subsequent drug release studies are carried out. To that end, the third part of our study focuses on understanding the kinetics and diffusion mechanisms of a model drug, Rhodamine B, through moderately-swelling (crosslinked) hydrogel nanofibers in comparison to rapidly-swelling (non-crosslinked) nanofibers. Along the way, our investigations led us to a novel electrospinning set-up that has a unique collector designed to capture aligned nanofibers. These aligned nanofiber bundles can then be twisted to hold them together like yarn. From a practical standpoint, these yarns are advantageous because they come freely suspended and without any attached support. As composites of aligned nanofibers, yarns potentially combine the inherent advantages of nanofibers with the strength and pliability of larger sized fibers. As such, we became interested in exploring the potential of nanofiber yarns as drug carriers. Our study evolved to accommodate comparative studies between the behavior of traditional nonwoven mats and nanofiber yarns. Throughout the process, we sought to answer the bigger question: Can guar galactomannan nanofibers be used as a new biodegradable platform for drug delivery?

Chu, Hsiao Mei Annie

174

Construction of paclitaxel-loaded poly (2-hydroxyethyl methacrylate)-g-poly (lactide)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine copolymer nanoparticle delivery system and evaluation of its anticancer activity  

PubMed Central

Background There is an urgent need to develop drug-loaded biocompatible nanoscale packages with improved therapeutic efficacy for effective clinical treatment. To address this need, a novel poly (2-hydroxyethyl methacrylate)-poly (lactide)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine [PHEMA-g-(PLA-DPPE)] copolymer was designed and synthesized to enable these nanoparticles to be pH responsive under pathological conditions. Methods The structural properties and thermal stability of the copolymer was measured and confirmed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, and thermogravimetric analysis. In order to evaluate its feasibility as a drug carrier, paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles were prepared using the emulsion-solvent evaporation method. Results The PHEMA-g-(PLA-DPPE) nanoparticles could be efficiently loaded with paclitaxel and controlled to release the drug gradually and effectively. In vitro release experiments demonstrated that drug release was faster at pH 5.0 than at pH 7.4. The anticancer activity of the PHEMA-g-(PLA-DPPE) nanoparticles was measured in breast cancer MCF-7 cells in vivo and in vitro. In comparison with the free drug, the paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles could induce more significant tumor regression. Conclusion This study indicates that PHEMA-g-(PLA-DPPE) nanoparticles are promising carriers for hydrophobic drugs. This system can passively target cancer tissue and release drugs in a controllable manner, as determined by the pH value of the area in which the drug accumulates.

Ma, Xiaowei; Wang, Huan; Jin, Shubin; Wu, Yan; Liang, Xing-Jie

2012-01-01

175

Is there a clinical future for polymeric nanoparticles as brain-targeting drug delivery agents?  

Microsoft Academic Search

Injectable nanosized carriers (5–250nm) are actively studied as anticancer drug delivery agents for targeted drug delivery to the brain. Among these, polymeric nanoparticles have been studied since 1995, but only five of them recently started Phase I clinical trials, and none of these targets brain pathologies. To date, clinical trials for brain drug delivery have started for macromolecular- and nanocarrier-based

Luca Costantino; Diana Boraschi

176

Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy  

PubMed Central

Paclitaxel is an anticancer agent effective for the treatment of breast, ovarian, lung, and head and neck cancer. Because of water insolubility, paclitaxel is formulated with the micelle-forming vehicle Cremophor EL to enhance drug solubility. However, the addition of Cremophor EL results in hypersensitivity reactions, neurotoxicity, and altered pharmacokinetics of paclitaxel. To circumvent these unfavorable effects resulting from the addition of Cremophor EL, efforts have been made to develop new delivery systems for paclitaxel administration. For example, ABI-007 is a Cremophor-free, albumin-stabilized, nanoparticle paclitaxel formulation that was found to have significantly less toxicity than Cremophor-containing paclitaxel in mice. Pharmacokinetic studies indicate that in contrast to Cremophor-containing paclitaxel, ABI-007 displays linear pharmacokinetics over the clinically relevant dose range of 135–300 mg/m2. In a phase III study conducted in patients with metastatic breast cancer, patients treated with ABI-007 achieved a significantly higher objective response rate and time to progression than those treated with Cremophor-containing paclitaxel. Together these findings suggest that nanoparticle albumin-bound paclitaxel may enable clinicians to administer paclitaxel at higher doses with less toxicity than is seen with Cremophor-containing paclitaxel. The role of this novel paclitaxel formulation in combination therapy with other antineoplastic agents needs to be determined.

Scripture, Charity D; Figg, William D; Sparreboom, Alex

2005-01-01

177

Src family kinases and paclitaxel sensitivity  

PubMed Central

Src-family Kinases (SFKs) participate in the regulation of proliferation, differentiation, apoptosis, autophagy, adhesion, migration, invasion and angiogenesis in normal and cancer cells. Abnormal expression of SFKs has been documented in cancers that arise in breast, colon, ovary, melanocyte, gastric mucosa, head and neck, pancreas, lung and brain. Targeting SFKs in cancer cells has been shown to be a promising therapeutic strategy in solid tumors, particularly in ovarian, colon and breast cancers. Paclitaxel is one of most widely used chemotherapeutic agents for the management of ovarian, breast, lung and head and neck cancers. As a microtubule-stabilizing agent, paclitaxel possesses both mitosis-dependent and mitosis-independent activities against cancer cells. A variety of mechanisms such as deregulation of P-glycoprotein, alteration of tubulin isotypes, alteration of microtubule-regulatory proteins, deregulation of apoptotic signaling pathways, mutation of tubulins and overexpression of copper transporters have been implicated in the development of primary or secondary resistance to paclitaxel. By affecting cancer cell survival, proliferation, autophagy, microtubule stability, motility, and/or angiogenesis, SFKs interact with mechanisms that regulate paclitaxel sensitivity. Inhibition of SFKs can potentiate the anti-tumor activity of paclitaxel by enhancing apoptosis, autophagy and microtubule stability. Based on pre-clinical observations, administration of SFK inhibitors in combination with paclitaxel could improve treatment for ovarian, breast, lung and head and neck cancers. Identification and validation of predictive biomarkers could also permit personalization of the therapy.

2011-01-01

178

Targeted gene delivery of BMPR2 attenuates pulmonary hypertension.  

PubMed

Pulmonary arterial hypertension (PAH) remains a fatal disease despite modern pharmacotherapy. Mutations in the gene for bone morphogenetic protein receptor type II (BMPR2) lead to reduced BMPR2 expression, which is causally linked to PAH. BMPR2 is predominantly expressed on pulmonary endothelium and has complex interactions with transforming growth factor (TGF)-? signalling mechanisms. Our objectives were to assess the effect on PAH of upregulating BMPR2 by targeted adenoviral BMPR2 gene delivery to the pulmonary vascular endothelium. We used two established rat models of PAH: chronic hypoxia and monocrotaline (MCT). In both hypertensive models, those receiving BMPR2 had less right ventricular hypertrophy, less pulmonary vascular resistance, improved cardiac function and reduced vascular remodelling. In the MCT model, there was an increase in TGF-?, which was prevented by BMPR2 treatment. In vitro, TGF-?1-induced endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells, which was associated with reduced BMPR2 expression. EndMT was partially ameliorated by stimulating BMPR2 signalling with appropriate ligands even in the ongoing presence of TGF-?1. Collectively, these results indicate therapeutic potential for upregulation of the BMPR2 axis in PAH, which may be, in part, mediated by countering the remodelling effects of TGF-?. PMID:21737550

Reynolds, A M; Holmes, M D; Danilov, S M; Reynolds, P N

2012-02-01

179

Galactosylated chitosan nanoparticles for hepatocyte-targeted delivery of oridonin.  

PubMed

In this study, oridonin-loaded nanoparticles coated with galactosylated chitosan (ORI-GC-NP) were prepared for tumor targeting and their characteristics were evaluated for the morphologies, particle size and zeta potential. Oridonin-loaded nanoparticles (ORI-NP) without galactosylated chitosan were prepared as a control. The entrapment efficiency of ORI-GC-NP and ORI-NP were 72.15% and 85.31%, respectively. The in vitro drug release behavior from nanoparticles displayed biphasic drug release pattern with initial burst release and consequently sustained release. Next, the pharmacokinetics and tissue distribution of ORI-GC-NP, ORI-NP and ORI solution were carried out. Pharmacokinetic analysis showed that ORI-GC-NP and ORI-NP could prolong the drug plasma levels compared with ORI solution. Meanwhile, the distribution of ORI-GC-NP to liver was higher than that of ORI-NP and free drug. In conclusion, ORI-GC-NP, as a promising intravenous drug delivery system for ORI, could be developed as an alternative to the conventional ORI preparations. PMID:22732673

Zheng, Dandan; Duan, Cunxian; Zhang, Dianrui; Jia, Lejiao; Liu, Guangpu; Liu, Yue; Wang, Feihu; Li, Caiyun; Guo, Hejian; Zhang, Qiang

2012-10-15

180

Exploring targeted pulmonary delivery for treatment of lung cancer  

PubMed Central

Lung cancer is the most malignant cancer today. The treatment of lung cancer continues to be a challenge for oncologists. The direct delivery of chemotherapeutic agents to the lungs could represent a novel therapeutic approach for patients with pulmonary metastases. The large alveolar surface area, the low thickness of the epithelial barrier, and an extensive vascularization make the pulmonary route an ideal route for administration of oncolytics. This paper reviews the research performed over the last and current decades on the delivery of various oncolytics for pulmonary delivery for the treatment of lung cancer. Inhaled drug delivery devices in cancer therapy are also discussed in the present manuscript.

Goel, Amit; Baboota, Sanjula; Sahni, Jasjeet K; Ali, Javed

2013-01-01

181

Cytotoxicity of liposomal Paclitaxel in breast cancer cell line mcf-7.  

PubMed

Regarding that the breast cancer is the most prevalent disease among women, paclitaxel, an anti-cancer drug, could be used in treatment of this disease. As paclitaxel has adverse effects, it was used of nanoliposome drug delivery technology in order to reduce adverse effects and improve drug efficacy. Certain ratios of phosphatidylcholine, cholesterol and paclitaxel were synthesized to prepare nanoliposomal paclitaxel. Using Zeta sizer device, the mean diameter of nanoliposomal paclitaxel was obtained 421.4 nm and its encapsulation efficiency was 91.3 %. By dialysis, drug release in nanoliposome paclitaxel formulation within 28 h was studied which was 5.53 %. This study showed that cytotoxicity effect of nanoliposomal paclitaxel is more than that of the standard form. PMID:24426237

Esfahani, Maedeh Koohi Moftakhari; Alavi, Seyed Ebrahim; Movahedi, Fatemeh; Alavi, Fatemeh; Akbarzadeh, Azim

2013-10-01

182

Colon Targeted Drug Delivery Systems: A Review on Primary and Novel Approaches  

PubMed Central

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process.

Philip, Anil K.; Philip, Betty

2010-01-01

183

Inhibitory Effect of Paclitaxel on Endothelial Cell Adhesion and Migration  

Microsoft Academic Search

The long-term success of percutaneous coronary interventions has been limited by restenosis. Therefore, local delivery of paclitaxel, an antiproliferative agent, using drug-eluting stents has been applied to prevent in-stent restenosis. However, paclitaxel not only inhibits smooth muscle cell proliferation, but also delays re-endothelialization of the damaged site, which may cause potentially life-threatening cardiovascular adverse events, especially late and very late

Hua Li; Li-jun Zhang; Bai-hua Chen; Xuan Zhou; Ke Su; Wen-tao Shi; Jun-zhu Wu; Hong Yu; Lei Wei

2010-01-01

184

Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability  

Microsoft Academic Search

Purpose: Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement

Luka Milas; Kathryn A Mason; Nancy Hunter; Chun Li; Sidney Wallace

2003-01-01

185

Delivery and application of dietary polyphenols to target organs, tissues and intracellular organelles.  

PubMed

At present, dietary polyphenols are popular with consumers because regular consumption of polyphenol-rich foods is likely to be beneficial for human health. However, administrated polyphenols are extensively metabolized in the digestive tract or some other parts before reaching the target organs. Additionally, some of the polyphenols are photosensitive, easily oxidized and are in unfavorable forms. Therefore, a lot of work has been performed to ensure delivery of intact polyphenols to the target organs. We here summarize recent progress in polyphenol-delivery to individual organs, tissues, and cells, in regard to relatively new delivery systems. Polyphenol-delivery systems can be divided into three categories: (i) before delivery into the blood stream (skin, mouth, gastrointestine), (ii) in the blood stream (plasma), and (iii) after the blood stream (brain, spleen, bone marrow, kidney). Polyphenols before the delivery into blood stream must overcome several obstacles to avoid converting into inactive forms by commensal microorganisms, environmental pH, and some others. In the blood, plasma-polyphenol interactions and modifications are very effective for the bioavailability of polyphenols with numerous enzymes. Native forms of polyphenols, successfully out of the blood stream, further go through obstacles such as the blood brain barrier to reach target organs. Recent progress in delivering polyphenols is here discussed on 3 main delivery systems, nanoparticle, liposome, and microemulsion. Moreover, we also focused on delivery systems to intracellular organelles (cell surface, lysosome, mitochondria, nucleus), which are the final targets of polyphenols to perform their beneficial reactions. PMID:24328691

Ohara, Masaru; Ohyama, Yoshihiko

2014-01-01

186

Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery  

Microsoft Academic Search

Skin is an attractive target for delivery of genetic therapies and vaccines. However, new approaches are needed to access this tissue more effectively. Here, we describe a new delivery technology based on arrays of structurally precise, micron-scale silicon projections, which we term microenhancer arrays (MEAs). In a human clinical study, these devices effectively breached the skin barrier, allowing direct access

Jason B. Alarcon; John M. Brittingham; Diane E. Sutter; Ronald J. Pettis; Noel G. Harvey; John A. Mikszta

2002-01-01

187

Polyaspartic acid functionalized gold nanoparticles for tumor targeted doxorubicin delivery.  

PubMed

In this paper, we present polyaspartic acid, a biodegradable polymer as a reducing and functionalizing agent for the synthesis of doxorubicin loaded gold nanoparticles by a green process. Gold nanoparticles were stable to electrolytes and pH. Secondary amino groups of polyaspartic acid enabled reduction of gold chloride to form gold nanoparticles of size 55 +/-10 nm, with face centered cubic crystalline structure as confirmed by UV, TEM, SAED and XRD studies. Cationic doxorubicin was readily loaded onto anionic polyaspartic acid gold nanoparticles by ionic complexation. Fluorescence studies confirmed doxorubicin loading while FTIR spectra confirmed ionic complexation. Doxorubicin loading onto polyaspartic acid gold nanoparticles was studied at doxorubicin/polyaspartic acid molar ratios 1:10 to 1:1. As the molar ratio tended to unity, although loading up to 60% was achieved, colloidal instability resulted and is attributed to effective covering of negative charges of polyaspartic acid. Stable doxorubicin loaded polyaspartic acid gold nanoparticles of 105 +/- 15.1 nm with doxorubicin loading of 23.85% w/w and zeta potential value of -28 +/- 0.77 mV were obtained at doxorubicin/polyaspartic acid molar ratio 1:10. Higher doxorubicin release rate from the doxorubicin loaded polyaspartic acid gold nanoparticles in an acid medium (i.e., pH 5.5) as compared to that in pH 7.4 and deionized water is a desirable characteristic for tumor targeted delivery. Enhanced cytotoxicity and 3 fold higher uptake of doxorubicin loaded polyaspartic acid gold nanoparticles as compared to doxorubicin solution were seen in MCF-7 breast cancer cells while polyaspartic acid gold nanoparticles revealed no cytotoxicity confirming safety. Prominent regression in tumor size in-vivo in fibrosarcoma tumor induced mouse model was observed upto 59 days with doxorubicin loaded polyaspartic acid gold nanoparticles while doxorubicin solution treated mice showed regrowth beyond 23rd day. Moreover, a decrease of body weight of 35% indicating severe toxicity with doxorubicin solution as compared to only 20% with gradual recovery after day 30 in case of doxorubicin loaded polyaspartic acid gold nanoparticles confirmed their lower toxicity and enhanced efficacy. PMID:24724506

Khandekar, Sameera V; Kulkarni, M G; Devarajan, Padma V

2014-01-01

188

Mesenchymal Stem Cell as Targeted-Delivery Vehicle in Breast Cancer.  

National Technical Information Service (NTIS)

Mesenchymal stem cells (MSCs) have been proposed to be cellular vehicles for the targeted delivery and local production of biological agents in tumors. In this proposal we will stably transfect mesenchymal stem cells with a lentiviral vector containing a ...

Z. Cheng

2010-01-01

189

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy.  

National Technical Information Service (NTIS)

Breast cancer cells drug resistance mechanisms are the major factors to reduce the cytotoxic effects and even the chemotherapeutic efficacy of anti- cancer drugs. Nanocarriers for drug delivery based on the EPR effect targeted to cell cytosol subject to v...

M. Radosz W. J. Murdoch Y. Shen

2013-01-01

190

Cell-mediated Delivery and Targeted Erosion of Noncovalently Crosslinked Hydrogels  

NASA Technical Reports Server (NTRS)

A method for targeted delivery of therapeutic compounds from hydrogels is presented. The method involves administering to a cell a hydrogel in which a therapeutic compound is noncovalently bound to heparin.

Kiick, Kristi L. (Inventor); Yamaguchi, Nori (Inventor)

2013-01-01

191

PACLITAXEL GELATIN NANOPARTICLES FOR INTRAVESICAL BLADDER CANCER THERAPY  

PubMed Central

Purpose We have shown that inadequate drug delivery to tumor cells is a major cause of failures in intravesical therapy of nonmuscle-invading bladder cancer. This is partly due to the dilution of drug concentration by urine production during treatment. To address this problem, we developed gelatin nanoparticles of paclitaxel (PNP) designed to yield constant drug concentrations. The hypothesis that constant, therapeutic concentrations in urine, bladder tissue and tumors can be attained was evaluated in dogs. Materials and methods We studied the drug release from PNP in culture medium in vitro. In vivo studies were performed in tumor-free dogs and in pet dogs with naturally occurring transitional cell carcinoma, where the pharmacokinetics (plasma, urine and tumors) of PNP was determined. Results The release of paclitaxel from PNP in vitro and in vivo was rate-limited by the drug solubility in aqueous medium. This property yielded constant drug concentrations independent of changes in the urine volume over the 2-hr treatment. Intravesical PNP showed low systemic absorption and favorable bladder tissue/tumor targeting and retention properties, with pharmacologically active concentrations retained in tumors for at least 1 week. Conclusions The constant drug release from PNP may overcome the problem of drug dilution by newly produced urine and the sustained drug levels in tumors may reduce the treatment frequency.

Lu, Ze; Yeh, Teng-Kuang; Wang, Jie; Chen, Ling; Lyness, Greg; Xin, Yan; Wientjes, M. Guillaume; Bergdall, Valerie; Couto, Guillermo; Alvarez-Berger, Francisco; Kosarek, Carrie E.; Au, Jessie L-S.

2013-01-01

192

Targeted drug delivery and penetration into solid tumors.  

PubMed

Delivery and penetration of chemotherapeutic drugs into tumors are limited by a number of factors related to abnormal vasculature and altered stroma composition in neoplastic tissues. Coupling of chemotherapeutic drugs with tumor vasculature-homing peptides or administration of drugs in combination with biological agents that affect the integrity of the endothelial lining of tumor vasculature is an appealing strategy to improve drug delivery to tumor cells. Promising approaches to achieve this goal are based on the use of Asn-Gly-Arg (NGR)-containing peptides as ligands for drug delivery and of NGR-TNF, a peptide-tumor necrosis factor-? fusion protein that selectively alters drug penetration barriers and that is currently tested in a randomized Phase III trial in patients with malignant pleural mesothelioma. PMID:21287572

Corti, Angelo; Pastorino, Fabio; Curnis, Flavio; Arap, Wadih; Ponzoni, Mirco; Pasqualini, Renata

2012-09-01

193

Development of paclitaxel-TyroSpheres for topical skin treatment  

PubMed Central

A potential topical psoriasis therapy has been developed consisting of tyrosine-derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4,000 times greater than PBS) by effective encapsulation and enable sustained, dose-controlled release over 72 hours under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations >100 ng/cm2 of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC50 of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape.

Kilfoyle, Brian E.; Sheihet, Larisa; Zhang, Zheng; Laohoo, Marissa; Kohn, Joachim; Michniak-Kohn, Bozena B.

2012-01-01

194

Coupled Particulate and Continuum Model for Nanoparticle Targeted Delivery  

PubMed Central

Prediction of nanoparticle (NP) distribution in a vasculature involves transport phenomena at various scales and is crucial for the evaluation of NP delivery efficiency. A combined particulate and continuum model is developed to model NP transport and delivery processes. In the particulate model ligand-receptor binding kinetics is coupled with Brownian dynamics to study NP binding on a microscale. An analytical formula is derived to link molecular level binding parameters to particulate level adhesion and detachment rates. The obtained NP adhesion rates are then coupled with a convection-diffusion-reaction model to study NP transport and delivery at macroscale. The binding results of the continuum model agree well with those from the particulate model. The effects of shear rate, particle size and vascular geometry on NP adhesion are investigated. Attachment rates predicted by the analytical formula also agree reasonably well with the experimental data reported in literature. The developed coupled model that links ligand-receptor binding dynamics to NP adhesion rate along with macroscale transport and delivery processes may serve as a faster evaluation and prediction tool to determine NP distribution in complex vascular networks.

Tan, Jifu; Wang, Shunqiang; Yang, Jie; Liu, Yaling

2013-01-01

195

Solid lipid nanoparticles for targeted brain drug delivery  

Microsoft Academic Search

The present review discusses the potential use of solid lipid nanoparticles for brain drug targeting purposes. The state of the art on surfactant-coated poly(alkylcyanoacrylate) nanoparticles specifically designed for brain targeting is given by emphasizing the transfer of this technology to solid lipid matrices. The available literature on solid lipid nanoparticles and related carriers for brain drug targeting is revised as

Paolo Blasi; Stefano Giovagnoli; Aurélie Schoubben; Maurizio Ricci; Carlo Rossi

2007-01-01

196

[Research progress of gene recombinant mesenchymal stem cells as tumor targeting delivery vehicles].  

PubMed

The applications of targeting gene delivery systems in tumor therapy have attracted extensive attention of researchers in recent years, as they can selectively deliver the therapeutic gene to tumor sites, improve the success rate of gene therapy and reduce the side effects. Therefore, design and development of novel gene delivery vehicles have been a hot area of current research. Recent studies have shown that mesenchymal stem cells (MSCs) have the ability to migrate towards and engraft into the tumor sites. Therefore, these properties make them a great hope for efficient targeted-delivery vehicles in cancer gene therapy. In this review, we examine the promising of utilization of MSCs as a targeted-delivery vehicle for cancer gene therapy, and summarize various challenges and concerns regarding this therapy. PMID:24187826

Zhang, Tian-Yuan; Hu, Yu-Lan; Liang, Wen-Quan; Gao, Jian-Qing

2013-08-01

197

A two-component drug delivery system using Her-2-targeting thermosensitive liposomes.  

PubMed

We report on a new method for enhancing the specificity of drug delivery for tumor cells, using thermosensitive immunoliposomes. The liposomes are conjugated to the antibody trastuzumab (Herceptin), which targets the human epidermal growth factor receptor 2 (Her-2), a cell membrane receptor overexpressed in many human cancers. Being thermosensitive, the liposomes only release their contents when heated slightly above body temperature, allowing for the possibility of tissue targeting through localized hyperthermia. Using self-quenching calcein, we demonstrate the release of liposome contents into cell endosomes after brief heating to 42 degrees C. To further increase targeting specificity, we incorporate the concept of a two-component delivery system that requires the interaction of two different liposomes within the same endosome for cytoplasmic delivery. Experimental evaluation of the technique using fluorescently labeled liposomes shows that a two-component delivery system, combined with intracellular disruption of liposomes by hyperthermia, significantly increases specificity for Her-2-overexpressing tumor cells. PMID:19089689

Kullberg, Max; Mann, Kristine; Owens, Jesse Lee

2009-02-01

198

Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues  

PubMed Central

Non-invasive treatment of injuries and disorders affecting bones and connective tissue is a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair.

Nichols, Scott P.; Storm, Wesley L.; Koh, Ahyeon; Schoenfisch, Mark H.

2012-01-01

199

Size matters: gold nanoparticles in targeted cancer drug delivery  

PubMed Central

Cancer is the current leading cause of death worldwide, responsible for approximately one quarter of all deaths in the USA and UK. Nanotechnologies provide tremendous opportunities for multimodal, site-specific drug delivery to these disease sites and Au nanoparticles further offer a particularly unique set of physical, chemical and photonic properties with which to do so. This review will highlight some recent advances, by our laboratory and others, in the use of Au nanoparticles for systemic drug delivery to these malignancies and will also provide insights into their rational design, synthesis, physiological properties and clinical/preclinical applications, as well as strategies and challenges toward the clinical implementation of these constructs moving forward.

