Science.gov

Sample records for targeted paclitaxel delivery

  1. Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

    PubMed

    Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil

    2015-04-01

    Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics. PMID:25686010

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

    NASA Astrophysics Data System (ADS)

    Li, Yuanpei; Pan, Shirong; Zhang, Wei; Du, Zhuo

    2009-02-01

    Novel thermo-sensitive nanoparticles self-assembled from poly(N,N-diethylacrylamide- co-acrylamide)-block-poly(γ-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), circular dichroism (CD), fluorescence spectroscopy, dynamic light scattering (DLS), and atom force microscopy (AFM). The mean diameter of the nanoparticles increased slightly from 110 to 129 nm when paclitaxel (PTX), a poorly water-soluble anti-tumor drug, was encapsulated. A stability study in bovine serum albumin (BSA) solution indicated that the PTX loaded nanoparticles may have a long circulation time under physiological environments as the LCST was above physiological body temperature and the shell remained hydrophilic at 37 °C. The PTX release profiles showed thermo-sensitive controlled behavior. The proliferation inhibiting activity of PTX loaded nanoparticles was evaluated against Hela cells in vitro, compared with Taxol (a formulation of paclitaxel dissolved in Cremophor EL and ethanol). The cytotoxicity of PTX loaded nanoparticles increased obviously when hyperthermia was performed. The nanoparticles synthesized here could be an ideal candidate for thermal triggered anti-tumor PTX delivery system.

  3. Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases

    PubMed Central

    Kisiel, Walter; Lu, Yang J.; Petersen, Lars C.; Ndungu, John M.; Moore, Terry W.; Parker, Ernest T.; Sun, Aiming; Liotta, Dennis C.; El-Rayes, Bassel F.; Brat, Daniel J.; Snyder, James P.; Shoji, Mamoru

    2014-01-01

    Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01–0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis. PMID:25574399

  4. Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity.

    PubMed

    Esfandyari-Manesh, Mehdi; Darvishi, Behrad; Ishkuh, Fatemeh Azizi; Shahmoradi, Elnaz; Mohammadi, Ali; Javanbakht, Mehran; Dinarvand, Rassoul; Atyabi, Fatemeh

    2016-05-01

    The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 ± 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC50) of 4.9 ± 0.9, 7.4 ± 0.5 and 32.8 ± 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells. PMID:26952466

  5. Folate-modified lipid–polymer hybrid nanoparticles for targeted paclitaxel delivery

    PubMed Central

    Zhang, Linhua; Zhu, Dunwan; Dong, Xia; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

    2015-01-01

    The purpose of this study was to develop a novel lipid–polymer hybrid drug carrier comprised of folate (FA) modified lipid-shell and polymer-core nanoparticles (FLPNPs) for sustained, controlled, and targeted delivery of paclitaxel (PTX). The core-shell NPs consist of 1) a poly(ε-caprolactone) hydrophobic core based on self-assembly of poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCL-PEG-PCL) amphiphilic copolymers, 2) a lipid monolayer formed with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000), 3) a targeting ligand (FA) on the surface, and were prepared using a thin-film hydration and ultrasonic dispersion method. Transmission electron microscopy and dynamic light scattering analysis confirmed the coating of the lipid monolayer on the hydrophobic polymer core. Physicochemical characterizations of PTX-loaded FLPNPs, such as particle size and size distribution, zeta potential, morphology, drug loading content, encapsulation efficiency, and in vitro drug release, were also evaluated. Fluorescent microscopy proved the internalization efficiency and targeting ability of the folate conjugated on the lipid monolayer for the EMT6 cancer cells which overexpress folate receptor. In vitro cytotoxicity assay demonstrated that the cytotoxic effect of PTX-loaded FLPNPs was lower than that of Taxol®, but higher than that of PTX-loaded LPNPs (without folate conjugation). In EMT6 breast tumor model, intratumoral administration of PTX-loaded FLPNPs showed similar antitumor efficacy but low toxicity compared to Taxol®. More importantly, PTX-loaded FLPNPs showed greater tumor growth inhibition (65.78%) than the nontargeted PTX-loaded LPNPs (48.38%) (P<0.05). These findings indicated that the PTX loaded-FLPNPs with mixed lipid monolayer shell and biodegradable polymer core would be a promising nanosized drug formulation for tumor-targeted therapy. PMID:25844039

  6. Biological evaluation of paclitaxel-peptide conjugates as a model for MMP2-targeted drug delivery.

    PubMed

    Yamada, Roppei; Kostova, Maya B; Anchoori, Ravi Kumar; Xu, Shili; Neamati, Nouri; Khan, Saeed R

    2010-02-01

    Paclitaxel (PTX) is a highly effective cytotoxic agent widely used for the treatment of several solid tumors. However, PTX shows dose-limiting cytotoxicity and in most cases induces drug resistance followed by failure in treatment. To enhance the therapeutic index of a given drug, various drug delivery methods have been explored to systemically deliver sufficient amount of the drug to the desired site. In the present study, we designed and synthesized two PTX prodrugs by conjugating PTX at different sites with an octapeptide (AcGPLGIAGQ) that can be cleaved by MMP2 at tumor sites. As a result, PTX is expected to be released at the tumor sites, absorbed by the tumor cells, and thereby inhibit the tumor growth. We evaluated the in vitro activities of the two drugs in a panel of drug-sensitive and -resistant cancer cell lines and their in vivo efficacies in a HT1080 fibrosarcoma mouse xenograft model that overexpresses MMP2. Our in vitro results showed that the PTX-AcGPLGIAGQ conjugates inhibited cancer cell proliferation with higher activity compared to that observed for free PTX, both of which were mediated by an arrest of G(2)/M-phase of the cell cycle. Consistent with the in vitro results, treatment with PTX-octapeptide conjugate resulted in extensive areas of necrosis and a lower percentage of proliferating cells in xenograft tumor sections. Together, our results indicate the potential of the tumor-targeted delivery of PTX to exploit the specific recognition of MMP2, reduce toxicity, and selectively kill tumor cells. PMID:20023432