Dreaden, Erik C; Austin, Lauren A; Mackey, Megan A; El-Sayed, Mostafa A

2013-01-01

200

Magnetic nanoparticle drug delivery systems for targeting tumor  

NASA Astrophysics Data System (ADS)

Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature that lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones, whereas, conventional cancer therapies that work by blocking cell division are not effective to treat tumors within hypoxic zones. Under these circumstances the use of magnetic nanoparticles as a drug delivering agent system under the influence of external magnetic field has received much attention, based on their simplicity, ease of preparation, and ability to tailor their properties for specific biological applications. Hence in this review article we have reviewed current magnetic drug delivery systems, along with their application and clinical status in the field of magnetic drug delivery.

Mody, Vicky V.; Cox, Arthur; Shah, Samit; Singh, Ajay; Bevins, Wesley; Parihar, Harish

2014-04-01

201

The use of microbubbles to target drug delivery  

PubMed Central

Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed.

Tsutsui, Jeane M; Xie, Feng; Porter, Richard Thomas

2004-01-01

202

Depth-targeted transvascular drug delivery by using annular-shaped photomechanical waves  

Microsoft Academic Search

Laser-based drug delivery is attractive for the targeting capability due to high spatial controllability of laser energy. Recently, we found that photomechanical waves (PMWs) can transiently increase the permeability of blood vessels in skin, muscle and brain of rats. In this study, we examined the use of annular-shaped PMWs to increase pressure at target depths due to superposition effect of

Takuya Akiyama; Shunichi Sato; Hiroshi Ashida; Mitsuhiro Terakawa

2011-01-01

203

DMLC leaf-pair optimal control of IMRT delivery for a moving rigid target  

SciTech Connect

In dynamic multileaf collimation (DMLC), pairs of servo-controlled leaves sweep across the target to deliver the modulated radiation intensity map while the beam is on continuously. The mathematical model for dynamic, optimal control of a single leaf pair has been developed for the case of a rigid target, translating parallel to the leaf trajectories. This mathematical model ensures delivery of the modulated intensity map while minimizing beam-on time. Numerical solutions of the model are presented here for optimal IMRT delivery for stationary and oscillating targets, together with a discussion of the results. Comparisons between solutions for stationary and mobile targets, as well as comparisons between optimal and suboptimal algorithms, are provided. These comparisons allow us to estimate potential gains in the effectiveness of DMLC IMRT delivery when it is based on optimal algorithms.

Papiez, Lech [Department of Radiation Oncology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, Indiana 46202 (United States)

2004-10-01

204

Targeted delivery and controllable release of nanoparticles using a defect-decorated optical nanofiber.  

PubMed

Targeted drug delivery and controllable release are particularly beneficial in medical therapy. This work provides a demonstration of nanoparticles targeted delivery and controllable release using a defect-decorated optical nanofiber (NF). By using the NF, polystyrene particles (PSs) (713-nm diameter) suspended in water were successfully trapped, then delivered along the NF at an average velocity of 4.8 µm/s with the assistance of a laser beam of 980-nm wavelength at an optical power of 39 mW, and finally, assembled at the defect. Subsequently, by turning off the optical power, 90% of the assembled PSs can be released in 30 s. This method would be useful in targeted drug delivery and controllable release, and provide potential applications in targeted therapy. PMID:21747483

Xin, Hongbao; Li, Baojun

2011-07-01

205

Targeted Delivery of siRNA-Generating DNA Nanocassettes Using Multifunctional Nanoparticles  

PubMed Central

Molecular therapy using a small interfering RNA (siRNA) has shown promise in the development of novel therapeutics. Various formulations have been used for in vivo delivery of siRNAs. However, the stability of short double-stranded RNA molecules in the blood and efficiency of siRNA delivery into target organs or tissues following systemic administration have been the major issues that limit applications of siRNA in human patients. In this study, multifunctional siRNA delivery nanoparticles are developed that combine imaging capability of nanoparticles with urokinase plasminogen activator receptor-targeted delivery of siRNA expressing DNA nanocassettes. This theranostic nanoparticle platform consists of a nanoparticle conjugated with targeting ligands and double-stranded DNA nanocassettes containing a U6 promoter and a shRNA gene for in vivo siRNA expression. Targeted delivery and gene silencing efficiency of firefly luciferase siRNA nanogenerators are demonstrated in tumor cells and in animal tumor models. Delivery of survivin siRNA expressing nanocassettes into tumor cells induces apoptotic cell death and sensitizes cells to chemotherapy drugs. The ability of expression of siRNAs from multiple nanocassettes conjugated to a single nanoparticle following receptor-mediated internalization should enhance the therapeutic effect of the siRNA-mediated cancer therapy.

Cho, Y.-S.; Lee, G. Y.; Sajja, H. K.; Qian, W.; Cao, Z.; He, W.; Karna, P.; Chen, X.; Mao, H.; Wang, Y. A.; Yang, L.

2013-01-01

206

Cancer cell-targeted drug delivery utilizing oligopeptide transport activity.  

PubMed

To study the drug delivery to tumor by utilization of an oligopeptide transport activity, we examined the accumulation of dipeptides and the peptide-mimetic anti-cancer drug, bestatin, a substrate of oligopeptide transporter PepT1. Firstly, we established HeLa cells stably expressing human peptide transporter (hPepT1) (HeLa-hPepT1). Secondly, we constructed an experimental model by inoculation of HeLa-hPepT1 cells subcutaneously into Balb/c nu/nu mice to demonstrate the contribution of PepT1 to the tissue-selective drug delivery. The accumulations of a hydrolysis-resistant dipeptide [(3)H]carnosine and bestatin in solid tumors formed by HeLa-hPepT1 or HeLa-pcDNA3, which are transfected with vector DNA (pcDNA3) were measured. After I.V. administration, tissue-to-plasma concentration ratios (K(p)) of both compounds, in HeLa-hPepT1 tumor was significantly greater than that of [(14)C]inulin, a marker for extracellular fluid space, those of dipeptides in muscle, or those in HeLa-pcDNA3 tumor. Furthermore, bestatin exhibited growth inhibition of HeLa-hPepT1 in vitro. In vivo, repeated oral administration of bestatin for 28 days suppressed the growth of HeLa-hPepT1 tumor specifically. When HT-1080 cells, which may naturally express oligopeptide transport activity, were transplanted, K(p) of [(3)H]carnosine was significantly increased in comparison with that in muscle. In addition, oligopeptide transport activities among various human cell lines were examined. These results provide the first demonstration for the selective delivery of oligopeptides to tumors by specific oligopeptide transport activity. PMID:11004680

Nakanishi, T; Tamai, I; Takaki, A; Tsuji, A

2000-10-15

207

Polymeric micelles: nanocarriers for cancer-targeted drug delivery.  

PubMed

Polymeric micelles represent an effective delivery system for poorly water-soluble anticancer drugs. With small size (10-100 nm) and hydrophilic shell of PEG, polymeric micelles exhibit prolonged circulation time in the blood and enhanced tumor accumulation. In this review, the importance of rational design was highlighted by summarizing the recent progress on the development of micellar formulations. Emphasis is placed on the new strategies to enhance the drug/carrier interaction for improved drug-loading capacity. In addition, the micelle-forming drug-polymer conjugates are also discussed which have both drug-loading function and antitumor activity. PMID:24700296

Zhang, Yifei; Huang, Yixian; Li, Song

2014-08-01

208

Aptamer-targeted DNA nanostructures for therapeutic delivery.  

PubMed

DNA-based nanostructures have been widely used in various applications due to their structural diversity, programmability, and uniform structures. Their intrinsic biocompatibility and biodegradability further motivates the investigation of DNA-based nanostructures as delivery vehicles. Incorporating AS1411 aptamers into DNA pyramids leads to enhanced intracellular uptake and selectively inhibits the growth of cancer cells, achieved without the use of transfection reagents. Furthermore, aptamer-displaying pyramids are found to be substantially more resistant to nuclease degradation than single-stranded aptamers. These findings, along with their modularity, reinforce the potential of DNA-based nanostructures for therapeutic applications. PMID:24739136

Charoenphol, Phapanin; Bermudez, Harry

2014-05-01

209

Lipid-Coated Nanoscale Coordination Polymers for Targeted Delivery of Antifolates to Cancer Cells  

PubMed Central

Nanoscale coordination polymers (NCPs) have been demonstrated as an interesting platform for drug delivery, as they possess many advantages over small-molecule chemotherapeutics, such as high payloads, lower systemic toxicity, tunability, and enhanced tumor uptake. Existing formulations for the delivery of methotrexate (MTX), an antifolate cancer drug, have very low drug loadings. Herein, we report the incorporation of MTX as a building block in an NCP formulation with exceptionally high drug loadings (up to 79.1 wt%) and the selective delivery of the NCP to cancer cells. Encapsulation of the NCP in a functionalized lipid bilayer allows for targeted delivery and controlled release to cancer cells. A phosphor can be doped into the NCPs for monitoring particle uptake by optical imaging. The lipid-coated and anisamide-targeted NCPs have superior in vitro efficacy against acute lymphoblastic leukemia cells when compared to free drug.

Huxford, Rachel C.; deKrafft, Kathryn E.; Boyle, William S.; Liu, Demin

2013-01-01

210

Transcriptional Profiling of Targets for Combination Therapy of Lung Carcinoma with Paclitaxel and Mitogen-activated Protein\\/Extracellular Signal-regulated Kinase Kinase Inhibitor1  

Microsoft Academic Search

A combination of paclitaxel (Taxol) and mitogen-activated protein\\/ extracellular signal-regulated kinase kinase (MEK\\/Erk) inhibitor repre- sents a rational new approach to chemotherapy. We performed Af- fymetrix microarray analysis to understand the global effects of this combination in lung carcinoma. Genes involved in cell cycle control, apoptosis, adhesion, proliferation, invasion, and metastasis were modu- lated. We observed similar patterns of gene

Debra J. Taxman; Jeffrey P. MacKeigan; Casey Clements; Daniel T. Bergstralh

2003-01-01

211

Carboxymethyl starch and lecithin complex as matrix for targeted drug delivery: I. Monolithic mesalamine forms for colon delivery.  

PubMed

For drugs expected to act locally in the colon, and for successful treatment, a delivery device is necessary, in order to limit the systemic absorption which decreases effectiveness and causes important side effects. Various delayed release systems are currently commercialized; most of them based on pH-dependent release which is sensitive to gastrointestinal pH variation. This study proposes a novel excipient for colon delivery. This new preparation consists in the complexation between carboxymethyl starch (CMS) and Lecithin (L). As opposed to existing excipients, the new complex is pH-independent, inexpensive, and easy to manufacture and allows a high drug loading. FTIR, X-ray, and SEM structural analysis all support the hypothesis of the formation of a complex. By minor variation of the excipient content within the tablet, it is possible to modulate the release time and delivery at specific sites of the gastrointestinal tract. This study opens the door to a new pH-independent delivery system for mesalamine targeted administration. Our novel formulation fits well with the posology of mesalamine, used in the treatment of Inflammatory Bowel Disease (IBD), which requires repeated administrations (1g orally four times a day) to maintain a good quality of life. PMID:23562535

Mihaela Friciu, Maria; Canh Le, Tien; Ispas-Szabo, Pompilia; Mateescu, Mircea Alexandru

2013-11-01

212

In vivo drug release behavior in dogs from a new colon-targeted delivery system  

Microsoft Academic Search

The colon-targeted delivery capsule (CTDC), a new capsule-type dosage form for colonic delivery of drugs, was investigated for the in vivo drug release behavior in dogs. A CTDC formulation with prednisolone as a model drug and theophylline as a marker substance for gastric emptying was prepared for this study. The enteric-coated capsule (ECC) formulation with a similar composition was also

Takashi Ishibashi; Harumi Hatano; Masao Kobayashi; Masakazu Mizobe; Hiroyuki Yoshino

1999-01-01

213

Choline transporter-targeting and co-delivery system for glioma therapy.  

PubMed

Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-L-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood-brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system. PMID:23993342

Li, Jianfeng; Guo, Yubo; Kuang, Yuyang; An, Sai; Ma, Haojun; Jiang, Chen

2013-12-01

214

New development and application of ultrasound targeted microbubble destruction in gene therapy and drug delivery.  

PubMed

Ultrasound is a common used technique for clinical imaging. In recent years, with the advances in preparation technology of microbubbles and the innovations in ultrasound imaging, ultrasound is no longer confined to detection of tissue perfusion, but extends to specific ultrasound molecular imaging and target therapy gradually. With the development of research, ultrasound molecular imaging and target therapy have made great progresses. Targeted microbubbles for molecular imaging are achieved by binding target molecules, specific antibody or ligand to the surface of microbubbles to obtain specific imaging by attaching to target tissues. Meanwhile, it can also achieve targeting gene therapy or drug delivery by ultrasound targeted microbubble destruction (UTMD) mediating genes or drugs to specific target sites. UTMD has a number of advantages, such as target-specific, highly effective, non-invasivity, relatively low-cost and no radiation, and has broad application prospects, which is regarded as one hot spot in medical studies. We reviewed the new development and application of UTMD in gene therapy and drug delivery in this paper. With further development of technology and research, the gene or drug delivery system and related methods will be widely used in application and researches. PMID:23721204

Chen, Zhi-Yi; Yang, Feng; Lin, Yan; Zhang, Jin-Shan; Qiu, Ri-Xiang; Jiang, Lan; Zhou, Xing-Xing; Yu, Jiang-Xiu

2013-08-01

215

Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles.  

PubMed

Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine. PMID:24806291

Zhen, Zipeng; Tang, Wei; Chuang, Yen-Jun; Todd, Trever; Zhang, Weizhong; Lin, Xin; Niu, Gang; Liu, Gang; Wang, Lianchun; Pan, Zhengwei; Chen, Xiaoyuan; Xie, Jin

2014-06-24

216

A polyvalent aptamer system for targeted drug delivery.  

PubMed

Poor efficacy and off-target systemic toxicity are major problems associated with current chemotherapeutic approaches to treat cancer. We developed a new form of polyvalent therapeutics that is composed of multiple aptamer units synthesized by rolling circle amplification and physically intercalated chemotherapy agents (termed as "Poly-Aptamer-Drug"). Using a leukemia cell-binding aptamer and doxorubicin as a model system, we have successfully constructed Poly-Aptamer-Drug systems and demonstrated that the Poly-Aptamer-Drug is significantly more effective than its monovalent counterpart in targeting and killing leukemia cells due to enhanced binding affinity (? 40 fold greater) and cell internalization via multivalent effects. We anticipate that our Poly-Aptamer-Drug approach will yield new classes of tunable therapeutics that can be utilized to effectively target and treat cancers while minimizing the side effects of chemotherapy. PMID:24044994

Zhang, Zhiqing; Ali, M Monsur; Eckert, Mark A; Kang, Dong-Ku; Chen, Yih Yang; Sender, Leonard S; Fruman, David A; Zhao, Weian

2013-12-01

217

Targeted delivery of Tet1 peptide functionalized polymersomes to the rat cochlear nerve  

PubMed Central

Polymersomes are nanosized vesicles formed from amphiphilic block copolymers, and have been identified as potential drug delivery vehicles to the inner ear. The aim of this study was to provide targeting to specific cells within the inner ear by functionalizing the polymersome surface with Tet1 peptide sequence. Tet1 peptide specifically binds to the trisialoganglioside clostridial toxin receptor on neurons and was expected to target the polymersomes toward the cochlear nerve. The Tet1 functionalized PEG-b-PCL polymersomes were administered using routine drug delivery routes: transtympanic injection and cochleostomy. Delivery via cochleostomy of Tet1 functionalized polymersomes resulted in cochlear nerve targeting; in contrast this was not seen after transtympanic injection.

Zhang, Ya; Zhang, Weikai; Johnston, Alexander H; Newman, Tracey A; Pyykko, Ilmari; Zou, Jing

2012-01-01

218

Targeted Delivery System of Nanobiomaterials in Anticancer Therapy: From Cells to Clinics  

PubMed Central

Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancer. Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancer drugs into the diseased sites. In particular, nanobiomaterial-based nanocarriers, so-called nanoplatforms, are the design of the targeted delivery systems such as liposomes, polymeric nanoparticles/micelles, nanoconjugates, norganic materials, carbon-based nanobiomaterials, and bioinspired phage system, which are based on the nanosize of 1–100?nm in diameter. In this review, the design and the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics. We believe that this review can offer recent advances in the targeted delivery systems of nanobiomaterials regarding in vitro and in vivo applications and the translation of nanobiomaterials to nanomedicine in anticancer therapy.

Jin, Su-Eon; Jin, Hyo-Eon; Hong, Soon-Sun

2014-01-01

219

Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors  

PubMed Central

Introduction Entry of blood circulating agents into the brain is highly selectively con-trolled by specific transport machineries at the blood brain barrier (BBB), whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results Brain capillary endothelial cells (BCECs) form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics). Conclusion The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.

Omidi, Yadollah; Barar, Jaleh

2012-01-01

220

First line treatment of advanced non-small-cell lung cancer - specific focus on albumin bound paclitaxel  

PubMed Central

Lung cancer is the leading cause of cancer mortality worldwide in both men and women. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for more than 80% of cases. Paclitaxel has a broad spectrum of activity against various malignancies, including NSCLC. Paclitaxel is poorly soluble in water and thus, until recently, its commercially available preparations contained a non-ionic solvent Cremophor EL®. Cremophor EL® improves the solubility of paclitaxel and allows its intravenous administration. However, certain side-effects associated with paclitaxel, such as hypersensitivity reactions, myelosuppression, and peripheral neuropathy, are known to be worsened by Cremophor®. Nanoparticle albumin-bound paclitaxel ([nab-paclitaxel] ABRAXANE® ABI-007) is a new generation formulation of paclitaxel that obviates the need for Cremophor®, resulting in a safer and faster infusion without requiring the use of premedications to avoid hypersensitivity. Albumin-binding receptor-mediated delivery and lack of sequestering Cremophor® micelles allow higher intratumoral concentration of pharmacologically active paclitaxel. Multiple clinical trials have demonstrated a superior tolerability profile of nab-paclitaxel in comparison to solvent-bound paclitaxel (sb-paclitaxel). A recent Phase III trial compared the effects of weekly nab-paclitaxel in combination with carboplatin versus sb-paclitaxel in combination with carboplatin given every 3 weeks for first line treatment of NSCLC. This trial highlights the weekly nab-paclitaxel combination as an alternate treatment option for NSCLC, with higher response rate in squamous cell NSCLC and longer survival in elderly patients. This review will focus on the properties of nab-paclitaxel and its use in the first line treatment of NSCLC.

Gupta, Neha; Hatoum, Hassan; Dy, Grace K

2014-01-01

221

Azo polymeric hydrogels for colon targeted drug delivery  

Microsoft Academic Search

Azo polymeric hydrogels were developed for colon specific targeting. Methacryloyloxy azobenzene was synthesized and hydrogels were prepared by copolymerizing with hydroxyethyl methacrylate. These hydrogels were characterized by various spectral techniques such as Fourier transform infrared spectroscopy, thermogravimetric analysis and scanning electron microscopy. Equilibrium swelling measurements of the hydrogels were carried out in distilled water and also in simulated gastric and

K. L. Shantha; P. Ravichandran; K. Panduranga Rao

1995-01-01

222

Method for Targeted Therapeutic Delivery of Proteins into Cells  

Cancer.gov

Current methods to deliver proteins into cells (e.g., using retrovirus, DNA transfection, protein transduction, microinjection, complexing the protein with lipids, etc.) have many shortcomings, such as lack of target specificity toxicity, or unwanted random integration into the host chromosome.

223

Advances in lipid nanodispersions for parenteral drug delivery and targeting  

Microsoft Academic Search

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application

Panayiotis P. Constantinides; Mahesh V. Chaubal; Robert Shorr

2008-01-01

224

Tuning Pharmacokinetics and Biodistribution of a Targeted Drug Delivery System Through Incorporation of a Passive Targeting Component  

PubMed Central

Major challenges in the development of drug delivery systems (DDSs) have been the short half-life, poor bioavailability, insufficient accumulation and penetration of the DDSs into the tumor tissue. Understanding the pharmacokinetic (PK) parameters of the DDS is essential to overcome these challenges. Herein we investigate how surface chemistry affects the PK profile and organ distribution of a gold nanoparticle-based DDS containing both a passive and active targeting moiety via two common routes of administration: intravenous and intraperitoneal injections. Using LC/MS/MS, ELISA and INAA we report the half-life, peak plasma concentrations, area under the curve, ability to cross the peritoneal barrier and biodistribution of the nanoconjugates. The results highlight the design criteria for fine-tuning the PK parameters of a targeted drug delivery system that exploits the benefits of both active and passive targeting.

Kudgus, Rachel A.; Walden, Chad A.; McGovern, Renee M.; Reid, Joel M.; Robertson, J. David; Mukherjee, Priyabrata

2014-01-01

225

Methotrexate delivery via folate targeted dendrimer-based nanotherapeutic platform  

PubMed Central

This paper provides a synopsis of the advancements made in advancing a dendrimer-based nanomedicine towards human clinical trials by the Michigan Nanotechnology Institute for Medicine and Biological Sciences. A brief description of the synthesis and characterization of a targeted multifunctional therapeutic will demonstrate the simple yet delicate task of producing novel chemotherapeutic agents. The results obtained from in vitro and in vivo studies not only authenticate the potential of using nanoparticles to target therapeutics but also provide valuable insight towards the future directions of this technology. A fundamental, cross-disciplinary collaboration was necessary to achieve the synthesis and testing of this technology, and was the keystone to establishing this innovative invention. Throughout this paper, we will stress that the unique collaboration that facilitated the evolution of this technology is vital to the success of future developments in nanomedicine.

Majoros, Istvan J.; Williams, Christopher R.; Becker, Andrew; Baker, James R.

2010-01-01

226

Fingerloop activates cargo delivery and unloading during cotranslational protein targeting  

PubMed Central

During cotranslational protein targeting by the signal recognition particle (SRP), information about signal sequence binding in the SRP's M domain must be effectively communicated to its GTPase domain to turn on its interaction with the SRP receptor (SR) and thus deliver the cargo proteins to the membrane. A universally conserved “fingerloop” lines the signal sequence–binding groove of SRP; the precise role of this fingerloop in protein targeting has remained elusive. In this study, we show that the fingerloop plays important roles in SRP function by helping to induce the SRP into a more active conformation that facilitates multiple steps in the pathway, including efficient recruitment of SR, GTPase activation in the SRP•SR complex, and most significantly, the unloading of cargo onto the target membrane. On the basis of these results and recent structural work, we propose that the fingerloop is the first structural element to detect signal sequence binding; this information is relayed to the linker connecting the SRP's M and G domains and thus activates the SRP and SR for carrying out downstream steps in the pathway.

Ariosa, Aileen R.; Duncan, Stacy S.; Saraogi, Ishu; Lu, Xiaodong; Brown, April; Phillips, Gregory J.; Shan, Shu-Ou

2013-01-01

227

A Nonpolycationic Fully Proteinaceous Multiagent System for Potent Targeted Delivery of siRNA.  

PubMed

Protein-based methods of targeted short-interfering RNA (siRNA) delivery have the potential to solve some of the problems faced by nanoparticle-based methods, such as poor pharmacokinetics and biodistribution, low tumor penetration, and polydispersity. However, protein-based targeted delivery has been limited to fusion proteins with polycationic peptides as siRNA carriers, whose high charge density in some cases results in undesirable biophysical and in vivo properties. Here, we present a fully proteinaceous, multiagent approach for targeted siRNA delivery to epidermal growth factor receptor (EGFR), using a nonpolycationic carrier for siRNA. Each agent contributes a fundamentally different mechanism of action that work together for potent targeted RNA interference. The first agent is an EGFR-targeted fusion protein that uses a double-stranded RNA-binding domain as a nonpolycationic siRNA carrier. This double-stranded RNA-binding domain fusion protein can deliver siRNA to the endosomes of an EGFR-expressing cell line. A second agent delivers the cholesterol-dependent cytolysin, perfringolysin O, in a targeted manner, which enhances the endosomal escape of siRNA and induces gene silencing. A third agent that clusters EGFR increases gene-silencing potency and decreases cytolysin toxicity. Altogether, this system is potent, with only 16 nmol/l siRNA required for gene silencing and a therapeutic window that spans two orders of magnitude of targeted cytolysin concentrations. PMID:24825362

Liu, David V; Yang, Nicole J; Wittrup, K Dane

2014-01-01

228

A Nonpolycationic Fully Proteinaceous Multiagent System for Potent Targeted Delivery of siRNA  

PubMed Central

Protein-based methods of targeted short-interfering RNA (siRNA) delivery have the potential to solve some of the problems faced by nanoparticle-based methods, such as poor pharmacokinetics and biodistribution, low tumor penetration, and polydispersity. However, protein-based targeted delivery has been limited to fusion proteins with polycationic peptides as siRNA carriers, whose high charge density in some cases results in undesirable biophysical and in vivo properties. Here, we present a fully proteinaceous, multiagent approach for targeted siRNA delivery to epidermal growth factor receptor (EGFR), using a nonpolycationic carrier for siRNA. Each agent contributes a fundamentally different mechanism of action that work together for potent targeted RNA interference. The first agent is an EGFR-targeted fusion protein that uses a double-stranded RNA-binding domain as a nonpolycationic siRNA carrier. This double-stranded RNA-binding domain fusion protein can deliver siRNA to the endosomes of an EGFR-expressing cell line. A second agent delivers the cholesterol-dependent cytolysin, perfringolysin O, in a targeted manner, which enhances the endosomal escape of siRNA and induces gene silencing. A third agent that clusters EGFR increases gene-silencing potency and decreases cytolysin toxicity. Altogether, this system is potent, with only 16 nmol/l siRNA required for gene silencing and a therapeutic window that spans two orders of magnitude of targeted cytolysin concentrations.

Liu, David V; Yang, Nicole J; Wittrup, K Dane

2014-01-01

229

Human cancer cell line microRNAs associated with in vitro sensitivity to paclitaxel  

PubMed Central

Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI50) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson’s correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC50, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (?0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC50, 17.8 nM, low miR-367 (?0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics.

CHEN, NING; CHON, HYE SOOK; XIONG, YIN; MARCHION, DOUGLAS C.; JUDSON, PATRICIA L.; HAKAM, ARDESHIR; GONZALEZ-BOSQUET, JESUS; PERMUTH-WEY, JENNIFER; WENHAM, ROBERT M.; APTE, SACHIN M.; CHENG, JIN Q.; SELLERS, THOMAS A.; LANCASTER, JOHNATHAN M.

2014-01-01

230

Ligand-functionalized nanoliposomes for targeted delivery of galantamine.  

PubMed

The purpose of this study was to design ligand-functionalized nanoliposomes that are proficient in providing effective intracellular delivery of an alkaloid drug (galantamine) into PC12 neuronal cells in response to managing Alzheimer's disease (AD). Ligand-functionalized nanoliposomes were produced and validated for their physicochemical properties, in silico molecular mechanics energy relationships, ex vivo cytotoxicity, peptide coupling efficiency (PCE), drug entrapment efficiency (DEE), drug release, fluorometry and confocal microscopy. Particle sizes of the nanoliposomes ranged from 127 nm to 165 nm (PdI=0.39-0.03), zeta potential values of -18 mV to -36 mV, PCE from 40% to 78% while DEE ranged from 42% to 79%. The surface morphology of the nanoliposomes was stable, spherically and uniform in shape. Thermal behavior and Fourier transform infrared (FTIR) analyses confirmed that galantamine and the peptide-ligand were incorporated into the inner core and surface of the nanoliposomes, respectively. The optimized formulation showed sustained drug release (30% of drug released within 48 h). Fluorometry and confocal microscopy revealed that the ligand-functionalized nanoliposomes facilitated galantamine uptake into PC12 neuronal cells via the Serpin Enzyme Complex Receptor in a mediated manner. CytoTox-Glo™ cytotoxicity assay established the low cytotoxicity on PC12 neuronal cells when exposed to native nanoliposomes and the ligand-functionalized nanoliposomes. Response surface analysis demonstrated there was a high degree of correlation between the experimental and fitted values. Furthermore, ex vivo studies showed that the high galantamine accumulation into PC12 neuronal cells was influenced by the post-engineering of peptides on the surface of the galantamine-loaded nanoliposomes. MMER analysis aptly corroborated the experimental findings. PMID:23535346

Mufamadi, Maluta S; Choonara, Yahya E; Kumar, Pradeep; Modi, Girish; Naidoo, Dinesh; van Vuuren, Sandy; Ndesendo, Valence M K; Toit, Lisa C du; Iyuke, Sunny E; Pillay, Viness

2013-05-01

231

Near-infrared-controlled, targeted hydrophobic drug-delivery system for synergistic cancer therapy.  

PubMed

Hydrophobicity has been an obstacle that hinders the use of many anticancer drugs. A critical challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. In this study, we have developed a targeted near-infrared (NIR)-regulated hydrophobic drug-delivery platform based on gold nanorods incorporated within a mesoporous silica framework (AuMPs). Upon application of NIR light, the photothermal effect of the gold nanorods leads to a rapid rise in the local temperature, thus resulting in the release of the entrapped drug molecules. By integrating chemotherapy and photothermotherapy into one system, we have studied the therapeutic effects of camptothecin-loaded AuMP-polyethylene glycol-folic acid nanocarrier. Results revealed a synergistic effect in vitro and in vivo, which would make it possible to enhance the therapeutic effect of hydrophobic drugs and decrease drug side effects. Studies have shown the feasibility of using this nanocarrier as a targeted and noninvasive remote-controlled hydrophobic drug-delivery system with high spatial/temperal resolution. Owing to these advantages, we envision that this NIR-controlled, targeted drug-delivery method would promote the development of high-performance hydrophobic anticancer drug-delivery system in future clinical applications. PMID:23765904

Yang, Xinjian; Liu, Zhen; Li, Zhenhua; Pu, Fang; Ren, Jinsong; Qu, Xiaogang

2013-07-29

232

Laser-induced disruption of systemically administered liposomes for targeted drug delivery  

NASA Astrophysics Data System (ADS)

Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.

Mackanos, Mark A.; Larabi, Malika; Shinde, Rajesh; Simanovskii, Dmitrii M.; Guccione, Samira; Contag, Christopher H.

2009-07-01

233

Novel chitosan coated magnetic nanocarriers for the targeted Diclofenac delivery.  

PubMed

New magnetic devices consisting of magnetite functionalized with oleic acid and chitosan have been synthesized and employed to the loading of Diclofenac as potential tool for treatment of targeted inflammatory diseases. Magnetic loaded and un-loaded nanoparticles have been thoroughly characterized by infrared spectroscopy, transmission electron microscopy, determination of hydrodynamic diameter by Dynamic light scattering and zeta potential measurements at different pH conditions. A study of the release of Diclofenac has been performed in vitro and available mathematical models have been used to determine the release kinetic. Both properties and release data reveal that this nanomagnetic platform would be suitable for in vivo assays. PMID:24734550

Agotegaray, Mariela; Palma, Santiago; Lassalle, Verónica

2014-05-01

234

Synthesis and evaluation of water-soluble polymeric bone-targeted drug delivery systems.  

PubMed

Four polymeric bone-targeting conjugates were synthesized based on poly(ethylene glycol) (PEG, two conjugates) and poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA, two conjugates). The well-known bone-targeting compounds, alendronate and aspartic acid peptide, were used as bone-targeting moieties. Fluorescein isothiocyanate (FITC) was attached to the conjugates as a model drug for detection purposes. The bone-targeting potential of these conjugates was tested in vitro with hydroxyapatite (HA) and in mice. The data obtained indicated that these novel delivery systems could specifically accumulate in the bone tissue. PMID:13129387

Wang, Dong; Miller, Scott; Sima, Monika; Kopecková, Pavla; Kopecek, Jindrich

2003-01-01

235

Targeted Drug Delivery Systems Mediated by a Novel Peptide in Breast Cancer Therapy and Imaging  

PubMed Central

Targeted delivery of drugs to tumors represents a significant advance in cancer diagnosis and therapy. Therefore, development of novel tumor-specific ligands or pharmaceutical nanocarriers is highly desirable. In this study, we utilized phage display to identify a new targeting peptide, SP90, which specifically binds to breast cancer cells, and recognizes tumor tissues from breast cancer patients. We used confocal and electron microscopy to reveal that conjugation of SP90 with liposomes enables efficient delivery of drugs into cancer cells through endocytosis. Furthermore, in vivo fluorescent imaging demonstrated that SP90-conjugated quantum dots possess tumor-targeting properties. In tumor xenograft and orthotopic models, SP90-conjugated liposomal doxorubicin was found to improve the therapeutic index of the chemotherapeutic drug by selectively increasing its accumulation in tumors. We conclude that the targeting peptide SP90 has significant potential in improving the clinical benefits of chemotherapy in the treatment and the diagnosis of breast cancer.

Chiu, Chien-Yu; Lin, Wei-Chuan; Yan, Shin-Long; Wang, Yi-Ping; Kuo, Yuan-Sung; Yeh, Chen-Yun; Lo, Albert; Wu, Han-Chung

2013-01-01

236

Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors.  

PubMed

Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including ?v?3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors. PMID:23933441

Buckway, Brandon; Wang, Yongjian; Ray, Abhijit; Ghandehari, Hamidreza

2013-11-01

237

Enhancement of the efficiency of magnetic targeting for drug delivery: Development and evaluation of magnet system  

NASA Astrophysics Data System (ADS)

Deep magnetic capture and clinical application are the current trends for magnetic targeted drug delivery system. More promising and possible strategies are needed to overcome the current limitations and further improve the magnetic targeting technique. Recent advances in the development of targeting magnet system show promise in progressing this technology from the laboratory to the clinic. Starting from well-known basic concepts, current limitations of magnetic targeted drug delivery system are analyzed. Meanwhile, the design concepts and evaluations of some effective improvements in magnet system are discussed and reviewed with reference to (i) reasonable design of magnet system; (ii) control modes of magnet system used to generate dynamical magnetic fields; and (iii) magnetic field driving types.

Cao, Quanliang; Han, Xiaotao; Li, Liang

2011-08-01

238

Actively targeting solid tumours with thermoresponsive drug delivery systems that respond to mild hyperthermia.  

PubMed

A diverse range of drug delivery vehicles have been developed to specifically target chemotherapeutics to solid tumours while avoiding systemic dose-limiting toxicity. Many of these active targeting strategies display limited efficacy because they rely on subtle differences in expression patterns between pathogenic tissue and healthy tissue. In contrast, drug delivery systems that exploit thermoresponsive behaviour allow a clinician to spatially and temporally control the accumulation and/or release of the toxic agents within tumour tissue by simply applying mild hyperthermia (defined as 39-43?°C) to the desired site. Although thermally sensitive materials comprise a significant portion of the literature on novel drug delivery systems, only a few systems have been methodically tuned to respond within this narrowly defined physiological temperature range in an in vivo environment. This review discusses the materials and strategies developed to control the primary tumour through the combined application of hyperthermia and chemotherapy. PMID:23924317

McDaniel, Jonathan R; Dewhirst, Mark W; Chilkoti, Ashutosh

2013-09-01

239

Targeted delivery of Epirubicin to cancer cells by PEGylated A10 aptamer.  

PubMed

Clinical administrations of anthracyclines are limited by cardiotoxicity and myelosuppression. Targeted delivery of anticancer agents is especially important in reducing their side effects. In this work, A10 (Apt), an aptamer for prostate-specific membrane anytigen (PSMA), was applied for targeted delivery of Epirubicin (Epi) to LNCaP cells (PSMA(+)). Flow cytometry analysis showed that PEG-Apt-Epi complex was internalized effectively to LNCaP cells (PSMA(+)), but not to PC3 cells (PSMA(-)). This fact was confirmed by less cytotoxicity of PEG-Apt-Epi complex in PC3 cells in comparison with Epi alone. No significant change in viability between Epi- and complex-treated LNCaP cells was observed. In conclusion, PEG-Apt-Epi complex is an efficient and simple system for specific delivery of drug to PSMA-expressing cell lines. PMID:23815443

Taghdisi, Seyed Mohammad; Danesh, Noor Mohammad; Sarreshtehdar Emrani, Ahmad; Tabrizian, Kaveh; Zandkarimi, Majid; Ramezani, Mohammad; Abnous, Khalil

2013-09-01

240

Catching target receptors for drug and vaccine delivery using TOGA gene expression profiling.  

PubMed

Drug delivery technologies are commonly directed towards formulations to control the delivery of therapeutic compounds. However, many processes in the human body have evolved to regulate the transport of various molecules, cells, or particles across epithelial barriers. To take advantage of this biology, we used TOGA gene expression profiling to identify receptor or transporter molecules to target delivery vehicles for transport across an epithelial barrier. In the case of intestinal epithelium, we sought molecules associated with the transport of particles by Peyer's patch M cells. We have identified genes specific to Peyer's patch epithelium, some of which appear to be M cell specific. Discoveries made by this process will provide targets for development of new vaccines, but also provide new insights into the biology of transepithelial transport. The power of this gene profiling approach also suggests application to other systems, such as the response to metabolic changes or drug treatments. PMID:12393302

Lo, David; Hilbush, Brian; Mah, Steven; Brayden, David; Byrne, Daragh; Higgins, Lisa; O'Mahony, Daniel J

2002-11-01

241

Targeted delivery of small interfering RNA to angiogenic endothelial cells with liposome-polycation-DNA particles  

Microsoft Academic Search

Angiogenesis is an attractive target for cancer therapy, due to its central position in tumor growth and development. Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFRs) play a key role in the angiogenic process. A promising strategy for targeting VEGF-mediated angiogenesis is RNA interference (RNAi) using short interfering RNA (siRNA). However, for efficacious RNAi a well-designed siRNA delivery system

P. Vader; B. J. Crielaard; S. M. van Dommelen; R. van der Meel; G. Storm; R. M. Schiffelers

242

In vivo gene silencing in solid tumors by targeted electrically mediated siRNA delivery  

Microsoft Academic Search

RNA interference (RNAi)-mediated gene silencing approaches appear very promising for therapies based on the targeted inhibition of disease-relevant genes. The major hurdle to the therapeutic development of RNAi strategies remains, however, the efficient delivery of the RNAi-inducing molecules, the short interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs), to the target tissue. With respect to cancer treatment the development of

M Golzio; L Mazzolini; A Ledoux; A Paganin; M Izard; L Hellaudais; A Bieth; M J Pillaire; C Cazaux; J S Hoffmann; B Couderc; J Teissié

2007-01-01

243

Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice  

Microsoft Academic Search

Background:An effective cancer therapeutic must selectively target tumours with minimal systemic toxicity. Expression of a cytotoxic protein using Salmonella typhimurium would enable spatial and temporal control of delivery because these bacteria preferentially target tumours over normal tissue.Methods:We engineered non-pathogenic S. typhimurium to secrete murine TNF-related apoptosis-inducing ligand (TRAIL) under the control of the prokaryotic radiation-inducible RecA promoter. The response of

S Ganai; R B Arenas; N S Forbes

2009-01-01

244

In Vivo PEG-Modification of Vascular Surfaces for Targeted Delivery  

Microsoft Academic Search

ObjectiveThrombosis and restenosis remain problematic for many intravascular procedures. Previously, it has been demonstrated that modifying an injured vascular surface with a protein-reactive polymer could block undesirable platelet deposition. As an added benefit, it would be advantageous if one could target therapeutics to the injured site. This study investigates a site-specific delivery system to target microspheres to vascular surfaces modified

Timothy E. Deglau; Timothy M. Maul; Flordeliza S. Villanueva; William R. Wagner

245

Synthesis, characterization, and evaluation of a novel amphiphilic polymer RGD-PEG-Chol for target drug delivery system.  

PubMed

An amphiphilic polymer RGD-PEG-Chol which can be produced in large scale at a very low cost has been synthesized successfully. The synthesized intermediates and final products were characterized and confirmed by ¹H nuclear magnetic resonance spectrum (¹H NMR) and Fourier transform infrared spectrum (FT-IR). The paclitaxel- (PTX-) loaded liposomes based on RGD-PEG-Chol were then prepared by film formation method. The liposomes had a size within 100?nm and significantly enhanced the cytotoxicity of paclitaxel to B16F10 cell as demonstrated by MTT test (IC?? = 0.079? ?g/mL of RGD-modified PTX-loaded liposomes compared to 9.57? ?g/mL of free PTX). Flow cytometry analysis revealed that the cellular uptake of coumarin encapsulated in the RGD-PEG-Chol modified liposome was increased for HUVEC cells. This work provides a reasonable, facile, and economic approach to prepare peptide-modified liposome materials with controllable performances and the obtained linear RGD-modified PTX-loaded liposomes might be attractive as a drug delivery system. PMID:24578646

Zeng, Shi; Wu, Fengbo; Li, Bo; Song, Xiangrong; Zheng, Yu; He, Gu; Peng, Cheng; Huang, Wei

2014-01-01

246

Synthesis, Characterization, and Evaluation of a Novel Amphiphilic Polymer RGD-PEG-Chol for Target Drug Delivery System  

PubMed Central

An amphiphilic polymer RGD-PEG-Chol which can be produced in large scale at a very low cost has been synthesized successfully. The synthesized intermediates and final products were characterized and confirmed by 1H nuclear magnetic resonance spectrum (1H NMR) and Fourier transform infrared spectrum (FT-IR). The paclitaxel- (PTX-) loaded liposomes based on RGD-PEG-Chol were then prepared by film formation method. The liposomes had a size within 100?nm and significantly enhanced the cytotoxicity of paclitaxel to B16F10 cell as demonstrated by MTT test (IC50 = 0.079??g/mL of RGD-modified PTX-loaded liposomes compared to 9.57??g/mL of free PTX). Flow cytometry analysis revealed that the cellular uptake of coumarin encapsulated in the RGD-PEG-Chol modified liposome was increased for HUVEC cells. This work provides a reasonable, facile, and economic approach to prepare peptide-modified liposome materials with controllable performances and the obtained linear RGD-modified PTX-loaded liposomes might be attractive as a drug delivery system.

Zeng, Shi; Li, Bo; Song, Xiangrong; Zheng, Yu; Peng, Cheng; Huang, Wei

2014-01-01

247

Doxorubicin loaded magneto-niosomes for targeted drug delivery.  

PubMed

In chemotherapy the magnetic drug targeting to a specific organ or tissue is proposed on the assumption that magnetic fields are harmless to biological systems. In this light we have vehiculated doxorubicin as model drug by novel magneto-niosomes in order to evaluate the physico-chemical properties of the obtained formulations and the in vitro release profile. Tween 60 and Pluronic L64 have been used as surfactants and the formulation cytotoxicity has been performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide and trypan blue dye esclusion tests. Results show that niosome dimensions and doxorubicin entrapment efficiencies are influenced by bilayer composition. In addition, formulations are able to control the deliver and release of the drug active form in a retarded manner. No additional toxicity, due to the encapsulation of ferrofluid into niosomes core, has been detected. PMID:23107959

Tavano, Lorena; Vivacqua, Marco; Carito, Valentina; Muzzalupo, Rita; Caroleo, Maria Cristina; Nicoletta, Fiore

2013-02-01

248

Development and characterization of drug delivery systems for targeting mammalian cells and tissues: a review.  

PubMed

Recent advances in the development of diagnostics and therapeutics in the fields of recombinant biochemistry, solid phase peptide synthesis as well as in galenical research have resulted in highly specific and efficient components. Presently, millions of patients can profit from these new therapeutic modalities. The application of an effective anti-tumor dose of drugs can lead to marked toxicity in patients. Therefore, safe and efficient possibilities to transport these compounds to the target are of outmost importance. The importance of drug delivery is pivotal in the wide area of pharmacological research. However, until now, this issue is still to be solved. The main goal of every drug delivery system is the delivery of a precise amount of a drug at a pre-programmed rate to the desired location in order to achieve the necessary drug concentration in the targeted organ for effective treatment. The key problem still remains the achievement of curative doses in a pharmacologically active state in the desired target while avoiding side effects. Although respectable advances can be recognized in this field, the currently applied mechanisms for the transport of therapeutic molecules across biological membranes still remain far from being efficient. Helper molecules could improve delivery to desired target sites. Presently, a number of efforts are made and a huge spectrum of biochemical, biological, medical, pharmaceutical and physical possibilities are arising. However, the design and development of successful therapies based on this technology still remains a great challenge. PMID:16101505

Braun, K; Pipkorn, R; Waldeck, W

2005-01-01

249

Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles - opportunities & challenges  

NASA Astrophysics Data System (ADS)

One of the big challenges of medicine today is to deliver drugs specifically to defected cells. Nanoparticulate drug carriers have the potential to answer to this call, as nanoparticles can cross physiological barriers and access different tissues, and also be provided in a targetable form aimed at enhancing cell specificity of the carrier. Recent developments within material science and strong collaborative efforts crossing disciplinary borders have highlighted the potential of mesoporous silica nanoparticles (MSNs) for such targeted drug delivery. Here we outline recent advances which in this sense push MSNs to the forefront of drug delivery development. Relatively straightforward inside-out tuning of the vehicles, high flexibility, and potential for sophisticated release mechanisms make these nanostructures promising candidates for targeted drug delivery such as `smart' cancer therapies. Moreover, due to the large surface area and the controllable surface functionality of MSNs, they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting, simultaneously carrying traceable (fluorescent or magnetically active) modalities, also making them highly interesting as theragnostic agents. However, the increased relative surface area and small size, and flexible surface functionalization which is beneficially exploited in nanomedicine, consequently also includes potential risks in their interactions with biological systems. Therefore, we also discuss some safety issues regarding MSNs and highlight how different features of the drug delivery platform influence their behaviour in a biological setting. Addressing these burning questions will facilitate the application of MSNs in nanomedicine.

Rosenholm, Jessica M.; Sahlgren, Cecilia; Lindén, Mika

2010-10-01

250

In vitro studies on guar gum based formulation for the colon targeted delivery of Sennosides  

Microsoft Academic Search

PURPOSE: The objective of the present study is to develop colon targeted drug delivery sys- tems for sennosides using guar gum as a carrier. METHODS: Matrix tablets containing various pro- portions of guar gum were prepared by wet granula- tion technique using starch paste as a binder. The tablets were evaluated for content uniformity and in vitro drug release study

Munira Momin; K. Pundarikakshudu

251

Feasibility of targeted drug delivery to selective areas of the retina  

Microsoft Academic Search

A new method was developed to deliver locally a bolus dose of a drug to the retinal vasculature. The targeted delivery system was based on encapsulating the drug in heat-sensitive liposomes, which are injected intravenously and lysed in the retinal vessels by a heat pulse generated by a laser. To test if substances delivered in the vessels could also penetrate

Y. Ogura; T. Guran; M. Shahidi; M. T. Mori; R. C. Zeimer

1991-01-01

252

Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery.  

PubMed

Sodium dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte-Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems. PMID:22420308

Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Mitra, Ashim K

2012-06-01

253

A novel mitotropic oligolysine nanocarrier: Targeted delivery of covalently bound D-Luciferin to cell mitochondria  

Microsoft Academic Search

New and emerging therapeutic approaches focus on the targeted delivery of therapeutic agents to cell mitochondria with high specificity. Herein we present a novel mitotropic nanocarrier based on an oligolysine scaffold by addition of two triphenylphosphonium cations per oligomer. Although the parent oligolysine failed to enter healthy cells, the triphenylphosphonium modified carrier, with or without d-Luciferin, attached as cargo molecule,

Theodossis A. Theodossiou; Zili Sideratou; Dimitris Tsiourvas; Constantinos M. Paleos

2011-01-01

254

Targeted nanoparticles for drug delivery through the blood–brain barrier for Alzheimer's disease  

Microsoft Academic Search

Alzheimer's disease (AD) is the most common cause of dementia among the elderly, affecting 5% of Americans over age 65, and 20% over age 80. An excess of senile plaques (?-amyloid protein) and neurofibrillary tangles (tau protein), ventricular enlargement, and cortical atrophy characterizes it. Unfortunately, targeted drug delivery to the central nervous system (CNS), for the therapeutic advancement of neurodegenerative

Celeste Roney; Padmakar Kulkarni; Veera Arora; Peter Antich; Frederick Bonte; Aimei Wu; N. N. Mallikarjuana; Sanjeev Manohar; Hsiang-Fa Liang; Anandrao R. Kulkarni; Hsing-Wen Sung; Malladi Sairam; Tejraj M. Aminabhavi

2005-01-01

255

Mesoporous Silica Nanoparticles as Drug Delivery Systems for Targeted Inhibition of Notch Signaling in Cancer  

PubMed Central

Notch signaling, a key regulator of stem cells, is frequently overactivated in cancer. It is often linked to aggressive forms of cancer, evading standard treatment highlighting Notch as an exciting therapeutic target. Notch is in principle “druggable” by ?-secretase inhibitors (GSIs), inhibitory peptides and antibodies, but clinical use of Notch inhibitors is restricted by severe side effects and there is a demand for alternative cancer-targeted therapy. Here, we present a novel approach, using imagable mesoporous silica nanoparticles (MSNPs) as vehicles for targeted delivery of GSIs to block Notch signaling. Drug-loaded particles conjugated to targeting ligands induced cell-specific inhibition of Notch activity in vitro and exhibited enhanced tumor retainment with significantly improved Notch inhibition and therapeutic outcome in vivo. Oral administration of GSI-MSNPs controlled Notch activity in intestinal stem cells further supporting the in vivo applicability of MSNPs for GSI delivery. MSNPs showed tumor accumulation and targeting after systemic administration. MSNPs were biocompatible, and particles not retained within the tumors, were degraded and eliminated mainly by renal excretion. The data highlights MSNPs as an attractive platform for targeted drug delivery of anticancer drugs with otherwise restricted clinical application, and as interesting constituents in the quest for more refined Notch therapies.

Mamaeva, Veronika; Rosenholm, Jessica M; Bate-Eya, Laurel Tabe; Bergman, Lotta; Peuhu, Emilia; Duchanoy, Alain; Fortelius, Lina E; Landor, Sebastian; Toivola, Diana M; Linden, Mika; Sahlgren, Cecilia

2011-01-01

256

Synthesis of Biomolecule-Modified Mesoporous Silica Nanoparticles for Targeted Hydrophobic Drug Delivery to Cancer Cells  

PubMed Central

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.

Ferris, Daniel P.; Lu, Jie; Gothard, Chris; Yanes, Rolando; Thomas, Courtney R.; Olsen, John-Carl; Stoddart, J. Fraser; Tamanoi, Fuyuhiko; Zink, Jeffrey I.

2011-01-01

257

Depth-targeted transvascular drug delivery by using annular-shaped photomechanical waves  

NASA Astrophysics Data System (ADS)

Laser-based drug delivery is attractive for the targeting capability due to high spatial controllability of laser energy. Recently, we found that photomechanical waves (PMWs) can transiently increase the permeability of blood vessels in skin, muscle and brain of rats. In this study, we examined the use of annular-shaped PMWs to increase pressure at target depths due to superposition effect of pressure waves. This can increase the permeability of blood vessels located in the specific depth regions, enabling depth-targeted transvascular drug delivery. Annular PMWs were produced by irradiating a laser-absorbing material with annular-shaped pulsed laser beams that were produced by using an axicon lens. We first examined propagation and pressure characteristics of annular PMWs in tissue phantoms and confirmed an increased pressure at a target depth, which can be controlled by changing laser parameters. We injected Evans blue (EB) into a rat tail vein, and annular PMWs (inner diameter, 3 mm; outer diameter, 5 mm) were applied from the myofascial surface of the anterior tibialis muscle. After perfusion fixation, we observed fluorescence originating from EB in the tissue. We observed intense fluorescence at a target depth region of around 5 mm. These results demonstrate the capability of annular PMWs for depth-targeted transvascular drug delivery.

Akiyama, Takuya; Sato, Shunichi; Ashida, Hiroshi; Terakawa, Mitsuhiro

2011-02-01

258

Intramural Delivery of Rapamycin With ?v?3-Targeted Paramagnetic Nanoparticles Inhibits Stenosis After Balloon Injury  

PubMed Central

Background Drug eluting stents prevent vascular restenosis but can delay endothelial healing. A rabbit femoral artery model of stenosis formation after vascular injury was used to study the effect of intramural delivery of ?v?3-integrin–targeted rapamycin nanoparticles on vascular stenosis and endothelial healing responses. Methods and Results Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were locally treated with either (1) ?v?3-targeted rapamycin nanoparticles, (2) ?v?3-targeted nanoparticles without rapamycin, (3) nontargeted rapamycin nanoparticles, or (4) saline. Intramural binding of integrin-targeted paramagnetic nanoparticles was confirmed with MR molecular imaging (1.5 T). MR angiograms were indistinguishable between targeted and control arteries at baseline, but 2 weeks later they showed qualitatively less luminal plaque in the targeted rapamycin treated segments compared with contralateral control vessels. In a first cohort of 19 animals (38 vessel segments), microscopic morphometric analysis of the rapamycin-treated segments revealed a 52% decrease in the neointima/media ratio (P<0.05) compared to control. No differences (P>0.05) were observed among balloon injured vessel segments treated with ?v?3-targeted nanoparticles without rapamycin, nontargeted nanoparticles with rapamycin, or saline. In a second cohort of 29 animals, endothelial healing followed a parallel pattern over 4 weeks in the vessels treated with ?v?3-targeted rapamycin nanoparticles and the 3 control groups. Conclusions Local intramural delivery of ?v?3-targeted rapamycin nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury.

Cyrus, Tillmann; Zhang, Huiying; Allen, John S.; Williams, Todd A.; Hu, Grace; Caruthers, Shelton D.; Wickline, Samuel A.; Lanza, Gregory M.

2009-01-01

259

Synthesis of Doxorubicin loaded magnetic chitosan nanoparticles for pH responsive targeted drug delivery.  

PubMed

Targeted drug delivery is a promising alternative to overcome the limitations of classical chemotherapy. In an ideal targeted drug delivery system carrier nanoparticles would be directed to the tumor tissue and selectively release therapeutic molecules. As a novel approach, chitosan coated magnetic nanoparticles (CS MNPs) maintain a pH dependent drug delivery which provides targeting of drugs to the tumor site under a magnetic field. Among various materials, chitosan has a great importance as a pH sensitive, natural, biodegradable, biocompatible and bioadhesive polymer. The aim of this study was to obtain an effective targeted delivery system for Doxorubicin, using chitosan coated MNPs. Different sized CS MNPs were produced by in situ synthesis method. The anti-cancer agent Doxorubicin was loaded onto CS MNPs which were characterized previously. Doxorubicin loading was confirmed by FTIR. Drug loading and release characteristics, and stability of the nanoparticles were investigated. Our results showed that the CS MNPs have pH responsive release characteristics. The cellular internalization of Doxorubicin loaded CS MNPs were visualized by fluorescent microscopy. Doxorubicin loaded CS MNPs are efficiently taken up by MCF-7 (MCF-7/S) and Doxorubicin resistant MCF-7 (MCF-7/1?M) breast cancer cells, which increases the efficacy of drug and also maintains overcoming the resistance of Doxorubicin in MCF-7/Dox cells. Consequently, CS MNPs synthesized at various sizes can be effectively used for the pH dependent release of Doxorubicin in cancer cells. Results of this study can provide new insights in the development of pH responsive targeted drug delivery systems to overcome the side effects of conventional chemotherapy. PMID:24931189

Unsoy, Gozde; Khodadust, Rouhollah; Yalcin, Serap; Mutlu, Pelin; Gunduz, Ufuk

2014-10-01

260

Alveolar targeting of aerosol pentamidine. Toward a rational delivery system  

SciTech Connect

Nebulizer systems that deposit a high proportion of aerosolized pentamidine on large airways are likely to be associated with marked adverse side effects, which may lead to premature cessation of treatment. We have measured alveolar deposition and large airway-related side effects (e.g., cough, breathlessness, and effect on pulmonary function) after aerosolization of 150 mg pentamidine isethionate labeled with {sup 99m}Tc-Sn-colloid. Nine patients with AIDS were studied using three nebulizer systems producing different droplet size profiles: the Acorn System 22, Respirgard II, and Respirgard II with the inspiratory baffle removed. Alveolar deposition was greatest and side effects least with the nebulizer producing the smallest droplet size profile (Respirgard II), whereas large airway-related side effects were prominent and alveolar deposition lowest with the nebulizer producing the largest droplet size (Acorn System 22). Values for alveolar deposition and adverse airway effects were intermediate using the Respirgard with inspiratory baffle removed, thus indicating the importance of the baffle valve in determining droplet size. Addition of a similar baffle valve to the Acorn System 22 produced a marked improvement in droplet size profile. Selection of a nebulizer that produces an optimal droplet size range offers the advantage of enhancing alveolar targeting of aerosolized pentamidine while reducing large airway-related side effects.

Simonds, A.K.; Newman, S.P.; Johnson, M.A.; Talaee, N.; Lee, C.A.; Clarke, S.W. (Royal Free Hospital, London (England))

1990-04-01

261

Targeted delivery of curcumin for treating type 2 diabetes.  

PubMed

Type 2 diabetes is a chronic condition in which cells have reduced insulin signalling, leading to hyperglycemia and long-term complications, including heart, kidney and liver disease. Macrophages activated by dying or stressed cells, induce the transcription factor nuclear factor kappa-B leading to the production of pro-inflammatory cytokines including TNF and IL-6. These inflammatory macrophages in liver and adipose tissue promote insulin resistance, and medications which reduce inflammation and enhance insulin signalling improve glucose control. Curcumin is an anti-oxidant and nuclear factor kappa-B inhibitor derived from turmeric. A number of studies have shown that dietary curcumin reduces inflammation and delays or prevents obesity-induced insulin resistance and associated complications, including atherosclerosis and immune mediate liver disease. Unfortunately dietary curcumin is poorly absorbed by the digestive system and undergoes glucuronidation and excretion rather than being released into the serum and systemically distributed. This confounds understanding of how dietary curcumin exerts its beneficial effects in type 2 diabetes and associated diseases. New improved methods of delivering curcumin are being developed including nanoparticles and lipid/liposome formulations that increase absorption and bioavailability of curcumin. Development and refinement of these technologies will enable cell-directed targeting of curcumin and improved therapeutic outcome. PMID:23495213

Maradana, Muralidhara Rao; Thomas, Ranjeny; O'Sullivan, Brendan J

2013-09-01

262

Nanomaterials for targeted drug delivery to cancer stem cells.  

PubMed

Recent developments in cancer biology have identified the existence of a sub-poplulation of cells - cancer stem cells (CSC) that are resistant to most traditional therapies (e.g. chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. These findings have necessitated a break with traditional oncology management and encouraged new perspectives concerning cancer treatment. Understanding the functional biology of CSCs - especially the signaling pathways that are involved in their self-renewal mechanisms - is crucial for discovering new forms of treatment. In this review, we highlight current and future prospects for potential cancer therapies based on the use of nano-sized materials. Nanomaterials could revolutionize cancer management because of their distinctive features - unique surface chemistry, strong electronic, optic, and magnetic properties - that are found neither in bulk materials nor in single molecules. Based on these distinct properties, we believe that nanomaterials could be excellent candidates for use in CSC research in order to optimize cancer therapeutics. Moreover, we propose these nanomaterials for the inhibition of the self-renewal pathways of CSCs by focusing on the Hedgehog, Notch, and Wnt/?-catenin self-renewal mechanisms. By introducing these methods for the detection, targeting, and destruction of CSCs, an efficient alternative treatment for the incurable disease of cancer could be provided. PMID:24697156

Orza, Anamaria; Casciano, Daniel; Biris, Alexandru

2014-05-01

263

Iron Oxide Nanoparticles as a Drug Delivery Vehicle for MRI Monitored Magnetic Targeting of Brain Tumors  

PubMed Central

This study explored the possibility of utilizing iron oxide nanoparticles as a drug delivery vehicle for minimally invasive, MRI-monitored magnetic targeting of brain tumors. In vitro determined hydrodynamic diameter of ~100nm, saturation magnetization of 94 emu/g Fe and T2 relaxivity of 43 s?1mM?1 of the nanoparticles suggested their applicability for this purpose. In vivo effect of magnetic targeting on the extent and selectivity of nanoparticle accumulation in tumors of rats harboring orthotopic 9L-gliosarcomas was quantified with MRI. Animals were intravenously injected with nanoparticles (12 mg Fe/kg) under a magnetic field density of 0 T (control) or 0.4 T (experimental) applied for 30 minutes. MR images were acquired prior to administration of nanoparticles and immediately after magnetic targeting at 1 hour intervals for 4 hours. Image analysis revealed that magnetic targeting induced a 5-fold increase in the total glioma exposure to magnetic nanoparticles over non-targeted tumors (p=0.005) and a 3.6-fold enhancement in the target selectivity index of nanoparticle accumulation in glioma over the normal brain (p=0.025). In conclusion, accumulation of iron oxide nanoparticles in gliosarcomas can be significantly enhanced by magnetic targeting and successfully quantified by MR imaging. Hence, these nanoparticles appear to be a promising vehicle for glioma-targeted drug delivery.

Chertok, Beata; Moffat, Bradford A.; David, Allan E.; Yu, Faquan; Bergemann, Christian; Ross, Brian D.; Yang, Victor C.

2009-01-01

264

Controlled antibody/(bio-) conjugation of inorganic nanoparticles for targeted delivery.  

PubMed

Arguably targeting is one of the biggest problems for controlled drug delivery. In the case that drugs can be directed with high efficiency to the target tissue, side effects of medication are drastically reduced. Colloidal inorganic nanoparticles (NPs) have been proposed and described in the last 10years as new platforms for in vivo delivery. However, though NPs can introduce plentiful functional properties (such as controlled destruction of tissue by local heating or local generation of free radicals), targeting remains an issue of intense research efforts. While passive targeting of NPs has been reported (the so-called enhanced permeation and retention, EPR effect), still improved active targeting would be highly desirable. One classical approach for active targeting is mediated by molecular recognition via capture molecules, i.e. antibodies (Abs) specific for the target. In order to apply this strategy for NPs, they need to be conjugated with Abs against specific biomarkers. Though many approaches have been reported in this direction, the controlled bioconjugation of NPs is still a challenge. In this article the strategies of controlled bioconjugation of NPs will be reviewed giving particular emphasis to the following questions: 1) how can the number of capture molecules per NP be precisely adjusted, and 2) how can the Abs be attached to NP surfaces in an oriented way. Solution of both questions is a cornerstone in controlled targeting of the inorganic NPs bioconjugates. PMID:23280372

Montenegro, Jose-Maria; Grazu, Valeria; Sukhanova, Alyona; Agarwal, Seema; de la Fuente, Jesus M; Nabiev, Igor; Greiner, Andreas; Parak, Wolfgang J

2013-05-01

265

Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation.  

PubMed

Multifunctional nanomedicine holds considerable promise as the next generation of medicine that allows for targeted therapy with minimal toxicity. Most current studies on Nanoparticle (NP) drug delivery consider a Newtonian fluid with suspending NPs. However, blood is a complex biological fluid composed of deformable cells, proteins, platelets, and plasma. For blood flow in capillaries, arterioles and venules, the particulate nature of the blood needs to be considered in the delivery process. The existence of the cell-free-layer and NP-cell interaction will largely influence both the dispersion and binding rates, thus impact targeted delivery efficacy. In this paper, a particle-cell hybrid model is developed to model NP transport, dispersion, and binding dynamics in blood suspension. The motion and deformation of red blood cells is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell-particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of red blood cells, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increases as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications. PMID:22375153

Tan, Jifu; Thomas, Antony; Liu, Yaling

2011-12-22

266

Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation  

PubMed Central

Multifunctional nanomedicine holds considerable promise as the next generation of medicine that allows for targeted therapy with minimal toxicity. Most current studies on Nanoparticle (NP) drug delivery consider a Newtonian fluid with suspending NPs. However, blood is a complex biological fluid composed of deformable cells, proteins, platelets, and plasma. For blood flow in capillaries, arterioles and venules, the particulate nature of the blood needs to be considered in the delivery process. The existence of the cell-free-layer and NP-cell interaction will largely influence both the dispersion and binding rates, thus impact targeted delivery efficacy. In this paper, a particle-cell hybrid model is developed to model NP transport, dispersion, and binding dynamics in blood suspension. The motion and deformation of red blood cells is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell-particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of red blood cells, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increases as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications.

Tan, Jifu; Thomas, Antony; Liu, Yaling

2012-01-01

267

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

PubMed

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. PMID:24882040

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

2014-06-12

268

Targeted delivery of EV peptide to tumor cell cytoplasm using lipid coated calcium carbonate nanoparticles.  

PubMed

Intracellular-acting peptide drugs are effective for inhibiting cytoplasmic protein targets, yet face challenges with penetrating the cancer cell membrane. We have developed a lipid nanoparticle formulation that utilizes a pH-sensitive calcium carbonate complexation mechanism to enable the targeted delivery of the intracellular-acting therapeutic peptide EEEEpYFELV (EV) into lung cancer cells. Lipid-calcium-carbonate (LCC) nanoparticles were conjugated with anisamide, a targeting ligand for the sigma receptor which is expressed on lung cancer cells. LCC EV nanoparticle treatment provoked severe apoptotic effects in H460 non-small cell lung cancer cells in vitro. LCC NPs also mediated the specific delivery of Alexa-488-EV peptide to tumor tissue in vivo, provoking a high tumor growth retardation effect with minimal uptake by external organs and no toxic effects. PMID:22796364

Kim, Sang Kyoon; Foote, Michael B; Huang, Leaf

2013-07-01

269

MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation  

PubMed Central

Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the “first-pass” accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

Kean, Thomas J.; Caplan, Arnold I.; Dennis, James E.

2013-01-01

270

Dual-Modality Monitoring of Targeted Intraarterial Delivery of Mesenchymal Stem Cells After Transient Ischemia  

PubMed Central

Background and Purpose In animal models of stroke, functional improvement has been obtained after stem cell transplantation. Successful therapy depends largely on achieving a robust and targeted cell engraftment, with intraarterial (IA) injection being a potentially attractive route of administration. We assessed the suitability of laser Doppler flow (LDF) signal measurements and magnetic resonance (MR) imaging for noninvasive dual monitoring of targeted IA cell delivery. Methods Transient cerebral ischemia was induced in adult Wistar rats (n = 25) followed by IA or intravenous (IV) injection of mesenchymal stem cells (MSCs) labeled with superparamagnetic iron oxide. Cell infusion was monitored in real time with transcranial laser Doppler flowmetry while cellular delivery was assessed with MRI in vivo (4.7T) and ex vivo (9.4T). Results Successful delivery of magnetically labeled MSCs could be readily visualized with MRI after IA but not IV injection. IA stem cell injection during acute stroke resulted in a high variability of cerebral engraftment. The amount of LDF reduction during cell infusion (up to 80%) was found to correlate well with the degree of intracerebral engraftment, with low LDF values being associated with significant morbidity. Conclusions High cerebral engraftment rates are associated with impeded cerebral blood flow. Noninvasive dual-modality imaging enables monitoring of targeted cell delivery, and through interactive adjustment may improve the safety and efficacy of stem cell therapy.

Walczak, Piotr; Zhang, Jian; Gilad, Assaf A.; Kedziorek, Dorota A.; Ruiz-Cabello, Jesus; Young, Randell G.; Pittenger, Mark F.; van Zijl, Peter C.M.; Huang, Judy; Bulte, Jeff W.M.

2010-01-01

271

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

NASA Astrophysics Data System (ADS)

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 reduce toxicity by increasing targeted delivery towards malignant cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00019f

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

272

Dual-functional liposomes based on pH-responsive cell-penetrating peptide and hyaluronic acid for tumor-targeted anticancer drug delivery.  

PubMed

Dual-functional liposomes with pH-responsive cell-penetrating peptide (CPP) and active targeting hyaluronic acid (HA) were fabricated for tumor-targeted drug delivery. A series of synthetic tumor pH-triggered CPPs rich in arginines and histidines were screened by comparing tumor cellular uptake efficiency at pH 6.4 with at pH 7.4, and R6H4 (RRRRRRHHHH) was obtained with the optimal pH-response. To construct R6H4-modified liposomes (R6H4-L), stearyl R6H4 was anchored into liposomes due to hydrophobic interaction. HA was utilized to shield positive charge of R6H4-L to assemble HA-coated R6H4-L (HA-R6H4-L) by electrostatic effect for protecting the liposomes from the attack of plasma proteins. The rapid degradation of HA by hyaluronidase (HAase) was demonstrated by the viscosity and zeta potential detection, allowing the R6H4 exposure of HA-R6H4-L at HAase-rich tumor microenvironment as the protection by HA switches off and cell-penetrating ability of R6H4 turns on. After HAase treatment, paclitaxel-loaded HA-R6H4-L (PTX/HA-R6H4-L) presented a remarkably stronger cytotoxicity toward the hepatic cancer (HepG2) cells at pH 6.4 relative to at pH 7.4, and additionally coumarin 6-loaded HA-R6H4-L (C6/HA-R6H4-L) showed efficient intracellular trafficking including endosomal/lysosomal escape and cytoplasmic liberation by confocal laser scanning microscopy (CLSM). In vivo imaging suggested the reduced accumulation of near infrared dye 15 (NIRD15)-loaded HA-R6H4-L (NIRD/HA-R6H4-L) at the tumor site, when mice were pre-treated with an excess of free HA, indicating the active tumor targeting of HA. Indeed, PTX/HA-R6H4-L had the strongest antitumor efficacy against murine hepatic carcinoma (Heps) tumor xenograft models in vivo. These findings demonstrate the feasibility of using tumor pH-sensitive CPPs and active targeting HA to extend the applications of liposomal nanocarriers to efficient anticancer drug delivery. PMID:23031530

Jiang, Tianyue; Zhang, Zhenhai; Zhang, Yinlong; Lv, Huixia; Zhou, Jianping; Li, Caocao; Hou, Lulu; Zhang, Qiang

2012-12-01

273

Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel.  

PubMed

It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p. and i.v. dosing. Patients received an i.p. tracer dose of [G-(3)H]paclitaxel in ethanol without CrEL (100 microCi diluted further in isotonic saline) on day 1, i.p. paclitaxel formulated in CrEL (Taxol; 125 mg/m(2)) on day 4, an i.v. tracer of [G-(3)H]paclitaxel on day 22, and i.v. Taxol (175 mg/m(2)) on day 24. Four patients (age range, 54-74 years) were studied, and serial plasma samples up to 72 h were obtained and analyzed for total radioactivity, paclitaxel, and CrEL. In the presence of CrEL, i.v. paclitaxel clearance was 10.2 +/- 3.76 liters/h/m(2) (mean +/- SD), consistent with previous findings. The terminal disposition half-life was substantially prolonged after i.p. dosing (17.0 +/- 11.3 versus 28.7 +/- 8.72 h), as was the mean residence time (7.28 +/- 2.76 versus 40.7 +/- 13.8 h). The bioavailability of paclitaxel was 31.4 +/- 5.18%, indicating insignificant systemic concentrations after i.p. treatment. CrEL levels were undetectable after i.p. dosing (<0.05 microl/ml), whereas after i.v. dosing, the mean clearance was 159 +/- 58.4 ml/h/m(2), in line with earlier observations. In the absence of CrEL, the bioavailability and systemic concentrations of i.p. paclitaxel were significantly increased. This finding is consistent with the postulated concept that CrEL is largely responsible for the pharmacokinetic advantage for peritoneal cavity exposure to total paclitaxel compared with systemic delivery. PMID:11948138

Gelderblom, Hans; Verweij, Jaap; van Zomeren, Desirée M; Buijs, Dirk; Ouwens, Linda; Nooter, Kees; Stoter, Gerrit; Sparreboom, Alex

2002-04-01

274

Molecular design and nanoparticle-mediated intracellular delivery of functional proteins to target cellular pathways  

NASA Astrophysics Data System (ADS)

Intracellular delivery of specific proteins and peptides represents a novel method to influence stem cells for gain-of-function and loss-of-function. Signaling control is vital in stem cells, wherein intricate control of and interplay among critical pathways directs the fate of these cells into either self-renewal or differentiation. The most common route to manipulate cellular function involves the introduction of genetic material such as full-length genes and shRNA into the cell to generate (or prevent formation of) the target protein, and thereby ultimately alter cell function. However, viral-mediated gene delivery may result in relatively slow expression of proteins and prevalence of oncogene insertion into the cell, which can alter cell function in an unpredictable fashion, and non-viral delivery may lead to low efficiency of genetic delivery. For example, the latter case plagues the generation of induced pluripotent stem cells (iPSCs) and hinders their use for in vivo applications. Alternatively, introducing proteins into cells that specifically recognize and influence target proteins, can result in immediate deactivation or activation of key signaling pathways within the cell. In this work, we demonstrate the cellular delivery of functional proteins attached to hydrophobically modified silica (SiNP) nanoparticles to manipulate specifically targeted cell signaling proteins. In the Wnt signaling pathway, we have targeted the phosphorylation activity of glycogen synthase kinase-3beta (GSK-3beta) by designing a chimeric protein and delivering it in neural stem cells. Confocal imaging indicates that the SiNP-chimeric protein conjugates were efficiently delivered to the cytosol of human embryonic kidney cells and rat neural stem cells, presumably via endocytosis. This uptake impacted the Wnt signaling cascade, indicated by the elevation of beta-catenin levels, and increased transcription of Wnt target genes, such as c-MYC. The results presented here suggest that functional proteins can be delivered intracellularly in vitro using nanoparticles and used to target key signaling proteins and regulate cell signaling pathways. The same concept of naturally occurring protein-protein interactions can also be implemented to selectively bring intracellular protein targets in close proximity to proteasomal degradation machinery in cells and effect their depletion from the cellular compartments. This approach will be able to not only target entire pool of proteins to ubiquitination-mediated degradation, but also to specific sub-pools of posttranslationally modified proteins in the cell, provided peptides having distinct binding affinities are identified for posttranslational modifications. This system can then be tested for intracellular protein delivery using nanoparticle carriers to identify roles of different posttranslational modifications on the protein's activity. In future work, we propose to develop a cellular detection system, based on GFP complementation, which can be used to evaluate the efficiency of different protein delivery carriers to internalize proteins into the cell cytosol. We envision the application of nanoscale materials as intracellular protein delivery vehicles to target diverse cell signaling pathways at the posttranslational level, and subsequent metabolic manipulation, which may have interesting therapeutic properties and can potentially target stem cell fate.

Shah, Dhiral Ashwin

275

Targeted drug delivery for cancer therapy: the other side of antibodies  

PubMed Central

Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients.

2012-01-01

276

Folate-polyethylene glycol conjugated carboxymethyl chitosan for tumor-targeted delivery of 5-fluorouracil.  

PubMed

Targeted drug delivery has been evolving at an increasing rate due to its potential to reduce the minimum effective dose of a drug and its accompanying side effects. It has shown improved therapeutic efficacy at equivalent plasma concentrations; however, the development of effective targeted delivery systems has remained a major task. In this study, a drug carrier was designed and synthesized by conjugation of folate acid (FA) to carboxymethyl chitosan (CMCS) through a polyethylene glycol (PEG) spacer. The resulting conjugates were confirmed by 1H nuclear magnetic resonance and infrared spectroscopy. The cytotoxicity of CMCS and CMCS?5?fluorouracil (5?FU) was determined by a crystal violet stain assay. The potential of CMCS?PEG?FA for use in the targeted delivery of 5?FU was investigated using 3?(4,5?dimethylthiazol?2?yl)?2,5?diphenyltetrazolium bromide analysis in two cell lines, HeLa and A549, which contain different numbers of folate receptors on their surfaces. The MTT results revealed that in HeLa cells, the cytotoxicity of (CMCS?5?FU)?PEG?FU cells is greater compared with CMCS?5?FU, suggesting that folate receptor?mediated endocytosis may affect the cellular uptake efficiency of 5?FU?loaded CMCS?PEG?FA. The CMCS?PEG?FA conjugates presented in this study show promise as carriers for chemotherapeutic agents due to their solubility at physiological pH, efficiency in carrying chemotherapeutic agents, low cytotoxicity and targeting ability. PMID:24469407

Li, Hai-Lang; He, Ya-Xing; Gao, Qian-Hong; Wu, Guo-Zhong

2014-03-01

277

Tumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery.  

PubMed

Introduction: Cancer cells acclimatize to the harsh tumor microenvironment by altering cellular metabolism in favor of aerobic glycolysis. This process provides a source of energy and also generates essential components for macromolecular biosynthesis, which enables cellular survival. As the dependence of cancer cells on glycolysis affects tumorigenesis, it has become an attractive target for therapeutic intervention. Several preclinical studies have shown the effectiveness of using biological targets from the glycolytic pathway for anticancer therapy. Areas covered: This review provides an insight into the glycolytic pathway, highlighting potential targets for glycolytic inhibition. We then discuss recent advancement in delivery strategies that have the potential to circumvent some of the problems posed by current glycolytic inhibitors, enabling resurrection of abandoned therapeutic agents. Expert opinion: Targeting the glycolysis pathway is a tactical approach for cancer therapy. However, the current nonspecific therapeutic strategies have several drawbacks such as poor bioavailability, unfavorable pharmacokinetic profile and associated nonspecific toxicity, thereby limiting preclinical investigation. In recent years, nanoparticle systems have received recognition for the delivery of therapeutic agents directly to the tumor tissue. Thus, it is envisaged that this strategy can be expanded for the delivery of current glycolytic inhibitors specifically to tumor tissues providing improved anticancer activity. PMID:24762115

Talekar, Meghna; Boreddy, Srinivas Reddy; Singh, Amit; Amiji, Mansoor

2014-08-01

278

Targeted delivery of small interfering RNA to angiogenic endothelial cells with liposome-polycation-DNA particles.  

PubMed

Angiogenesis is an attractive target for cancer therapy, due to its central position in tumor growth and development. Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFRs) play a key role in the angiogenic process. A promising strategy for targeting VEGF-mediated angiogenesis is RNA interference (RNAi) using short interfering RNA (siRNA). However, for efficacious RNAi a well-designed siRNA delivery system is crucial. Liposome-Polycation-DNA (LPD) particles form a promising system for siRNA delivery to tumors. In order to target angiogenic endothelial cells, LPD particles may be modified with a targeting ligand, such as a cyclic Arg-Gly-Asp (RGD) peptide that specifically binds to integrins expressed on tumor-associated endothelial cells. In the current study, RGD-targeted PEGylated LPD particles containing VEGFR-2 siRNA were prepared and optimized with respect to their size and charge by varying protamine content, carrier DNA content for stronger complexation, and PEGylation density. The size of the optimized particles was around 200 nm and the ?-potential was approximately +20 mV. The uptake and silencing efficacy of the RGD-targeted PEGylated LPD particles were evaluated in H5V cells (murine endothelial cells) and Human Umbilical Vein Endothelial cells (HUVECs). When compared to non-targeted LPD particles, enhanced uptake and silencing of VEGFR-2 expression was observed for RGD-targeted PEGylated LPD particles. In conclusion, the RGD-targeted PEGylated LPD particles containing VEGFR-2 siRNA presented here may be a promising approach for targeting VEGF-mediated angiogenesis in cancer therapy. PMID:21983283

Vader, P; Crielaard, B J; van Dommelen, S M; van der Meel, R; Storm, G; Schiffelers, R M

2012-06-10

279

LHRH-targeted nanogels as a delivery system for cisplatin to ovarian cancer.  

PubMed

Targeted drug delivery using multifunctional polymeric nanocarriers is a modern approach for cancer therapy. Our purpose was to prepare targeted nanogels for selective delivery of chemotherapeutic agent cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor overexpressing tumor in vivo. Building blocks of such delivery systems consisted of innovative soft block copolymer nanogels with ionic cores serving as a reservoir for cisplatin (loading 35%) and a synthetic analogue of LHRH conjugated to the nanogels via poly(ethylene glycol) spacer. Covalent attachment of (D-Lys6)-LHRH to nanogels was shown to be possible without loss in either the ligand binding affinity or the nanogel drug incorporation ability. LHRH-nanogel accumulation was specific to the LHRH-receptor positive A2780 ovarian cancer cells and not toward LHRH-receptor negative SKOV-3 cells. The LHRH-nanogel cisplatin formulation was more effective and less toxic than equimolar doses of free cisplatin or untargeted nanogels in the treatment of receptor-positive ovarian cancer xenografts in mice. Collectively, the study indicates that LHRH mediated nanogel-cisplatin delivery is a promising formulation strategy for therapy of tumors that express the LHRH receptor. PMID:23957812

Nukolova, Natalia V; Oberoi, Hardeep S; Zhao, Yi; Chekhonin, Vladimir P; Kabanov, Alexander V; Bronich, Tatiana K

2013-10-01

280

Surface-Engineered Targeted PPI Dendrimer for Efficient Intracellular and Intratumoral siRNA Delivery  

PubMed Central

Low penetration ability of Small Interfering RNA (siRNA) through the cellular plasma membrane combined with its limited stability in blood, limits the effectiveness of the systemic delivery of siRNA. In order to overcome such difficulties, we constructed a nanocarrier-based delivery system by taking advantage of the lessons learned from the problems in the delivery of DNA. In the present study, siRNA nanoparticles were first formulated with Poly(Propyleneimine) (PPI) dendrimers. To provide lateral and steric stability to withstand the aggressive environment in the blood stream, the formed siRNA nanoparticles were caged with a dithiol containing cross-linker molecules followed by coating them with Poly(Ethylene Glycol) (PEG) polymer. A synthetic analog of Luteinizing Hormone-Releasing Hormone (LHRH) peptide was conjugated to the distal end of PEG polymer to direct the siRNA nanoparticles specifically to the cancer cells. Our results demonstrated that this layer-by-layer modification and targeting approach confers the siRNA nanoparticles stability in plasma and intracellular bioavailability, provides for their specific uptake by tumor cells, accumulation of siRNA in the cytoplasm of cancer cells, and efficient gene silencing. In addition, in vivo body distribution data confirmed high specificity of the proposed targeting delivery approach which created the basis for the prevention of adverse side effects of the treatment on healthy organs.

Taratula, Oleh; Garbuzenko, Olga B.; Kirkpatrick, Paul; Pandya, Ipsit; Savla, Ronak; Pozharov, Vitaly P.; He, Huixin; Minko, Tamara

2009-01-01

281

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

PubMed Central

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.

Taranta, Monia; Naldi, Ilaria

2011-01-01

282

Synthesis and evaluation of folate-based chlorambucil delivery systems for tumor-targeted chemotherapy.  

PubMed

The development of tumor-targeting drug delivery systems, able to selectively transport cytotoxic agents into the tumor site by exploiting subtle morphological and physiological differences between healthy and malignant cells, currently stands as one of the most attractive anticancer strategies used to overcome the selectivity problems of conventional chemotherapy. Owing to frequent overexpression of folate receptors (FRs) on the surface of malignant cells, conjugation of cytotoxic agents to folic acid (FA) via suitable linkers have demonstrated to enhance selective drug delivery to the tumor site. Herein, the chemical synthesis and biological evaluation of two novel folate-conjugates bearing the anticancer agent chlorambucil (CLB) tethered to either an aminoether (4,7,10-trioxa-1,13-tridecanediamine) or a pseudo-?-dipeptide (?-Ala-ED-?-Ala) linker is reported. The two drug delivery systems have been prepared in high overall yields (54% and 34%) through straightforward and versatile synthetic routes. Evaluation of cell specificity was examined using three leukemic cell lines, undifferentiated U937 (not overexpressing FRs, FR(-)), TPA-differentiated U937 (overexpressing FRs, FR(+)), and TK6 (FR(+)) cells. Both conjugates exhibited high specificity only to FR(+) cells (particularly TK6), demonstrating comparable antitumor activity to CLB in its free form. These data confirm the reliability of folate-based drug delivery systems for targeted antitumor therapy; likewise, they lay the foundations for the development of other folate-conjugates with antitumor potential. PMID:22121907

Guaragna, Annalisa; Chiaviello, Angela; Paolella, Concetta; D'Alonzo, Daniele; Palumbo, Giuseppe; Palumbo, Giovanni

2012-01-18

283

Characterization and in vitro assessment of paclitaxel loaded lipid nanoparticles formulated using modified solvent injection technique.  

PubMed

This study investigates the design and characterization of solid lipid nanoparticles (SLNs) containing paclitaxel fabricated by a modified solvent injection technique using stearic acid as lipid and stabilized by a mixture of surfactants, for future evaluation of this colloidal carrier system for the oral delivery of paclitaxel, devoid of the side effects of Cremophor EL. SLN formulations of paclitaxel stabilized by mixture of surfactants i.e. lecithin/poloxamer 188 were developed with smaller size and narrow size distribution. The paclitaxel-loaded SLNs exhibited spherical shape with smooth surface as analyzed by transmission electron microscopy (TEM). The average particle size obtained through this method was found to be approximately 113 nm. The zeta potential was between -32 and -39 mV with poloxamer 188. Encapsulation efficiencies of about 72.18 +/- 3.7 and 89.0 +/- 2.4% were achieved using 0.05 and 0.25 mmol of paclitaxel, respectively. Paclitaxel showed a sustained in vitro release profile and was found to follow Higuchi kinetic equations. In vitro cytotoxicity assay confirmed that paclitxel entrapped in SLNs showed higher cytotoxicity against cultured hepatocelluler carcinoma cells than paclitaxel alone. The modified solvent injection technique used in this research proved to be a simple, easily available and effective method to produce SLNs and could be used for controlled delivery of different lipophilic drugs for cancer chemotherapy. PMID:19530440

Pandita, D; Ahuja, A; Velpandian, T; Lather, V; Dutta, T; Khar, R K

2009-05-01

284

DMLC IMRT delivery to targets moving in 2D in Beam's eye view.  

PubMed

The goal of this article is to present the algorithm for DMLC leaf control capable of delivering IMRT to tumors that experience motion in two dimensions in the beams eye view (BEV) plane. The generic, two-dimensional (2D) motion of the projection of the rigid target on BEV plane can be divided into two components. The first component describes the motion of the projection of the target along the x axis (parallel to the MLC leaf motions) and the other describes the motion of the target projection on the y axis (perpendicular to the leaf motion direction). First, time optimal leaf trajectories are calculated independently for each leaf pair of the MLC assembly to compensate the x-axis component of the 2D motion of the target on the BEV. These leaf trajectories are then synchronized following the mid time (MT) synchronization procedure. To compensate for the y-axis component of the motion of the target projection on the BEV plane, the procedure of "switching" leaf pair trajectories in the upward (or downward) direction is executed when the target's BEV projection moves upward (or downward) from its equilibrium position along the y axis. When the intensity function is a 2D histogram, the error between the intended and delivered intensity in 2D DMLC IMRT delivery will depend on the shape of the intensity map and on the MLC physical constraint (leaf width and maximum admissible leaf speed). The MT synchronization of leaf trajectories decreases the impact of above constraints on the error in 2D DMLC IMRT intensity map delivery. The proof is provided, that if hardware constraints in the 2D DMLC IMRT delivery strategy are removed, the errors between planned and delivered 2D intensity maps are entirely eliminated. Examples of 2D DMLC IMRT delivery to rigid targets moving along elliptical orbits on BEV planes are calculated and analyzed for 20 clinical fluence maps. The comparisons between the intensity delivered without motion correction, with motion correction along x axis only, and with motion correction for full 2D motion of the target are calculated and quantitatively evaluated. The fluence maps were normalized to 100 MU and the rms difference between the desired and delivered fluence was 12 MU for no motion compensation, 11.18 MU for 1D compensation, and 4.73 MU for 2D motion compensations. The advantage of correcting for full 2D motion of target projected on the BEV plane is demonstrated. PMID:18777936

Rangaraj, Dharanipathy; Palaniswaamy, Geethpriya; Papiez, Lech

2008-08-01

285

Targetable micelleplex hydrogel for long-term, effective, and systemic siRNA delivery.  

PubMed

We developed a targetable micelleplex hydrogel as a new efficient systemic siRNA delivery material that functions as a targetable gene carrier, and a hydrogel capable of controlled release to overcome drawbacks of multiple administrations of systemic siRNA carriers due to decreased fluctuation of them in the serum. The micelleplexes, complexes between polymeric micelles and siRNAs could turn into gel after subcutaneous injection and be slowly released from the gel. The released micelleplexes selectively accumulated in the tumor and showed anti-tumor effect due to gene silencing for an extended period of time with only one injection in anywhere in vivo model. Moreover, the duration of therapy can be controlled by adjusting the amount and properties of the hydrogel. Therefore, this micelleplex hydrogel is expected to be a new effective siRNA delivery material for systemic long-term gene silencing. PMID:24951047

Kim, Young-Min; Song, Soo-Chang

2014-09-01

286

Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges.  

PubMed

Dysregulation of miRNA expression has been associated with many cardiovascular diseases in animal models, as well as in patients. In the present review, we summarize recent findings on the role of miRNAs in cardiovascular diseases and discuss the opportunities, possibilities and challenges of using miRNAs as future therapeutic targets. Furthermore, we focus on the different approaches that can be used to deliver these newly developed miRNA therapeutics to their sites of action. Since siRNAs are structurally homologous with the miRNA therapeutics, important lessons learned from siRNA delivery strategies are discussed that might be applicable to targeted delivery of miRNA therapeutics, thereby reducing costs and potential side effects, and improving efficacy. PMID:24895056

Kwekkeboom, Rick F J; Lei, Zhiyong; Doevendans, Pieter A; Musters, René J P; Sluijter, Joost P G

2014-09-01

287

Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration  

PubMed Central

Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically.

Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin

2013-01-01

288

Occlusion of retinal vessels using targeted delivery of a platelet aggregating agent.  

PubMed Central

Local laser targeted delivery of a platelet aggregating agent to occlude retinal and choroidal vessels was evaluated in rabbits and rats. Liposomes containing adenosine diphosphate (ADP) were administered intravenously and an argon laser was used to lyse the liposomes in main retinal arteries. Control vessels were treated with the same energy of laser without administering ADP. Fluorescein angiography performed 2 weeks later showed that all the control vessels were perfused. Ninety percent of the ADP-treated arteries showed complete or partial occlusion. Successful occlusion increased with the laser energy and decreased with increasing vessel diameter. Histopathology showed that occlusion was achieved in retinal as well as choroidal vessels. The inner retina remained relatively unaffected at the treatment site but the outer retina was thermally damaged. These preliminary results suggest that targeted delivery of a platelet aggregating agent holds promise for occluding vessels in the fundus. Images

Ogura, Y; Guran, T; Takahashi, K; Zeimer, R

1993-01-01

289

DNA nanoflowers for multiplexed cellular imaging and traceable targeted drug delivery.  

PubMed

We present a facile approach to make aptamer-conjugated FRET (fluorescent resonance energy transfer) nanoflowers (NFs) through rolling circle replication for multiplexed cellular imaging and traceable targeted drug delivery. The NFs can exhibit multi-fluorescence emissions by a single-wavelength excitation as a result of the DNA matrix covalently incorporated with three dye molecules able to perform FRET. Compared with the conventional DNA nanostructure assembly, NF assembly is independent of template sequences, avoiding the otherwise complicated design of DNA building blocks assembled into nanostructures by base-pairing. The NFs were uniform and exhibited high fluorescence intensity and excellent photostability. Combined with the ability of traceable targeted drug delivery, these colorful DNA NFs provide a novel system for applications in multiplex fluorescent cellular imaging, effective screening of drugs, and therapeutic protocol development. PMID:24753303

Hu, Rong; Zhang, Xiaobing; Zhao, Zilong; Zhu, Guizhi; Chen, Tao; Fu, Ting; Tan, Weihong

2014-06-01

290

In Vivo PEG-Modification of Vascular Surfaces for Targeted Delivery  

PubMed Central

Objective Thrombosis and restenosis remain problematic for many intravascular procedures. Previously, it has been demonstrated that modifying an injured vascular surface with a protein-reactive polymer could block undesirable platelet deposition. As an added benefit, it would be advantageous if one could target therapeutics to the injured site. This study investigates a site-specific delivery system to target microspheres to vascular surfaces modified with a reactive polyethylene glycol tagged with biotin. Methods Rabbit femoral arteries were injured with a 2F embolectomy catheter. Modification of the vascular surface was achieved using a channeled balloon catheter or small diameter tube. Microspheres were injected intravenously through catheterization of the ear vein. Polymer modification on the injured surface and delivery of microspheres was quantified using epi-fluorescence microscopy at 0, 24, 48, and 72 h. Results Polymer modification of the vascular surface could be achieved using a channeled drug delivery catheter or small diameter tube with similar results. Maximum polymer coverage occurred at 0 h and decreased to 85% maximal at 24 h, 72% at 48 h, and 67% at 72 h. The initial number of microspheres per mm2 binding to modified, injured arteries was 304 versus 141 for the unmodified, damaged control (P < .01). At subsequent times, the number of adherent microspheres to modified, injured arteries decreased by 50%, 70%, and 84% at 24, 48, and 72 h, respectively; while non-specific binding to unmodified, injured arteries quickly decreased by 93%. Initial microsphere binding to modified, healthy arteries was 153 microspheres/mm2 as opposed to 26 for the unmodified, healthy controls (P < .01). Conclusions Chemical modification of injured vessels following intravascular procedures can be readily accomplished in vivo to create a substrate for targeted delivery systems. As a proof of concept, targeted microspheres preferentially adhered to polymer-modified surfaces as opposed to injured, unmodified or healthy vascular surfaces.

Deglau, Timothy E.; Maul, Timothy M.; Villanueva, Flordeliza S.; Wagner, William R.

2011-01-01

291

Targeted Delivery of RNAi Therapeutics With Endogenous and Exogenous Ligand-Based Mechanisms  

Microsoft Academic Search

Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) to hepatocytes in vivo; however, the precise mechanism by which this efficient delivery occurs has yet to be elucidated. We found that apolipoprotein E (apoE), which plays a major role in the clearance and hepatocellular uptake of physiological lipoproteins, also acts as an endogenous targeting ligand

Akin Akinc; William Querbes; Soma De; June Qin; Maria Frank-Kamenetsky; K. Narayanannair Jayaprakash; Muthusamy Jayaraman; Kallanthottathil G Rajeev; William L Cantley; J Robert Dorkin; James S Butler; LiuLiang Qin; Timothy Racie; Andrew Sprague; Eugenio Fava; Anja Zeigerer; Michael J Hope; Marino Zerial; Dinah WY Sah; Kevin Fitzgerald; Mark A Tracy; Muthiah Manoharan; Victor Koteliansky; Antonin de Fougerolles; Martin A Maier

2010-01-01

292

A smart multifunctional nanocomposite for intracellular targeted drug delivery and self-release  

NASA Astrophysics Data System (ADS)

A multifunctional 'all-in-one' nanocomposite is fabricated using a colloid, template and surface-modification method. This material encompasses magnetic induced target delivery, cell uptake promotion and controlled drug release in one system. The nanocomposite is characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, N2 adsorption and vibrating sample magnetometry. The prepared material has a diameter of 350-400 nm, a high surface area of 420.29 m2 g - 1, a pore size of 1.91 nm and a saturation magnetization of 32 emu g - 1. Doxorubicin (DOX) is loaded in mesopores and acid-sensitive blockers are introduced onto the orifices of the mesopores by a Schiff base linker to implement pH-dependent self-release. Folate was also introduced to improve DOX targeted delivery and endocytosis. The linkers remained intact to block pores with ferrocene valves and inhibit the diffusion of DOX at neutral pH. However, in lysosomes of cancer cells, which have a weak acidic pH, hydrolysis of the Schiff base group removes the nanovalves and allows the trapped DOX to be released. These processes are demonstrated by UV-visible absorption spectra, confocal fluorescence microscopy images and methyl thiazolyl tetrazolium assays in vitro, which suggest that the smart nanocomposite successfully integrates targeted drug delivery with internal stimulus induced self-release and is a potentially useful material for nanobiomedicine.

Wang, Chan; Lv, Piping; Wei, Wei; Tao, Shengyang; Hu, Tao; Yang, Jingbang; Meng, Changgong

2011-10-01

293

Formulation design for target delivery of iron nanoparticles to TCE zones  

NASA Astrophysics Data System (ADS)

Nanoparticles of zero-valent iron (NZVI) are effective reducing agents for some dense non-aqueous phase liquid (DNAPL) contaminants such as trichloroethylene (TCE). However, target delivery of iron nanoparticles to DNAPL zones in the aquifer remains an elusive feature for NZVI technologies. This work discusses three strategies to deliver iron nanoparticles to DNAPL zones. To this end, iron oxide nanoparticles coated with oleate (OL) ions were used as stable analogs for NZVI. The OL-coated iron oxide nanoparticles are rendered lipophilic via (a) the addition of CaCl2, (b) acidification, or (c) the addition of a cationic surfactant, benzethonium chloride (BC). Mixtures of OL and BC show promise as a target delivery strategy due to the high stability of the nanoparticles in water, and their preferential partition into TCE in batch experiments. Column tests show that while the OL-BC coated iron oxide nanoparticles remain largely mobile in TCE-free columns, a large fraction of these particles are retained in TCE-contaminated columns, confirming the effectiveness of this target delivery strategy.

Wang, Ziheng; Acosta, Edgar

2013-12-01

294

Magnetic Nanoparticles as Intraocular Drug Delivery System to Target Retinal Pigmented Epithelium (RPE)  

PubMed Central

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species.

Giannaccini, Martina; Giannini, Marianna; Calatayud, M. Pilar; Goya, Gerardo F.; Cuschieri, Alfred; Dente, Luciana; Raffa, Vittoria

2014-01-01

295

Formulation design for target delivery of iron nanoparticles to TCE zones.  

PubMed

Nanoparticles of zero-valent iron (NZVI) are effective reducing agents for some dense non-aqueous phase liquid (DNAPL) contaminants such as trichloroethylene (TCE). However, target delivery of iron nanoparticles to DNAPL zones in the aquifer remains an elusive feature for NZVI technologies. This work discusses three strategies to deliver iron nanoparticles to DNAPL zones. To this end, iron oxide nanoparticles coated with oleate (OL) ions were used as stable analogs for NZVI. The OL-coated iron oxide nanoparticles are rendered lipophilic via (a) the addition of CaCl2, (b) acidification, or (c) the addition of a cationic surfactant, benzethonium chloride (BC). Mixtures of OL and BC show promise as a target delivery strategy due to the high stability of the nanoparticles in water, and their preferential partition into TCE in batch experiments. Column tests show that while the OL-BC coated iron oxide nanoparticles remain largely mobile in TCE-free columns, a large fraction of these particles are retained in TCE-contaminated columns, confirming the effectiveness of this target delivery strategy. PMID:24096200

Wang, Ziheng; Acosta, Edgar

2013-12-01

296

Realizing the Clinical Potential of Cancer Nanotechnology by Minimizing Toxicological and Targeted Delivery Concerns  

PubMed Central

Nanotechnology has the potential to make smart drugs that would be capable of targeting cancer but not normal cells and loading combinations of cooperating agents into a single nano-sized particle to more effectively treat this disease. However, to realize the full potential of this technology the negative aspects associated with these nanoparticles needs to be overcome. This review discusses concerns in the field limiting realization of the full clinical potential of this technology, which are toxicity and targeted delivery. Strategies to overcome these hurdles are also reviewed which could lead to attainment of the full clinical potential of this exciting technology.

Singh, Sanjay; Sharma, Arati; Robertson, Gavin P.

2013-01-01

297

Tumor Delivery of Chemotherapy Combined with Inhibitors of Angiogenesis and Vascular Targeting Agents  

PubMed Central

Numerous angiogenesis-vascular targeting agents have been admitted to the ranks of cancer therapeutics; most are used in polytherapy regimens. This review looks at recent progress and our own preclinical experience in combining angiogenesis inhibitors, mainly acting on VEGF/VEGFR pathways, and vascular targeting agents with conventional chemotherapy, discussing the factors that determine the outcome of these treatments. Molecular and morphological modifications of the tumor microenvironment associated with drug distribution and activity are reviewed. Modalities to improve drug delivery and strategies for optimizing combination therapy are examined.

Cesca, Marta; Bizzaro, Francesca; Zucchetti, Massimo; Giavazzi, Raffaella

2013-01-01

298

Mathematical Modeling and Optimization of Drug Delivery from Intratumorally Injected Microspheres  

Microsoft Academic Search

Purpose: Paclitaxel is a highly promising phase-sensitive antitumor drug that could conceivably be improved by extended lower dosing as opposed to intermittent higher dosing. Although intratumoral delivery of paclitaxel to the whole tumor at different loads and rates has already been achieved, determining an optimal release mode of paclitaxel for tumor eradication remains difficult. This study set out to rationally

Abraham Rami Tzafriri; Elyakum Itzhak Lerner; Moshe Flashner-Barak; Michael Hinchcliffe; Eli Ratner; Hanna Parnas

2005-01-01

299

Development of Multifunctional Nanoparticles for Targeted Drug Delivery and Non-invasive Imaging of Therapeutic Effect  

PubMed Central

Nanotechnology is a multidisciplinary scientific field undergoing explosive development. Nanometer-sized particles offer novel structural, optical and electronic properties that are not attainable with individual molecules or bulk solids. Advances in nanomedicine can be made by engineering biodegradable nanoparticles such as magnetic iron oxide nanoparticles, polymers, dendrimers and liposomes that are capable of targeted delivery of both imaging agents and anticancer drugs. This leads toward the concept and possibility of personalized medicine for the potential of early detection of cancer lesions, determination of molecular signatures of the tumor by non-invasive imaging and, most importantly, molecular targeted cancer therapy. Increasing evidence suggests that the nanoparticles, whose surface contains a targeting molecule that binds to receptors highly expressed in tumor cells, can serve as cancer image contrast agents to increase sensitivity and specificity in tumor detection. In comparison with other small molecule contrast agents, the advantage of using nanoparticles is their large surface area and the possibility of surface modifications for further conjugation or encapsulation of large amounts of therapeutic agents. Targeted nanoparticles ferry large doses of therapeutic agents into malignant cells while sparing the normal healthy cells. Such multifunctional nanodevices hold the promise of significant improvement of current clinical management of cancer patients. This review explores the development of nanoparticles for enabling and improving the targeted delivery of therapeutic agents, the potential of nanomedicine, and the development of novel and more effective diagnostic and screening techniques to extend the limits of molecular diagnostics providing point-of-care diagnosis and more personalized medicine.

Sajja, Hari Krishna; East, Michael P.; Mao, Hui; Wang, Andrew Y.; Nie, Shuming; Yang, Lily

2011-01-01

300

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides  

PubMed Central

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals.

Liu, Shuang

2008-01-01

301

Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapy.  

PubMed

Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water solubility and inadequate selectivity, which are encountered by numerous chemical therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water solubility without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepared and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 microM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated. PMID:19420486

Sun, Yun; Chen, Zhi-Long; Yang, Xiao-Xia; Huang, Peng; Zhou, Xin-Ping; Du, Xiao-Xia

2009-04-01

302

Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapy  

NASA Astrophysics Data System (ADS)

Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water solubility and inadequate selectivity, which are encountered by numerous chemical therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water solubility without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepared and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 µM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated.

Sun, Yun; Chen, Zhi-long; Yang, Xiao-xia; Huang, Peng; Zhou, Xin-ping; Du, Xiao-xia

2009-04-01

303

‘One-pot’ synthesis of multifunctional GSH–CdTe quantum dots for targeted drug delivery  

NASA Astrophysics Data System (ADS)

A novel quantum dots-based multifunctional nanovehicle (DOX-QD-PEG-FA) was designed for targeted drug delivery, fluorescent imaging, tracking, and cancer therapy, in which the GSH–CdTe quantum dots play a key role in imaging and drug delivery. To exert curative effects, the antineoplastic drug doxorubicin hydrochloride (DOX) was loaded on the GSH–CdTe quantum dots through a condensation reaction. Meanwhile, a polyethylene glycol (PEG) shell was introduced to wrap the DOX-QD, thus stabilizing the structure and preventing clearance and drug release during systemic circulation. To actively target cancer cells and prevent the nanovehicles from being absorbed by normal cells, the nanoparticles were further decorated with folic acid (FA), allowing them to target HeLa cells that express the FA receptor. The multifunctional DOX-QD-PEG-FA conjugates were simply prepared using the ‘one pot’ method. In vitro study demonstrated that this simple, multifunctional nanovehicle can deliver DOX to the targeted cancer cells and localize the nanoparticles. After reaching the tumor cells, the FA on the DOX-QD-PEG surface allowed folate receptor recognition and increased the drug concentration to realize a higher curative effect. This novel, multifunctional DOX-QD-PEG-FA system shows great potential for tumor imaging, targeting, and therapy.

Chen, Xiaoqin; Tang, Yajun; Cai, Bing; Fan, Hongsong

2014-06-01

304

Transferrin Receptor-Targeted Lipid Nanoparticles for Delivery of an Antisense Oligodeoxyribonucleotide against Bcl-2  

PubMed Central

Antisense oligonucleotide G3139-mediated down-regulation of Bcl-2 is a potential strategy for overcoming chemoresistance in leukemia. However, the limited efficacy shown in recent clinical trials calls attention to the need for further development of novel and more efficient delivery systems. In order to address this issue, transferrin receptor (TfR)-targeted, protamine-containing lipid nanoparticles (Tf-LNs) were synthesized as delivery vehicles for G3139. The LNs were produced by an ethanol dilution method and lipid-conjugated Tf ligand was then incorporated by a post-insertion method. The resulting Tf-LNs had a mean particle diameter of ~ 90 nm and G3139 loading efficiency of 90.4%. Antisense delivery efficiency of Tf-LNs was evaluated in K562, MV4-11 and Raji leukemia cell lines. The results showed that Tf-LNs were more effective than non-targeted LNs and free G3139 (p <0.05) in decreasing Bcl-2 expression (by up to 62% at the mRNA level in K562 cells) and in inducing caspase-dependent apoptosis. In addition, Bcl-2 down-regulation and apoptosis induced by Tf-LN G3139 were shown to be blocked by excess free Tf and thus were TfR-dependent. Cell lines with higher TfR expression also showed greater Bcl-2 down-regulation. Furthermore, upregulation of TfR expression in leukemia cells by iron chelator deferoxamine resulted in a further increase in antisense effect (up to 79% Bcl-2 reduction in K562 at the mRNA level) and in caspase-dependent apoptosis (by ~ 3-fold) by Tf-LN. Tf-LN mediated delivery combined with TfR up-regulation by deferoxamine appears to be a potentially promising strategy for enhancing the delivery efficiency and therapeutic efficacy of antisense oligonucleotides.

Yang, Xiaojuan; Koh, Chee Guan; Liu, Shujun; Pan, Xiaogang; Santhanam, Ramasamy; Yu, Bo; Peng, Yong; Pang, Jiuxia; Golan, Sharon; Talmon, Yeshayahu; Jin, Yan; Muthusamy, Natarajan; Byrd, John C.; Chan, Kenneth K.; Lee, L. James; Marcucci, Guido; Lee, Robert J.

2013-01-01

305

Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes.  

PubMed

The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in non-tumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8(+) T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436-47. ©2014 AACR. PMID:24795356

Jeanbart, Laura; Ballester, Marie; de Titta, Alexandre; Corthésy, Patricia; Romero, Pedro; Hubbell, Jeffrey A; Swartz, Melody A

2014-05-01

306

Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo.  

PubMed

To further increase the therapeutic activity of drugs known to act on intracellular target sites, in vivo drug delivery approaches must actively mediate the specific delivery of drug molecules to the subcellular site of action. We show here that surface modification of nanocarriers with mitochondriotropic triphenylphosphonium cations facilitates the efficient subcellular delivery of a model drug to mitochondria of mammalian cells and improves its activity in vitro and in vivo. PMID:18611058

Boddapati, Sarathi V; D'Souza, Gerard G M; Erdogan, Suna; Torchilin, Vladimir P; Weissig, Volkmar

2008-08-01

307

Preparation and biological activity of a paclitaxel-single-walled carbon nanotube complex.  

PubMed

Single-walled carbon nanotubes (SWCNTs) have unique transmembrane abilities. The huge superficial area and abundance of ? electrons confer SWCNTs perfect absorptive capability toward proteins, nucleates, and many drugs. These characteristics make SWCNTs a new and efficient drug carrier. The purpose of this study was to disperse SWCNTs in water and have paclitaxel absorbed onto them in order to construct an asparagine-glycine-arginine (NGR)-SWCNT-Paclitaxel complex as a targeting nanoparticle system. The NGR-SWCNT-Paclitaxel complex was systematically studied, and analytical methods, including spectrophotometry for SWCNTs and high-performance liquid chromatography for paclitaxel, were employed. The preparation and the prescription of the NGR-SWCNT-Paclitaxel complex lyophilized powder were investigated. MCF-7 cancer cells, Sprague-Dawley rats, and S180 tumor-bearing mice were used as experimental subjects to evaluate the in vitro and in vivo activity of NGR-SWCNT-Paclitaxel complex dispersion. The complex dispersion showed obvious inhibition activity against MCF-7 cancer cells. Within 1 h, the NGR-SWCNT-Paclitaxel complex could be transferred to cells, and sustained the release of drugs. In addition, the tumor and liver targeting and improved therapeutic effects of the NGR-SWCNT-Paclitaxel complex were confirmed. PMID:24668633

Fu, X D; Zhang, Y Y; Wang, X J; Shou, J X; Zhang, Z Z; Song, L J

2014-01-01

308

Tumor targeting RGD conjugated bio-reducible polymer for VEGF siRNA expressing plasmid delivery.  

PubMed

Targeted delivery of therapeutic genes to the tumor site is critical for successful and safe cancer gene therapy. The arginine grafted bio-reducible poly (cystamine bisacrylamide-diaminohexane, CBA-DAH) polymer (ABP) conjugated poly (amido amine) (PAMAM), PAM-ABP (PA) was designed previously as an efficient gene delivery carrier. To achieve high efficacy in cancer selective delivery, we developed the tumor targeting bio-reducible polymer, PA-PEG1k-RGD, by conjugating cyclic RGDfC (RGD) peptides, which bind ?v?3/5 integrins, to the PAM-ABP using polyethylene glycol (PEG, 1 kDa) as a spacer. Physical characterization showed nanocomplex formation with bio-reducible properties between PA-PEG1k-RGD and plasmid DNA (pDNA). In transfection assays, PA-PEG1k-RGD showed significantly higher transfection efficiency in comparison with PAM-ABP or PA-PEG1k-RAD in ?v?3/5 positive MCF7 breast cancer and PANC-1 pancreatic cancer cells. The targeting ability of PA-PEG1k-RGD was further established using a competition assay. To confirm the therapeutic effect, the VEGF siRNA expressing plasmid was constructed and then delivered into cancer cells using PA-PEG1k-RGD. PA-PEG1k-RGD showed 20-59% higher cellular uptake rate into MCF7 and PANC-1 than that of non-targeted polymers. In addition, MCF7 and PANC-1 cancer cells transfected with PA-PEG1k-RGD/pshVEGF complexes had significantly decreased VEGF gene expression (51-71%) and cancer cell viability (35-43%) compared with control. These results demonstrate that a tumor targeting bio-reducible polymer with an anti-angiogenic therapeutic gene could be used for efficient and safe cancer gene therapy. PMID:24894645

Kim, Hyun Ah; Nam, Kihoon; Kim, Sung Wan

2014-08-01

309

Evaluation of Interacavitary Chemotherapy Delivery for Treatment of Mammary Carcinoma.  

National Technical Information Service (NTIS)

This project evaluated paclitaxel chemotherapy delivery from a gel polymer system placed into a wound bed following conservative (marginal) surgical removal of human breast cancers grown in nude mice. This delivery method was shown to control local tumor ...

W. S. Dernell

2005-01-01

310

Evaluation of Intracavitary Chemotherapy Delivery for Treatment of Mammary Carcinoma.  

National Technical Information Service (NTIS)

This project will evaluate paclitaxel chemotherapy delivery from a gel polymer system placed into a wound bed following conservative (marginal) surgical removal of human breast cancers grown in nude mice. This delivery method is proposed to control local ...

W. S. Dernell

2004-01-01

311

Evaluation of Intracavitary Chemotherapy Delivery for Treatment of Mammary Carcinoma.  

National Technical Information Service (NTIS)

This project will evaluate paclitaxel chemotherapy delivery from a gel polymer system placed into a wound bed following conservative surgical removal of human breast cancers grown in nude mice. This novel delivery method is proposed to control local tumor...

W. S. Dernell

2003-01-01

312

Extracellularly activated nanocarriers: A new paradigm of tumor targeted drug delivery  

PubMed Central

One of the main goals of nanomedicine is to develop a nanocarrier that can selectively deliver anti-cancer drugs to the targeted tumors. Extensive efforts have resulted in several tumor-targeted nanocarriers, some of which are approved for clinical use. Most nanocarriers achieve tumor-selective accumulation through the enhanced permeability and retention effect. Targeting molecules such as antibodies, peptides, ligands, or nucleic acids attached to the nanocarriers further enhance their recognition and internalization by the target tissues. While both the stealth and targeting features are important for effective and selective drug delivery to the tumors, achieving both features simultaneously is often found to be difficult. Some of the recent targeting strategies have the potential to overcome this challenge. These strategies utilize the unique extracellular environment of tumors to change the long-circulating nanocarriers to release the drug or interact with cells in a tumor-specific manner. This review discusses the new targeting strategies with recent examples, which utilize the environmental stimuli to activate the nanocarriers. Traditional strategies for tumor-targeted nanocarriers are briefly discussed with an emphasis on their achievements and challenges.

Gullotti, Emily; Yeo, Yoon

2009-01-01

313

To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery  

Microsoft Academic Search

Because of the particular characteristics of the tumor microenvironment and tumor angiogenesis, it is possible to design drug delivery systems that specifically target anti-cancer drugs to tumors. Most of the conventional chemotherapeutic agents have poor pharmacokinetics profiles and are distributed non-specifically in the body leading to systemic toxicity associated with serious side effects. Therefore, the development of drug delivery systems

Fabienne Danhier; Olivier Feron; Véronique Préat

2010-01-01

314

Targeted delivery of antibiotics to intracellular chlamydial infections using PLGA nanoparticles.  

PubMed

Chlamydia trachomatis and Chlamydia pneumoniae are intracellular bacterial pathogens that have been shown to cause, or are strongly associated with, diverse chronic diseases. Persistent infections by both organisms are refractory to antibiotic therapy. The lack of therapeutic efficacy results from the attenuated metabolic rate of persistently infecting chlamydiae in combination with the modest intracellular drug concentrations achievable by normal delivery of antibiotics to the inclusions within which chlamydiae reside in the host cell cytoplasm. In this research, we evaluated whether nanoparticles formulated using the biodegradable poly(d-L-lactide-co-glycolide) (PLGA) polymer can enhance the delivery of antibiotics to the chlamydial inclusion complexes. We initially studied the trafficking of PLGA nanoparticles in Chlamydia-infected cells. We then evaluated nanoparticles for the delivery of antibiotics to the inclusions. Intracellular trafficking studies show that PLGA nanoparticles efficiently concentrate in inclusions in both acutely and persistently infected cells. Further, encapsulation of rifampin and azithromycin antibiotics in PLGA nanoparticles enhanced the effectiveness of the antibiotics in reducing microbial burden. Combination of rifampin and azithromycin was more effective than the individual drugs. Overall, our studies show that PLGA nanoparticles can be effective carriers for targeted delivery of antibiotics to intracellular chlamydial infections. PMID:21652065

Toti, Udaya S; Guru, Bharath R; Hali, Mirabela; McPharlin, Christopher M; Wykes, Susan M; Panyam, Jayanth; Whittum-Hudson, Judith A

2011-09-01

315

Ultrasound-enhanced delivery of targeted echogenic liposomes in a novel ex vivo mouse aorta model  

PubMed Central

The goal of this study was to determine whether targeted, Rhodamine-labeled echogenic liposomes (Rh-ELIP) containing nanobubbles could be delivered to the arterial wall, and whether 1 MHz continuous wave ultrasound would enhance this delivery profile. Aortae excised from apolipoprotein-E-deficient (n = 8) and wild-type (n = 8) mice were mounted in a pulsatile flow system through which Rh-ELIP were delivered in a stream of bovine serum albumin. Half the aortae from each group were treated with 1-MHz continuous wave ultrasound at 0.49 MPa peak-to-peak pressure, and half underwent sham exposure. Ultrasound parameters were chosen to promote stable cavitation and avoid inertial cavitation. A broadband hydrophone was used to monitor cavitation activity. After treatment, aortic sections were prepared for histology and analyzed by an individual blinded to treatment conditions. Delivery of Rh-ELIP to the vascular endothelium was observed, and subendothelial penetration of Rh-ELIP was present in five of five ultrasound-treated aortae and was absent in those not exposed to ultrasound. However, the degree of penetration in the ultrasound-exposed aortae was variable. There was no evidence of ultrasound-mediated tissue damage in any specimen. Ultrasound-enhanced delivery within the arterial wall was demonstrated in this novel model, which allows quantitative evaluation of therapeutic delivery.

Hitchcock, Kathryn E.; Caudell, Danielle N.; Sutton, Jonathan T.; Klegerman, Melvin E.; Vela, Deborah; Pyne-Geithman, Gail J.; Abruzzo, Todd; Cyr, Peppar E. P.; Geng, Yong-Jian; McPherson, David D.; Holland, Christy K.

2010-01-01

316

Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues  

PubMed Central

Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity.

Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

2014-01-01

317

Non-Condensing Polymeric Nanoparticles for Targeted Gene and siRNA Delivery  

PubMed Central

Gene therapy has shown a tremendous potential to benefit patients in a variety of disease conditions. However, finding a safe and effective systemic delivery system is the major obstacle in this area. Although viral vectors showed promise for high transfection rate, the immunogenicity associated with these systems has hindered further development. As an alternative to viral gene delivery, this review focuses on application of novel safe and effective non-condensing polymeric systems that have shown high transgene expression when administered systemically or by the oral route. Type B gelatin-based engineered nanocarriers were evaluated for passive and active tumor-targeted delivery and transfection using both reporter and therapeutic plasmid DNA. Additionally, we have shown that nanoparticles-in-microsphere oral system (NiMOS) can efficiently deliver reporter and therapeutic gene constructs in the gastrointestinal tract. Additionally, there has been a significant recent interest in the use small interfering RNA (siRNA) as a therapeutic system for gene silencing. Both gelatin nanoparticles and NiMOS have shown activity in systemic and oral delivery of siRNA, respectively.

Xu, Jing; Ganesh, Shanthi; Amiji, Mansoor

2011-01-01

318

Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues.  

PubMed

Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633

Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

2014-07-01

319

Formulation of Functionalized PLGA-PEG Nanoparticles for In Vivo Targeted Drug Delivery  

PubMed Central

Nanoparticle (NP) size has been shown to significantly effect the biodistribution of targeted and non-targeted NPs in an organ specific manner. Herein we have developed NPs from carboxy-terminated poly (d,l-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) polymer and studied the effects of altering the following formulation parameters on the size of NPs, including: 1) polymer concentration, 2) drug loading, 3) water miscibility of solvent, and 4) the ratio of water to solvent. We found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient = 0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the Prostate Specific Membrane Antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in a LNCaP (PSMA+) xenograft mouse model of PCa. The surface functionalization of NPs with the A10 PSMA aptamer significantly enhanced delivery of NPs to tumors vs. equivalent NPs lacking the A10 PSMA aptamer (a 3.77-fold increase at 24 hrs; NP-Apt 0.83% ± 0.21% vs. NP 0.22% ± 0.07% of injected dose per gram of tissue; mean ± s.d., n = 4, p = 0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies.

Cheng, Jianjun; Teply, Benjamin A.; Sherifi, Ines; Sung, Josephine; Luther, Gaurav; Gu, Frank X.; Levy-Nissenbaum, Etgar; Radovic-Moreno, Aleksandar F.; Langer, Robert; Farokhzad, Omid C.

2009-01-01

320

Dendrimer-triglycine-EGF nanoparticles for tumor imaging and targeted nucleic acid and drug delivery  

PubMed Central

We designed an epidermal growth factor (EGF)-containing polyamidoamine (PAMAM) Generation 4 dendrimer vector labeled with quantum dots for targeted imaging and nucleic acid delivery. 1H-NMR, SDS-PAGE, and western blotting were applied to characterize the synthesized G4.0-GGG-EGF nanoparticles. Targeting efficiency, cell viability, proliferation, and intracellular signal transduction were evaluated using HN12, NIH3T3, and NIH3T3/EGFR cells. We found that EGF-conjugated dendrimers did not stimulate growth of EGFR-expressing cells at the selected concentration. Consistent with this, minimal stimulation of post-receptor signaling pathways was observed. These nanoparticles can localize within cells that express the EGFR in a receptor-dependent manner, whereas uptake into cells lacking the receptor was low. A well characterized vimentin shRNA (shVIM) and siRNA YFP were used to test the delivery and transfection efficiency of the constructed targeted vector. Significant knockdown of expression was observed, indicating that this vector is useful for introduction of nucleic acids or drugs into cells by a receptor-targeted mechanism.

Yuan, Quan; Lee, Eunmee; Yeudall, W. Andrew; Yang, Hu

2010-01-01

321

Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery.  

PubMed

Nanoparticles are used for delivering therapeutics into cells. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell-specific internalization, excretion, toxicity and efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, a lack of tissue specificity and potential toxicity. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer-targeting ligands (such as peptides and folate) on the nanoparticle surface can be controlled precisely. We show that at least three folate molecules per nanoparticle are required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t(1/2) ? 24.2 min) than the parent siRNA (t(1/2) ? 6 min). PMID:22659608

Lee, Hyukjin; Lytton-Jean, Abigail K R; Chen, Yi; Love, Kevin T; Park, Angela I; Karagiannis, Emmanouil D; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S; Jayaraman, Muthusamy; Peng, Chang G; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G

2012-06-01

322

Molecularly Self-Assembled Nucleic Acid Nanoparticles for Targeted In Vivo siRNA Delivery  

PubMed Central

Nanoparticles are employed for delivering therapeutics into cells1,2. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell specific internalization, excretion, toxicity, and efficacy3-7. A variety of materials have been explored for delivering small interfering RNAs (siRNAs) - a therapeutic agent that suppresses the expression of targeted genes8,9. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, lack of tissue specificity and potential toxicity10-12. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer targeting ligands (such as peptides and folate) on the nanoparticle surface can be precisely controlled. We show that at least three folate molecules per nanoparticle is required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t1/2 ? 24.2 min) than the parent siRNA (t1/2 ? 6 min).

Lee, Hyukjin; Lytton-Jean, Abigail K. R.; Chen, Yi; Love, Kevin T.; Park, Angela I.; Karagiannis, Emmanouil D.; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S.; Jayaraman, Muthusamy; Peng, Chang G.; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S.; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G.

2013-01-01

323

Carrier-free, functionalized pure drug nanorods as a novel cancer-targeted drug delivery platform  

NASA Astrophysics Data System (ADS)

A one-dimensional drug delivery system (1D DDS) is highly attractive since it has distinct advantages such as enhanced drug efficiency and better pharmacokinetics. However, drugs in 1D DDSs are all encapsulated in inert carriers, and problems such as low drug loading content and possible undesirable side effects caused by the carriers remain a serious challenge. In this paper, a novel, carrier-free, pure drug nanorod-based, tumor-targeted 1D DDS has been developed. Drugs are first prepared as nanorods and then surface functionalized to achieve excellent water dispersity and stability. The resulting drug nanorods show enhanced internalization rates mainly through energy-dependent endocytosis, with the shape-mediated nanorod (NR) diffusion process as a secondary pathway. The multiple endocytotic mechanisms lead to significantly improved drug efficiency of functionalized NRs with nearly ten times higher cytotoxicity than those of free molecules and unfunctionalized NRs. A targeted drug delivery system can be readily achieved through surface functionalization with targeting group linked amphipathic surfactant, which exhibits significantly enhanced drug efficacy and discriminates between cell lines with high selectivity. These results clearly show that this tumor-targeting DDS demonstrates high potential toward specific cancer cell lines.

Li, Yanan; Yang, Yinlong; An, Feifei; Liu, Zhuang; Zhang, Xiujuan; Zhang, Xiaohong

2013-01-01

324

Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells  

NASA Astrophysics Data System (ADS)

In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs). HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis. Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles. Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors.

Yu, Meihua; Jambhrunkar, Siddharth; Thorn, Peter; Chen, Jiezhong; Gu, Wenyi; Yu, Chengzhong

2012-12-01

325

Folate-conjugated hybrid SBA-15 particles for targeted anticancer drug delivery.  

PubMed

Surface functionalization is one of the key steps toward the utilization of mesoporous materials in drug delivery system. Here, the folic acid (FA) ligands are conjugated onto poly(ethylene imine) (PEI) modified SBA-15 particles (PEI/SBA-15) via amide reaction, which results in the FA/PEI/SBA-15 particles. Doxorubicin hydrochloride (DOX), an anticancer drug, is successfully loaded into these particles. The in vitro cytotoxicity and cellular uptake of the empty FA/PEI/SBA-15 particles and the DOX-loaded ones are evaluated on two kinds of cancer cells (HeLa cells and A549 cells). Specifically, an excellent cellular uptake using the current anticancer drug delivery vehicles (DOX-loaded FA/PEI/SBA-15 particles) mediated by the FA receptor is demonstrated by fluorescence microscope and flow cytometry. The FA/PEI/SBA-15 particles demonstrate a lower cytotoxicity comparing with the PEI/SBA-15 particles, while the DOX-loaded FA/PEI/SBA-15 particles exhibit much greater inhibition to the studied cancer cells. Furthermore, the in vitro release study shows that the targeted FA/PEI/SBA-15 particles have a typical sustained release behavior. This work therefore demonstrates that drug-loaded FA/PEI/SBA-15 particles have great potential application in targeted anticancer drug delivery for cancer therapy. PMID:23312579

Pang, Jianmei; Zhao, Lanxia; Zhang, Longlong; Li, Zhonghao; Luan, Yuxia

2013-04-01

326

Chlorotoxin Bound Magnetic Nanovector Tailored for Cancer Cell Targeting, Imaging, and siRNA Delivery  

PubMed Central

Ribonucleic acid interference (RNAi) is a powerful molecular tool that has potential to revolutionize the treatment of cancer. One major challenge of applying this technology for clinical application is the lack of site-specific carriers that can effectively deliver short interfering RNA (siRNA) to cancer cells. Here we report the development and assessment of a cancer-cell specific magnetic nanovector construct for efficient siRNA delivery and non-invasive monitoring through magnetic resonance imaging (MRI). The base of the nanovector construct is comprised of a superparamagnetic iron oxide nanoparticle core coated with polyethylene glycol (PEG)-grafted chitosan, and polyethylenimine (PEI). The construct was then further functionalized with siRNA and a tumor-targeting peptide, chlorotoxin (CTX), to improve tumor specificity and potency. Flow cytometry, quantitative RT-PCR, and fluorescence microscopy analyses confirmed receptor-mediated cellular internalization of nanovectors and enhanced gene knockdown through targeted siRNA delivery. The ability of this nanovector construct to generate specific contrast enhancement of brain tumor cells was demonstrated through MR imaging. These findings suggest that this CTX enabled nanoparticle carrier may be well suited for delivery of RNAi therapeutics to cancer cells.

Veiseh, Omid; Kievit, Forrest M.; Fang, Chen; Mu, Ni; Jana, Soumen; Leung, Matthew; Mok, Hyejung; Ellenbogen, Richard G.; Park, James O.; Zhang, Miqin

2010-01-01

327

Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent.  

PubMed

IR-780 iodide, a near-infrared fluorescent heptamethine dye, has been recently characterized to exhibit preferential accumulation property in the mitochondria of tumor cells. In this study, we investigated the possible mechanisms for its tumor selective activity and its potential as a drug delivery carrier. Results showed that the energy-dependent uptake of IR-780 iodide into the mitochondria of tumor cells was affected by glycolysis and plasma membrane potential. Moreover, OATP1B3 subtype of organic anion transporter peptides (OATPs) may play a dominant role in the transportation of IR-780 iodide into tumor cells, while cellular endocytosis, mitochondrial membrane potential and the ATP-binding cassette transporters did not show significant influence to its accumulation. We further evaluated the potential of IR-780 iodide as a drug delivery carrier by covalent conjugation of IR-780 with nitrogen mustard (IR-780NM). In vivo imaging showed that IR-780NM remained the tumor targeting property, indicating that IR-780 iodide could be potentially applied as a drug delivery agent for cancer targeted imaging and therapy. PMID:24148240

Zhang, Erlong; Luo, Shenglin; Tan, Xu; Shi, Chunmeng

2014-01-01

328

Focusing of photomechanical waves with an optical lens for depth-targeted molecular delivery  

NASA Astrophysics Data System (ADS)

We have been developing molecular delivery systems based on photomechanical waves (PMWs), which are generated by the irradiation of a laser absorbing material with nanosecond laser pulses. This method enables highly site-specific delivery in the horizontal plane of the tissue. However, targeting in the vertical direction is a remaining challenge. In this study, we developed a novel PMW focusing device for deeper tissue targeting. A commercial optical concave lens and black natural rubber sheet (laser absorber) were attached to the top and bottom end of a cylindrical spacer, respectively, which was filled with water. A laser pulse was transmitted through the lens and water and hit the rubber sheet to induce a plasma, generating a PMW. The PMW was propagated both downward and upward. The downward wave (1st wave) was diffused, while the upward (2nd wave) wave was reflected with the concave surface of the lens and focused at a depth determined by the geometrical parameters. To attenuate the 1st wave, a small-diameter silicon sponge rubber disk was adhered just under the rubber sheet concentrically with the laser axis. With the lens of f = -40 mm, the 2nd wave was focused to a diameter of 5.7 mm at a targeted depth of 20 mm, which was well agreed with the result of calculation by ray tracing. At a laser fluence of 5.1 J/cm2, peak pressure of the PMW reached ~40 MPa at the depth of 20 mm. Under this condition, we examined depth-targeted gene delivery to the rat skin.

Shimada, Takuichirou; Sato, Shunichi; Kawauchi, Satoko; Ashida, Hiroshi; Terakawa, Mitsuhiro

2014-02-01

329

Synthesis and Characterization of Polymer Nanocarriers for the Targeted Delivery of Therapeutic Enzymes  

PubMed Central

Protein drugs, such as recombinant enzymes useful for detoxification and replacement therapies, have extraordinary specificity and potency. However, inherently inadequate delivery to target sites and rapid inactivation limit their medical utility. Using chaperone polymeric particles designed within an injectible size range (sub-micron) may help solve these shortcomings. Such nanocarriers would (i) prevent premature inactivation of encapsulated therapeutic protein cargoes, (ii) provide a carrier that can be surface decorated by targeting ligands, and (iii) optimize sub-cellular localization of the drug. This chapter describes the techniques successfully employed for the preparation of polymer nanocarriers (PNC) loaded with the antioxidant enzyme, catalase, and targeted to endothelial cells. Methods of PNC synthesis, loading with catalase, characterization, coupling of a targeting moiety, and in vitro testing of the enzymatic and targeting activities are provided here. Advantages and disadvantages of specific designs are discussed. Due to the modular nature of the targeting methodology employed, it is believed that these protocols will provide a solid foundation for the formulation of a wide variety of enzymatic drug targeting strategies.

Simone, Eric; Dziubla, Thomas; Shuvaev, Vladimir; Muzykantov, Vladimir R.

2011-01-01

330

Paclitaxel-Induced Apoptosis Is BAK-Dependent, but BAX and BIM-Independent in Breast Tumor  

PubMed Central

Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim?/? MEFs (mouse embryonic fibroblasts), the bim?/? mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak?/? MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax?/? MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.

Nakajima, Wataru; Richardson, Amanda C.; Windle, Jolene J.; Harada, Hisashi

2013-01-01

331

Formulation/Preparation of Functionalized Nanoparticles for In Vivo Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

Targeted cancer therapy allows the delivery of therapeutic agents to cancer cells without incurring undesirable side effects on the neighboring healthy tissues. Over the past decade, there has been an increasing interest in the development of advanced cancer therapeutics using targeted nanoparticles. Here we describe the preparation of drug-encapsulated nanoparticles formulated with biocompatible and biodegradable poly( d, l-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2-fluoropyrimidine ribonucleic acid aptamers that recognize the extracellular domain of prostate-specific membrane antigen (PSMA), a well-characterized antigen expressed on the surface of prostate cancer cells. We show that the self-assembled nanoparticles can selectively bind to PSMA-targeted prostate cancer cells in vitro and in vivo. This formulation method may contribute to the development of highly selective and effective cancer therapeutic and diagnostic devices.

Gu, Frank; Langer, Robert; Farokhzad, Omid C.

332

Formulation/Preparation of Functionalized Nanoparticles for In Vivo Targeted Drug Delivery  

PubMed Central

Summary Targeted cancer therapy allows the delivery of therapeutic agents to cancer cells without incurring undesirable side effects on the neighboring healthy tissues. Over the past decade, there has been an increasing interest in the development of advanced cancer therapeutics using targeted nanoparticles. Here we describe the preparation of drug-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2-fluoropyrimidine ribonucleic acid aptamers that recognize the extracellular domain of prostate-specific membrane antigen (PSMA), a well-characterized antigen expressed on the surface of prostate cancer cells. We show that the self-assembled nanoparticles can selectively bind to PSMA-targeted prostate cancer cells in vitro and in vivo. This formulation method may contribute to the development of highly selective and effective cancer therapeutic and diagnostic devices.

Gu, Frank; Langer, Robert; Farokhzad, Omid C.

2014-01-01

333

Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging  

PubMed Central

Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents that have been developed for magnetic resonance (MR) imaging. These MNPs have traditionally been used for disease imaging via passive targeting, but recent advances have opened the door to cellular-specific targeting, drug delivery, and multi-modal imaging by these nanoparticles. As more elaborate MNPs are envisioned, adherence to proper design criteria (e.g. size, coating, molecular functionalization) becomes even more essential. This review summarizes the design parameters that affect MNP performance in vivo, including the physicochemical properties and nanoparticle surface modifications, such as MNP coating and targeting ligand functionalizations that can enhance MNP management of biological barriers. A careful review of the chemistries used to modify the surfaces of MNPs is also given, with attention paid to optimizing the activity of bound ligands while maintaining favorable physicochemical properties.

Veiseh, Omid; Gunn, Jonathan; Zhang, Miqin

2009-01-01

334

Gene Delivery System Targets Tumor Blood Vessels in Dogs with Cancer  

Cancer.gov

In a preliminary study of pet dogs with naturally occurring cancer, researchers have developed a way to target delivery of a gene to tumor blood vessels, where the gene product damages the vessels, disrupting blood flow to the tumors but not to the surrounding tissue. The delivery method was well tolerated, and in some dogs, the size of tumors decreased or remained stable. This study provides valuable information that may aid in the design of future clinical trials. These are the first results of the Comparative Oncology Trials Consortium, a novel multicenter network sponsored by NCI to integrate cancers that naturally develop in dogs into the developmental path of new therapies for cancers in humans.

335

Redox potential ultrasensitive nanoparticle for the targeted delivery of camptothecin to HER2-positive cancer cells.  

PubMed

Ideal "smart" nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer-drug conjugate of poly[2-(pyridin-2-yldisulfanyl)]-graft-poly(ethylene glycol) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. An in vitro drug release study found that HCN was stable in the physiological environment and supersensitive to the stimulus of elevated intracellular redox potential, releasing all payloads in less than 30 min. Furthermore, confocal microscopy revealed that HCN could specifically enter HER2-positive cancer cells. As a consequence, HCN could effectively kill HER2-positive cancer cells while not affecting HER2-negative cells. PMID:24779647

Remant, Bahadur K C; Chandrashekaran, Varun; Cheng, Bei; Chen, Hexin; Peña, Maria Marjorette O; Zhang, Jiajia; Montgomery, Janis; Xu, Peisheng

2014-06-01

336

Single walled carbon nanotubes as drug delivery vehicles: targeting doxorubicin to tumors.  

PubMed

Single walled carbon nanotubes (SWNTs) are emerging as promising delivery vehicles for cancer diagnostics and chemotherapies due to their unique properties, including, remarkable cell membrane penetrability, high drug-carrying capacities, pH-dependent therapeutic unloading, prolonged circulating times and intrinsic fluorescent, photothermal, photoacoustic and Raman properties. In this leading opinion paper, we systemically discuss and evaluate the relationship of the biological safety of SWNTs with their physicochemical properties such as their length, purity, agglomeration state, concentration and surface functionalization. Other relevant issues, including the cellular uptake mechanism, biodistribution and metabolism of SWNTs are also reviewed. The design and preparation of SWNT-based drug delivery systems (DDSs) and their pharmacokinetic, cancer targeting and therapeutic properties both in vitro and in vivo are highlighted. Future opportunities and challenges of SWNT-based DDSs are also discussed. PMID:22137127

Meng, Lingjie; Zhang, Xiaoke; Lu, Qinghua; Fei, Zhaofu; Dyson, Paul J

2012-02-01

337

Novel free paclitaxel-loaded poly(L-?-glutamylglutamine)-paclitaxel nanoparticles  

PubMed Central

The purpose of this study was to develop a novel formulation of paclitaxel (PTX) that would improve its therapeutic index. Here, we combined a concept of polymer–PTX drug conjugate with a concept of polymeric micelle drug delivery to form novel free PTX-loaded poly(L-?-glutamylglutamine) (PGG)–PTX conjugate nanoparticles. The significance of this drug formulation emphasizes the simplicity, novelty, and flexibility of the method of forming nanoparticles that contain free PTX and conjugated PTX in the same drug delivery system. The results of effectively inhibiting tumor growth in mouse models demonstrated the feasibility of the nanoparticle formulation. The versatility and potential of this dual PTX drug delivery system can be explored with different drugs for different indications. Novel and simple formulations of PTX-loaded PGG–PTX nanoparticles could have important implications in translational medicines.

Yang, Danbo; Van, Sang; Jiang, Xinguo; Yu, Lei

2011-01-01

338

Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide  

PubMed Central

Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting.

Li, Chong; Wang, Yixin; Zhang, Xiaolin; Deng, Li; Zhang, Yan; Chen, Zhangbao

2013-01-01

339

Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide.  

PubMed

Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting. PMID:23515368

Li, Chong; Wang, Yixin; Zhang, Xiaolin; Deng, Li; Zhang, Yan; Chen, Zhangbao

2013-01-01

340

Drug-loaded nano-microcapsules delivery system mediated by ultrasound-targeted microbubble destruction: A promising therapy method  

PubMed Central

The nano-microcapsules drug delivery system is currently a promising method for the treatment of many types of diseases, particularly tumors. However, the drug delivery efficiency does not reach a satisfactory level to meet treatment demands. Therefore, the effectiveness of delivery needs to be improved. Based on the alterations in the structure and modification of nano-microcapsules, ultrasound-targeted microbubble destruction (UTMD), a safe physical targeted method, may increase tissue penetration and cell membrane permeability, aiding the drug-loaded nano-microcapsules ingress the interior of targeted tissues and cells. The effectiveness and exact mechanism of action of the drug-loaded nano-microcapsules delivery system mediated by UTMD have yet to be fully elucidated. In this study, the latest advancement in UTMD-mediated drug loaded nano-microcapsules system technology was reviewed and the hindrances of UTMD-mediated drug delivery were assessed, in combination with a prospective study. The findings suggested that the drug delivery efficiency of nano-microcapsules mediated by UTMD was distinctly improved. Thus, the UTMD-mediated drug-loaded nano-microcapsules delivery system may significantly improve the efficiency of drug delivery, which may be a promising new therapeutic method.

MA, JING; DU, LIAN FANG; CHEN, MING; WANG, HANG HUI; XING, LING XI; JING, LI FANG; LI, YUN HUA

2013-01-01

341

Polymeric nanocarriers for magnetic targeted drug delivery: preparation, characterization, and in vitro and in vivo evaluation.  

PubMed

In this paper the preparation of magnetic nanocarriers (MNCs), containing superparamagnetic domains, is reported, useful as potential magnetically targeted drug delivery systems. The preparation of MNCs was performed by using the PHEA-IB-p(BMA) graft copolymer as coating material through the homogenization-solvent evaporation method. Magnetic and nonmagnetic nanocarriers containing flutamide (FLU-MNCs) were prepared. The prepared nanocarriers have been exhaustively characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and magnetic measurements. Biological evaluation was performed by in vitro cytotoxicity and cell uptake tests and in vivo biodistribution studies. Magnetic nanocarriers showed dimensions of about 300 nm with a narrow size distribution, an amount of loaded FLU of 20% (w/w), and a superparamagnetic behavior. Cell culture experiments performed on prostate cancer cell line LNCaP demonstrated the cytotoxic effect of FLU-MNCs. In vivo biodistribution studies carried out by the application of an external magnetic field in rats demonstrated the effect of the external magnet on modifying the biodistribution of FLU-MNCs. FLU-MNCs resulted efficiently internalized by tumor cells and susceptible to magnetic targeting by application of an external magnetic field. The proposed nanocarriers can represent a very promising approach to obtain an efficient magnetically targeted anticancer drug delivery system. PMID:24168360

Licciardi, Mariano; Scialabba, Cinzia; Fiorica, Calogero; Cavallaro, Gennara; Cassata, Giovanni; Giammona, Gaetano

2013-12-01

342

Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery  

SciTech Connect

A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic molecular probes were designed, synthesized, characterized, and subjected to the analysis of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.

Chen,J.; Wong,S.; Chen, S.; Zhao, X.; Kuznetsova, L.V.; and Ojima, I.

2008-11-14

343

New tumor-targeted nanosized delivery carrier for oligonucleotides: characteristics in vitro and in vivo  

PubMed Central

Background The purpose of this study was to investigate the in vitro and in vivo characteristics of a new tumor-targeted nanosized delivery carrier for antisense oligonucleotide (ASON). Methods Polyethylenimine (PEI) was used to condense ASON to form nanosized complexes (PEI/ASON), which were then modified using asparagine-glycine-arginine (NGR) peptide to obtain a tumor-targeted nanosized delivery carrier (NGR/PEI/ASON). The conditions required to form PEI/ASON were investigated. Results A linear correlation between the natural logarithm of the N/P ratio (PEI to ASON) and the zeta potential of the PEI/ASON complexes was found, ranging from 1.5 to 5.0. The pH of the solution strongly influenced the zeta potential of the PEI/ASON complexes. PEI/ASON and NGR/PEI/ASON were stable in RPMI-1640 culture medium in the presence of Dextran 70. Incorporation of ASON into PEI/ASON and NGR/PEI/ASON complexes prevented degradation of ASON by DNase I. Conclusion Both ASON/PEI and NGR/PEI/ASON complexes enhanced the uptake of ASON by EC9706 cells in vitro. In vivo, NGR/PEI/ASON complexes had the ability to target tumor tissues effectively.

Zhou, Tianyang; Jia, Xin; Li, Huixiang; Wang, Jin; Zhang, Hongling; A, Youmei; Zhang, Zhenzhong

2011-01-01

344

Enhanced Endothelial Delivery and Biochemical Effects of ?-Galactosidase by ICAM-1-Targeted Nanocarriers for Fabry Disease  

PubMed Central

Fabry disease due to deficiency of ?-galactosidase A (?-Gal) causes lysosomal accumulation of globotriaosylceramide (Gb3) in multiple tissues and prominently in the vascular endothelium. Although enzyme replacement therapy (ERT) by injection of recombinant ?-Gal improves the disease outcome, effects on the vasculopathy associated to life-threatening cerebrovascular, cardiac and renal complications are still limited. We designed a strategy to enhance delivery of ?-Gal to organs and endothelial cells (ECs). We targeted ?-Gal to intercellular adhesion molecule 1 (ICAM-1), a protein expressed on ECs throughout the vasculature, by loading this enzyme on nanocarriers coated with anti-ICAM (anti-ICAM/?-Gal NCs). In vitro radioisotope tracing showed efficient loading of ?-Gal on anti-ICAM NCs, stability of this formulation under storage and in model physiological fluids, and enzyme release in response to lysosome environmental conditions. In mice, delivery of 125I-?-Gal was markedly enhanced by anti-ICAM/125I-?-Gal NCs in brain, kidney, heart, liver, lung, and spleen, and transmission electron microscopy showed anti-ICAM/?-Gal NCs attached to and internalized into the vascular endothelium. Fluorescence microscopy proved targeting, endocytosis and lysosomal transport of anti-ICAM/?-Gal NCs in macro- and micro-vascular ECs, and a marked enhancement of Gb3 degradation. Therefore, ICAM-1-targeting strategy may help improve the efficacy of therapeutic enzymes for Fabry disease.

Hsu, Janet; Serrano, Daniel; Bhowmick, Tridib; Kumar, Kishan; Shen, Yang; Kuo, Yuan Chia; Garnacho, Carmen; Muro, Silvia

2010-01-01

345

Paclitaxel-Conjugated PAMAM Dendrimers Adversely Affect Microtubule Structure through Two Independent Modes of Action  

PubMed Central

Paclitaxel (Taxol®) is an anti-cancer drug that induces mitotic arrest via microtubule hyperstabilization, but causes side effects due to its hydrophobicity and cellular promiscuity. The targeted cytotoxicity of hydrophilic paclitaxel-conjugated polyamidoamine (PAMAM) dendrimers has been demonstrated in cultured cancer cells. Mechanisms of action responsible for this cytotoxicity are unknown—i.e., whether the cytotoxicity is due to paclitaxel stabilization of microtubules — as is whether paclitaxel is released intracellularly from the dendrimer. To determine whether the conjugated paclitaxel can bind microtubules, we used a combination of ensemble and single microtubule imaging techniques in vitro. We demonstrate that these conjugates adversely affect microtubules by: (1) promoting the polymerization and stabilization of microtubules in a paclitaxel-dependent manner; and (2) bundling pre-formed microtubules in a paclitaxel-independent manner, potentially due to protonation of tertiary amines in the dendrimer interior. Our results provide mechanistic insights into the cytotoxicity of paclitaxel-conjugated PAMAM dendrimers and uncover unexpected risks of using such conjugates therapeutically.

Cline, Erika N.; Li, Ming-Hsin; Choi, Seok Ki; Herbstman, Jeffrey F.; Kaul, Neha; Meyhofer, Edgar; Skiniotis, Georgios; Baker, James R.; Larson, Ronald G.; Walter, Nils G.

2013-01-01

346

Targeted liposomal drug delivery systems for the treatment of B cell malignancies.  

PubMed

Abstract Nanoparticulate systems have demonstrated significant potential for overcoming the limitations of non-specific adverse effects related to chemotherapy. The treatment of blood malignancies employing targeted particulate drug delivery systems presents unique challenges and considerable research has been focused towards the development of targeted liposomal formulations for B cell malignancies. These formulations are aimed at achieving selectivity towards the malignant cells by targeting several cell surface markers which are over-expressed in that specific malignancy. CD19, CD20, CD22 and CD74 are few of such markers of which CD19, CD22 and CD74 are internalizing and CD20 is non-internalizing. Systems which have been developed to target both types of these cell surface markers are discussed. Specifically, the efficacy and development of targeted liposomes is considered. A number of studies have demonstrated the advantages of targeted liposomal systems encapsulating doxorubicin or vincristine. However, liposomal encapsulation of newer anti-neoplastic agents such as AD 198 which are superior to doxorubicin should be considered. PMID:24433007

Mittal, Nivesh K; Bhattacharjee, Himanshu; Mandal, Bivash; Balabathula, Pavan; Thoma, Laura A; Wood, George C

2014-06-01

347

Dendrimer-based targeted delivery of an apoptotic sensor in cancer cells.  

PubMed

Our previous studies have demonstrated the applicability of poly(amidoamine) (PAMAM) dendrimers as a platform for the targeted delivery of chemotherapeutic drugs both in vitro and in vivo. To monitor the rate and extent of cell-killing caused by the delivered chemotherapeutic drug, we wished to analyze the degree of apoptosis in targeted cells on a real-time basis. As the apoptosis-regulating caspases are activated during the apoptotic process, several caspase-hydrolyzable, fluorescence resonance energy transfer (FRET)-based substrates have been marketed for the detection of apoptosis. However, the applicability of these agents is limited because of their nonspecificity and the consequent high background fluorescence in tissues. Here we show the synthesis, characterization, and in vitro targeting of an engineered PAMAM nanodevice in which folic acid (FA) is conjugated as the targeting molecule and a caspase-specific FRET-based agent (PhiPhiLux G1D2) is conjugated as the apoptosis-detecting agent. This conjugate specifically targets FA-receptor-positive, KB cells. In these cells, the apoptosis-inducing agent staurosporine caused a 5-fold increase in the cellular fluorescence. These results show, for the first time, the potential applicability of a targeted apoptosis-measuring nanodevice, which could be used for simultaneously monitoring the apoptotic potential of a delivered drug. PMID:17206782

Myc, Andrzej; Majoros, István J; Thomas, Thommey P; Baker, James R

2007-01-01

348

Smart ligand: aptamer-mediated targeted delivery of chemotherapeutic drugs and siRNA for cancer therapy.  

PubMed

Aptamers are a class of oligonucleotides that can specifically bind to different targets with high affinity. Since their discovery in 1980s, aptamers have attracted considerable interests in medical applications. So far, initial research using aptamers as delivery systems has produced exciting results. In this review, we summarize recent progress in aptamer-mediated chemotherapeutic drug and siRNA delivery systems in tumor treatment. With regard to chemotherapeutic drugs, the 2 main methods for targeted delivery using aptamers are as follows: aptamer-drug systems (in which aptamers directly deliver the drug both as a carrier and as a ligand) and aptamer-nanoparticles systems (in which nanoparticles function together with aptamers for targeted delivery of drugs). For delivery of siRNA, aptamers can be utilized by the following ways to facilitate targeting: (1) linked by a connector; (2) form a chimera; and (3) combined with nanoparticles. In co-delivery system, the advantages associated with the use of aptamers are beginning to become apparent also. Here, the challenges and new perspectives in the field of aptamer-mediated delivery have been discussed. PMID:23777885

Li, Xin; Zhao, Qinghe; Qiu, Liyan

2013-10-28

349

Lung surfactant microbubbles increase lipophilic drug payload for ultrasound-targeted delivery.  

PubMed

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta(®), Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload. PMID:23781287

Sirsi, Shashank R; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y; Mountford, Paul A; Borden, Mark A

2013-01-01

350

Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma.  

PubMed

Our laboratory has investigated the anticancer effects of combined manumycin (a farnesyltransferase inhibitor) and paclitaxel (a microtubule inhibitor) against anaplastic thyroid carcinoma (ATC). In this study we reported the in vivo efficacy of this combination against ATC cells and the lack of toxicity of this treatment in mice. We observed that manumycin-treated tumors looked paler than both control and paclitaxel-treated tumors. We hypothesized that angiogenesis inhibition mediated part of the in vivo effect of manumycin. This hypothesis was supported by the findings that manumycin significantly inhibited angiogenesis (as directly demonstrated by measurement of hemoglobin content and vascular area) in Matrigel implanted into mice, that manumycin decreased the vascular endothelial growth factor in hypoxic ATC cells, and that both manumycin and paclitaxel inhibited endothelial cell proliferation. Interestingly, inhibition of endothelial tubule formation in Matrigel was enhanced by combining manumycin and paclitaxel. As angiogenesis and tumor growth are continuous processes, we investigated the effect of sustained delivery of manumycin and found that paclitaxel plus slow release manumycin (13.25 mg/kg x week) inhibited ATC xenografts more than paclitaxel plus intermittent manumycin (15 mg/kg x week). In conclusion, manumycin plus paclitaxel is an effective combination against ATC, and inhibition of angiogenesis plays a role in the antineoplastic effect of this combination. PMID:11297616

Xu, G; Pan, J; Martin, C; Yeung, S C

2001-04-01

351

Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability.  

PubMed

A new, supersaturable self-emulsifying drug delivery system (S-SEDDS) of paclitaxel was developed employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S-SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC the SEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study was conducted in male Sprague-Dawley rats to assess exposure after an oral paclitaxel dose of 10 mg/kg in the SEDDS formulations with (S-SEDDS) and without HPMC. The paclitaxel S-SEDDS formulation shows approximately 10-fold higher maximum concentration (C(max)) and five-fold higher oral bioavailability (F approximately 9.5%) compared with that of the orally dosed Taxol formulation (F approximately 2.0%) and the SEDDS formulation without HPMC (F approximately 1%). Coadministration of cyclosporin A (CsA), an inhibitor of P-glycoprotein and CYP 3A4 enzyme, at a dose of 5 mg/kg with the S-SEDDS formulation further increased the oral bioavailability (F approximately 22.6%). This assessment demonstrates that the systemic exposure of paclitaxel following oral administration can be substantially improved via the S-SEDDS approach. PMID:14603484

Gao, Ping; Rush, Bobby D; Pfund, William P; Huang, Tiehua; Bauer, Juliane M; Morozowich, Walter; Kuo, Ming-Shang; Hageman, Michael J

2003-12-01

352

Urokinase Plasminogen Activator System Targeted Delivery of Nanobins as a Novel Ovarian Cancer Therapeutics  

PubMed Central

The urokinase system is overexpressed in epithelial ovarian cancer (OvCa) cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in OvCa, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA targeted nanobins were internalized by OvCa cells, while both ICP-MS and FACS analyses confirmed >4-fold higher uptake of targeted nanobins when compared to untargeted nanobins. In a co-culture assay, the targeted nanobins showed efficient uptake in OvCa cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either down-regulating uPA receptor expression in the OvCa cells using shRNA or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burden when treated with targeted nanobins than with untargeted nanobins (47% versus 27%; p<0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared to untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, ALDH1A1, expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy utilizing protease receptors.

Zhang, Yilin; Kenny, Hilary A.; Swindell, Elden P.; Mitra, Anirban K.; Hankins, Patrick L.; Ahn, Richard W.; Gwin, Katja; Mazar, Andrew P.; O'Halloran, Thomas V.; Lengyel, Ernst

2013-01-01

353

A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers  

Microsoft Academic Search

Lactose-based placebo tablets were coated using various combinations of two methacrylic acid copolymers, Eudragit® L100-55 and Eudragit® S100, by spraying from aqueous systems. The Eudragit® L100-55–Eudragit® S100 combinations (w\\/w) studied were 1:0, 4:1, 3:2, 1:1, 2:3, 1:4, 1:5 and 0:1. The coated tablets were tested in vitro for their suitability for pH dependent colon targeted oral drug delivery. The same

M. Zahirul I Khan; Željko Prebeg; Nevenka Kurjakovi?

1999-01-01

354

A novel mitotropic oligolysine nanocarrier: Targeted delivery of covalently bound D-Luciferin to cell mitochondria.  

PubMed

New and emerging therapeutic approaches focus on the targeted delivery of therapeutic agents to cell mitochondria with high specificity. Herein we present a novel mitotropic nanocarrier based on an oligolysine scaffold by addition of two triphenylphosphonium cations per oligomer. Although the parent oligolysine failed to enter healthy cells, the triphenylphosphonium modified carrier, with or without D-Luciferin, attached as cargo molecule, demonstrated striking mitochondrial specificity. Furthermore, the oligolysine bound d-Luciferin exhibited chemiluminescence, of lower intensity than free d-Luciferin, yet of remarkably longer steady-state temporal profile. PMID:21856448

Theodossiou, Theodossis A; Sideratou, Zili; Tsiourvas, Dimitris; Paleos, Constantinos M

2011-11-01

355

NIR-to-visible upconversion nanoparticles for fluorescent labeling and targeted delivery of siRNA  

Microsoft Academic Search

Near-infrared (NIR)-to-visible upconversion fluorescent nanoparticles\\u000a were synthesized and used for imaging and targeted delivery of small\\u000a interfering RNA (siRNA) to cancer cells. Silica-coated NaYF(4)\\u000a upconversion nanoparticles (UCNs) co-doped with lanthanide ions (Yb\\/Er)\\u000a were synthesized. Folic acid and anti-Her2 antibody conjugated UCNs were\\u000a used to fluorescently label the folate receptors of HT-29 cells and Her2\\u000a receptors of SK-BR-3 cells, respectively. The

Shan Jiang; Yong Zhang; Kian Meng Lim; Eugene K. W. Sim; Lei Ye

2009-01-01

356

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound  

PubMed Central

Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer’s disease. The requirements for clinical translation of FUS will be discussed.

2013-01-01

357

Potential of Negatively Charged Pectin Nanoparticles Encapsulating Paclitaxel: Preparation & Characterization  

Microsoft Academic Search

Sugars with their three dimensional structures are important for many biological functions. We report preparation of negatively charged pectin nanoparticles and its efficacy as a drug delivery vehicle for anticancer drug Paclitaxel assessed. Pectin nanoparticles were prepared by ionic gelation having a mean diameter of ~300350nm, and were stable over a wide range of temperature and pH. FT-IR spectra revealed

Anita K. Verma; A. Chanchal; A. Kumar

2011-01-01

358

Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound  

PubMed Central

Recombinant adeno-associated viral (rAAV) vectors are potentially powerful tools for gene therapy of CNS diseases, but their penetration into brain parenchyma is severely limited by the blood-brain barrier (BBB) and current delivery relies on invasive stereotactic injection. Here we evaluate the local, targeted delivery of rAAV vectors into the brains of mice by noninvasive, reversible, microbubble-facilitated focused ultrasound (FUS), resulting in BBB opening that can be monitored and controlled by magnetic resonance imaging (MRI). Using this method, we found that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (1×109 vg/g) can successfully penetrate the BBB-opened brain regions to express GFP. We show that MRI monitoring of BBB-opening could serve as an indicator of the scale and distribution of AAV transduction. Transduction peaked at 3 weeks and neurons and astrocytes were affected. This novel, noninvasive delivery approach could significantly broaden the application of AAV-viral-vector-based genes for treatment of CNS diseases.

Hsu, Po-Hung; Wei, Kuo-Chen; Huang, Chiung-Yin; Wen, Chih-Jen; Yen, Tzu-Chen; Liu, Chao-Lin; Lin, Ya-Tin; Chen, Jin-Chung; Shen, Chia-Rui; Liu, Hao-Li

2013-01-01

359

PEI-derivatized fullerene drug delivery using folate as a homing device targeting to tumor.  

PubMed

Fullerene (C60) has shown great potential in drug delivery. In this study, firstly, amine-functionalized C60 (C60-NH(2)) was achieved by introducing ethylenediamine onto the surface of C60, and then PEI-derivatized C60 (C60-PEI) was performed via a cationic polymerization of aziridine on the surface of C60-NH(2); FT-IR and TGA results verified the structure of water-soluble C60-PEI. C60-PEI was encapsulated with folic acid (FA) through an amide linker, and then docetaxel (DTX) was conjugated to C60-PEI-FA and obtained a drug delivery system, C60-PEI-FA/DTX. Compared with free DTX, the tumor targeting drug delivery could efficiently cross cell membranes, lead to more apoptosis and afford higher antitumor efficacy in a cultured PC3 cells in vitro. Furthermore, compared with free DTX in an in vivo murine tumor model, C60-PEI-FA/DTX afforded higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.5-fold higher DTX uptake of tumor, demonstrating that C60-PEI-FA/DTX may be promising for high treatment efficacy with minimal side effects in future therapy. PMID:23069706

Shi, Jinjin; Zhang, Hongling; Wang, Lei; Li, Lulu; Wang, Honghong; Wang, Zhenzhen; Li, Zhi; Chen, Chengqun; Hou, Lin; Zhang, Chaofeng; Zhang, Zhenzhong

2013-01-01

360

Synthesis of Bisethylnorspermine Lipid Prodrug as Gene Delivery Vector Targeting Polyamine Metabolism in Breast Cancer  

PubMed Central

Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery.

Dong, Yanmei; Zhu, Yu; Li, Jing; Zhou, Qing-Hui; Wu, Chao; Oupicky, David

2013-01-01

361

The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles.  

PubMed

The CD95/CD95L receptor-ligand system is mainly recognised in the induction of apoptosis. However, it has also been shown that CD95L is over-expressed in many cancer types where it modulates immune-evasion and together with its receptor CD95 promotes tumour growth. Here, we show that CD95 surface modification of relatively large microparticles >0.5 ?m in diameter, including those made from biodegradable polylactic-co-glycolic acid (PLGA), enhances intracellular uptake by a range of CD95L expressing cells in a process akin to phagocytosis. Using this approach we describe the intracellular uptake of microparticles and agent delivery in neurons, medulloblastoma, breast and ovarian cancer cells in vitro. CD95 modified paclitaxel-loaded PLGA microparticles are shown to be significantly more effective compared to conventional paclitaxel therapy (Taxol) at the same dose in subcutaneous medulloblastoma (???P < 0.0001) and orthotopic ovarian cancer xenograft models where a >65-fold reduction in tumour bioluminescence was measured after treatment (?P = 0.012). This drug delivery platform represents a new way of manipulating the normally advantageous tumour CD95L over-expression towards a therapeutic strategy. CD95 functionalised drug carriers could contribute to the improved function of cytotoxics in cancer, potentially increasing drug targeting and efficacy whilst reducing toxicity. PMID:21824652

Ateh, Davidson D; Leinster, Veronica H; Lambert, Sally R; Shah, Afsha; Khan, Ayub; Walklin, Hazel J; Johnstone, Jennifer V; Ibrahim, Nader I; Kadam, Mustafa M; Malik, Zain; Gironès, Míriam; Veldhuis, Gert J; Warnes, Gary; Marino, Silvia; McNeish, Iain A; Martin, Joanne E

2011-11-01

362

AAV-Mediated Delivery of Zinc Finger Nucleases Targeting Hepatitis B Virus Inhibits Active Replication  

PubMed Central

Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy.

Weber, Nicholas D.; Stone, Daniel; Sedlak, Ruth Hall; De Silva Feelixge, Harshana S.; Roychoudhury, Pavitra; Schiffer, Joshua T.; Aubert, Martine; Jerome, Keith R.

2014-01-01

363

Catechol Polymers for pH-Responsive, Targeted Drug Delivery to Cancer Cells  

PubMed Central

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug–polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug–polymer conjugates. The pH-sensitive catechol–boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.

2011-01-01

364

Mito-DCA: a mitochondria targeted molecular scaffold for efficacious delivery of metabolic modulator dichloroacetate.  

PubMed

Tumor growth is fueled by the use of glycolysis, which normal cells use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant to normal death processes. Targeting this unique tumor metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. However, its molecular form shows poor uptake and bioavailability and limited ability to reach its target mitochondria. Here, we describe a targeted molecular scaffold for construction of a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude enhanced potency and cancer cell specificity compared to DCA. Incorporation of a lipophilic triphenylphosphonium cation through a biodegradable linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did not show any significant metabolic effects toward normal cells but tumor cells with dysfunctional mitochondria were affected by Mito-DCA, which caused a switch from glycolysis to glucose oxidation and subsequent cell death via apoptosis. Effective delivery of DCA to the mitochondria resulted in significant reduction in lactate levels and played important roles in modulating dendritic cell (DC) phenotype evidenced by secretion of interleukin-12 from DCs upon activation with tumor antigens from Mito-DCA treated cancer cells. Targeting mitochondrial metabolic inhibitors to the mitochondria could lead to induction of an efficient antitumor immune response, thus introducing the concept of combining glycolysis inhibition with immune system to destroy tumor. PMID:24617941

Pathak, Rakesh K; Marrache, Sean; Harn, Donald A; Dhar, Shanta

2014-05-16

365

Delivery systems intended for in vivo gene therapy of cancer: targeting and replication competent viral vectors.  

PubMed

Cancer gene therapy represents one of the most rapidly evolving areas in pre-clinical and clinical cancer research. Application of gene transfer techniques in clinical trials has made increasingly obvious that several issues will need to be addressed prior to meaningful incorporation of gene therapy in the care of cancer patients. Two of the most important problems to overcome are lack of selectivity of the existing vectors and low efficiency of gene transfer. This review focuses on use of targeting and replication competent vectors in order to overcome these obstacles. Targeted gene therapy of malignancies can be achieved through vector targeting or transcriptional targeting and can improve the therapeutic index of gene transfer by preventing damage of normal tissues, an important requirement if systemic gene delivery is contemplated. Replication competent viral vectors can improve the efficiency of gene transfer. Provisionally replicating viruses can also improve the therapeutic index by targeting toxicity to tumor cells. A variety of provisionally replicating viruses, such as the attenuated adenovirus ONYX-015, the adenovirus CN706 that selectively replicates in prostate cancer cells, the double mutant herpes simplex virus G207, the human reovirus, and the Newcastle disease virus are currently in clinical trials. Early clinical results and limitations in the application of these vectors are discussed. PMID:11369253

Galanis, E; Vile, R; Russell, S J

2001-06-01

366

Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery  

PubMed Central

The poor aqueous solubility and low bioavailability of curcumin restrict its clinical application for cancer treatment. In this study, a novel tumor-targeting nanofiber carrier was developed to improve the solubility and tumor-targeting ability of curcumin using a self-assembled Nap-GFFYG-RGD peptide. The morphologies of the peptide nanofiber and the curcumin-encapsulated nanofiber were visualized by transmission electron microscopy. The tumor-targeting activity of the curcumin-encapsulated Nap-GFFYG-RGD peptide nanofiber (f-RGD-Cur) was studied in vitro and in vivo, using Nap-GFFYG-RGE peptide nanofiber (f-RGE-Cur) as the control. Curcumin was encapsulated into the peptide nanofiber, which had a diameter of approximately 10–20 nm. Curcumin showed sustained-release behavior from the nanofibers in vitro. f-RGD-Cur showed much higher cellular uptake in ?v?3 integrin-positive HepG2 liver carcinoma cells than did non-targeted f-RGE-Cur, thereby leading to significantly higher cytotoxicity. Ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration of f-RGD-Cur via the tail vein. These results indicate that Nap-GFFYG-RGD peptide self-assembled nanofibers are a promising hydrophobic drug delivery system for targeted treatment of cancer.

Liu, Jianfeng; Liu, Jinjian; Xu, Hongyan; Zhang, Yumin; Chu, Liping; Liu, Qingfen; Song, Naling; Yang, Cuihong

2014-01-01

367

Is a reduction in radiation lung volume and dose necessary with paclitaxel chemotherapy for node-positive breast cancer?  

SciTech Connect

Purpose: To evaluate and quantify the effect of irradiated lung volume, radiation dose, and paclitaxel chemotherapy on the development of radiation pneumonitis (RP) in breast cancer patients with positive lymph nodes. Methods and Materials: We previously reported the incidence of RP among 41 patients with breast cancer treated with radiotherapy (RT) and adjuvant paclitaxel-containing chemotherapy. We recorded the central lung distance, a measure of the extent of lung included in the RT volume, in these patients. We used this measure and the historical and observed rates of RP in our series to model the lung tolerance to RT in patients receiving chemotherapy (CHT) both with and without paclitaxel. To evaluate the risk factors for the development of RP, we performed a case-control study comparing paclitaxel-treated patients who developed RP with those who did not, and a second case-control study comparing patients receiving paclitaxel in addition to standard CHT/RT (n = 41) and controls receiving standard CHT/RT alone (n 192). Results: The actuarial rate of RP in the paclitaxel-treated group was 15.4% compared with 0.9% among breast cancer patients treated with RT and non-paclitaxel-containing CHT. Our mathematical model found that the effective lung tolerance for patients treated with paclitaxel was reduced by approximately 24%. No statistically significant difference was found with regard to the dose delivered to specific radiation fields, dose per fraction, central lung distance, or percentage of lung irradiated in the case-control study of paclitaxel-treated patients who developed RP compared with those who did not. In the comparison of 41 patients receiving RT and CHT with paclitaxel and 192 matched controls receiving RT and CHT without paclitaxel, the only significant differences identified were the more frequent use of a supraclavicular radiation field and a decrease in the RT lung dose among the paclitaxel-treated patients. This finding indicates that the major factor associated with development of RP was paclitaxel treatment. Conclusions: The use of paclitaxel chemotherapy and RT in the primary treatment of node-positive breast cancer is likely to increase the incidence of RP. In patients treated with paclitaxel, reducing the percentage of lung irradiated by 24% should reduce the risk of RP to 1%, according to our calculations of lung tolerance. Future clinical trials using combination CHT that includes paclitaxel and RT should carefully evaluate the incidence and severity of RP and should also accurately monitor the extent of lung included within the RT volume to develop safe guidelines for the delivery of what is becoming standard therapy for node-positive breast cancer.

Taghian, Alphonse G. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)]. E-mail: ataghian@partners.org; Assaad, Sherif I. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Niemierko, Andrzej [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Floyd, Scott R. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Powell, Simon N. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)

2005-06-01

368

Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery.  

PubMed

Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications. PMID:23046982

Li, Zhi Jie; Cho, Chi Hin

2012-09-19

369

Targeting of Deep Brain Structures with Microinjections for Delivery of Drugs, Viral Vectors, or Cell Transplants  

PubMed Central

Microinjections into the brain parenchyma are important procedures to deliver drugs, viral vectors or cell transplants. The brain lesion that an injecting needle produces during its trajectory is a major concern especially in the mouse brain for not only the brain is small but also sometimes multiple injections are needed. We show here a method to produce glass capillary needles with a 50-?m lumen which significantly reduces the brain damage and allows a precise targeting into the rodent brain. This method allows a delivery of small volumes (from 20 to 100 nl), reduces bleeding risks, and minimizes passive diffusion of drugs into the brain parenchyma. By using different size of capillary glass tubes, or changing the needle lumen, several types of substances and cells can be injected. Microinjections with a glass capillary tube represent a significant improvement in injection techniques and deep brain targeting with minimal collateral damage in small rodents.

Gonzalez-Perez, Oscar; Guerrero-Cazares, Hugo; Quinones-Hinojosa, Alfredo

2010-01-01

370

Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery  

PubMed Central

Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications.

2012-01-01

371

Targeted Drug Delivery to the Peripheral Nervous System using Gene Therapy  

PubMed Central

Gene transfer to target delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathy, or of inhibitory neurotransmitters for relief of chronic pain, offers the possibility of a highly selective targeted release of bioactive molecules within the nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in reducing-pain related behaviors in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer, and in preventing progression of sensory neuropathy caused by toxins, chemotherapeutic drugs or resulting from diabetes. Successful completion of the first phase 1 clinical trial of HSV-mediated gene transfer in patients with intractable pain from cancer has set the stage for further clinical trials of this approach.

Wolfe, Darren; Mata, Marina; Fink, David J.

2012-01-01

372

Nanotechnology-based drug delivery systems  

PubMed Central

Nanoparticles hold tremendous potential as an effective drug delivery system. In this review we discussed recent developments in nanotechnology for drug delivery. To overcome the problems of gene and drug delivery, nanotechnology has gained interest in recent years. Nanosystems with different compositions and biological properties have been extensively investigated for drug and gene delivery applications. To achieve efficient drug delivery it is important to understand the interactions of nanomaterials with the biological environment, targeting cell-surface receptors, drug release, multiple drug administration, stability of therapeutic agents and molecular mechanisms of cell signalling involved in pathobiology of the disease under consideration. Several anti-cancer drugs including paclitaxel, doxorubicin, 5-fluorouracil and dexamethasone have been successfully formulated using nanomaterials. Quantom dots, chitosan, Polylactic/glycolic acid (PLGA) and PLGA-based nanoparticles have also been used for in vitro RNAi delivery. Brain cancer is one of the most difficult malignancies to detect and treat mainly because of the difficulty in getting imaging and therapeutic agents past the blood-brain barrier and into the brain. Anti-cancer drugs such as loperamide and doxorubicin bound to nanomaterials have been shown to cross the intact blood-brain barrier and released at therapeutic concentrations in the brain. The use of nanomaterials including peptide-based nanotubes to target the vascular endothelial growth factor (VEGF) receptor and cell adhesion molecules like integrins, cadherins and selectins, is a new approach to control disease progression.

Suri, Sarabjeet Singh; Fenniri, Hicham; Singh, Baljit

2007-01-01

373

Nanotechnology-based drug delivery systems.  

PubMed

Nanoparticles hold tremendous potential as an effective drug delivery system. In this review we discussed recent developments in nanotechnology for drug delivery. To overcome the problems of gene and drug delivery, nanotechnology has gained interest in recent years. Nanosystems with different compositions and biological properties have been extensively investigated for drug and gene delivery applications. To achieve efficient drug delivery it is important to understand the interactions of nanomaterials with the biological environment, targeting cell-surface receptors, drug release, multiple drug administration, stability of therapeutic agents and molecular mechanisms of cell signalling involved in pathobiology of the disease under consideration. Several anti-cancer drugs including paclitaxel, doxorubicin, 5-fluorouracil and dexamethasone have been successfully formulated using nanomaterials. Quantom dots, chitosan, Polylactic/glycolic acid (PLGA) and PLGA-based nanoparticles have also been used for in vitro RNAi delivery. Brain cancer is one of the most difficult malignancies to detect and treat mainly because of the difficulty in getting imaging and therapeutic agents past the blood-brain barrier and into the brain. Anti-cancer drugs such as loperamide and doxorubicin bound to nanomaterials have been shown to cross the intact blood-brain barrier and released at therapeutic concentrations in the brain. The use of nanomaterials including peptide-based nanotubes to target the vascular endothelial growth factor (VEGF) receptor and cell adhesion molecules like integrins, cadherins and selectins, is a new approach to control disease progression. PMID:18053152

Suri, Sarabjeet Singh; Fenniri, Hicham; Singh, Baljit

2007-01-01

374

A Combinatorial Approach for Targeted Delivery using Small Molecules and Reversible Masking to Bypass Non-Specific Uptake In Vivo  

PubMed Central

We have developed a multi-disciplinary approach combining molecular biology, delivery technology, combinatorial chemistry, and reversible masking to create improved systemic, targeted delivery of plasmid DNA while avoiding non-specific uptake in vivo. We initially used a well characterized model targeting the asialolglycoprotein receptor in the liver. Using our bilamellar invaginated vesicle (BIV) liposomal delivery system with reversible masking, we increased expression in the liver by 76-fold, nearly equaling expression in first-pass organs using non-targeted complexes, with no expression in other organs. The same technology was then applied to efficiently target delivery to a human tumor microenvironment model. We achieved efficient, targeted delivery by attachment of specific targeting ligands to the surface of our BIV complexes in conjunction with reversible masking to bypass non-specific tissues and organs. We identified ligands that target a human tumor microenvironment created in vitro by co-culturing primary human endothelial cells with human lung or pancreatic cancer cells. The model was confirmed by increased expression of tumor endothelial phenotypes including CD31 and VEGF-A, and prolonged survival of endothelial capillary-like structures. The co-cultures were used for high-throughput screening of a specialized small-molecule library to identify ligands specific for human tumor-associated endothelial cells in vitro. We identified small molecules that enhanced the transfection efficiency of tumor-associated endothelial cells, but not normal human endothelial cells or cancer cells. Intravenous injection of our targeted, reversibly masked complexes into mice, bearing human pancreatic tumor and endothelial cells, specifically increased transfection to this tumor microenvironment about 200-fold. Efficacy studies using our optimized targeted delivery of a plasmid encoding thrombospondin-1 eliminated tumors completely after five intravenous injections administered once every week.

Shi, Qiaoyun; Nguyen, Andrew T.; Angell, Yu; Deng, Defeng; Na, Chang-Rim; Burgess, Kevin; Roberts, David D.; Brunicardi, F. Charles; Templeton, Nancy Smyth

2010-01-01

375

MRI-Visible Micellar Nanomedicine for Targeted Drug Delivery to Lung Cancer Cells  

PubMed Central

Polymeric micelles are emerging as a highly integrated nanoplatform for cancer targeting, drug delivery and tumor imaging applications. In this study, we describe a multifunctional micelle (MFM) system that is encoded with a lung cancer-targeting peptide (LCP), and encapsulated with superparamagnetic iron oxide (SPIO) and doxorubicin (Doxo) for MR imaging and therapeutic delivery, respectively. The LCP-encoded MFM showed significantly increased ?v?6-dependent cell targeting in H2009 lung cancer cells over a scrambled peptide (SP)-encoded MFM control as well as in an ?v?6-negative H460 cell control. 3H-Labeled MFM nanoparticles were used to quantify the time- and dose-dependent cell uptake of MFM nanoparticles with different peptide encoding (LCP vs SP) and surface densities (20% and 40%) in H2009 cells. LCP functionalization of the micelle surface increased uptake of the MFM by more than 3-fold compared to the SP control. These results were confirmed by confocal laser scanning microscopy, which further demonstrated the successful Doxo release from MFM and accumulation in the nucleus. SPIO clustering inside the micelle core resulted in high T2 relaxivity (>400 Fe mM?1 s?1) of the resulting MFM nanoparticles. T2-weighted MRI images showed clear contrast differences between