  7. Anti-HER2/neu peptide-conjugated iron oxide nanoparticles for targeted delivery of paclitaxel to breast cancer cells

    NASA Astrophysics Data System (ADS)

    Mu, Qingxin; Kievit, Forrest M.; Kant, Rajeev J.; Lin, Guanyou; Jeon, Mike; Zhang, Miqin

    2015-10-01

    Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (~30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular targeting and selective killing in human HER2/neu-positive breast cancer cells.Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (~30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular

  8. Reconstituted high density lipoprotein mediated targeted co-delivery of HZ08 and paclitaxel enhances the efficacy of paclitaxel in multidrug-resistant MCF-7 breast cancer cells.

    PubMed

    Zhang, Fangrong; Wang, Xiaoyi; Xu, Xiangting; Li, Min; Zhou, Jianping; Wang, Wei

    2016-09-20

    In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could

  9. PEG-Farnesyl Thiosalicylic Acid Telodendrimer Micelles as an Improved Formulation for Targeted Delivery of Paclitaxel

    PubMed Central

    2015-01-01

    We have recently designed and developed a dual-functional drug carrier that is based on poly(ethylene glycol) (PEG)-derivatized farnesylthiosalicylate (FTS, a nontoxic Ras antagonist). PEG5K-FTS2 readily form micelles (20–30 nm) and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these micelles. PTX formulated in PEG5K-FTS2 micelles showed an antitumor activity that was more efficacious than Taxol in a syngeneic mouse model of breast cancer (4T1.2). In order to further improve our PEG-FTS micellar system, four PEG-FTS conjugates were developed that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/FTS (1/2 vs 1/4) in the conjugates. These conjugates were characterized including CMC, drug loading capacity, stability, and their efficacy in delivery of anticancer drug PTX to tumor cells in vitro and in vivo. Our data showed that the conjugates with four FTS molecules were more effective than the conjugates with two molecules of FTS and that FTS conjugates with PEG5K were more effective than the counterparts with PEG2K in forming stable mixed micelles. PTX formulated in PEG5K-FTS4 micelles was the most effective formulation in inhibiting the tumor growth in vivo. PMID:24987803

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

    PubMed

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

    2013-11-30

    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

  11. Heparin modification enhances the delivery and tumor targeting of paclitaxel-loaded N-octyl-N-trimethyl chitosan micelles.

    PubMed

    Zhang, Feiran; Fei, Jia; Sun, Minjie; Ping, Qineng

    2016-09-10

    Polycations have been widely used as efficient drug and gene carriers. However, the further application of polycation nanocarriers is greatly hampered by the serious cytotoxicity caused by exposed positive charges. Despite recent progress towards the therapeutic delivery of nucleic acids, there remains a compelling need for development of novel delivery systems for various types of drug. Here, we created mixed micelles based on N-octyl-N-trimethyl chitosan (OTMC) and coated them with an anionic polymer for delivery of paclitaxel (PTX). OTMC/PEG-100 stearate (S-100) micelles (PTX-SN) were firstly prepared by a dialysis method with a high drug loading efficiency and positive charge. PTX-SN micelles were then coated with two anionic polymers, heparin sodium (PTX-HSN) and sodium carboxymethyl cellulose (PTX-CSN) to shield positive charges. Both PTX-HSN and PTX-CSN micelles showed decreased cytotoxicity and hemolysis while retaining high uptake efficiency. PTX-HSN micelles were taken up more effectively than PTX-CSN by HeLa cells, which over-express heparanase. PTX-HSN micelles persisted longer in the circulation of rats than free drug in pharmacokinetic studies. DIR-HSN micelles accumulated strongly in tumors, and PTX-HSN micelles significantly inhibited tumor growth in tumor-bearing mice. Overall, the results validate heparin-coated OTMC micelles as safe and effective tumor-targeting carriers that are suitable for anti-tumor drug delivery. PMID:27426109

  12. Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles

    PubMed Central

    Shi, Yang; van der Meel, Roy; Theek, Benjamin; Blenke, Erik Oude; Pieters, Ebel H.E.; Fens, Marcel H.A.M.; Ehling, Josef; Schiffelers, Raymond M.; Storm, Gert; van Nostrum, Cornelus F.; Lammers, Twan; Hennink, Wim E.

    2015-01-01

    Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achieve prolonged circulation kinetics. As a result, PTX deposition in tumors is increased while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed paclitaxel (PTX)-loaded micelles which are stable without chemical crosslinking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol® or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid μCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses while they induced complete tumor regression in two different xenograft models (i.e. A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index. PMID:25831471

  13. Complex Structured Fluorescent Polythiophene Graft Copolymer as a Versatile Tool for Imaging, Targeted Delivery of Paclitaxel, and Radiotherapy.

    PubMed

    Guler, Emine; Akbulut, Huseyin; Geyik, Caner; Yilmaz, Tulay; Gumus, Z Pinar; Barlas, F Baris; Ahan, Recep Erdem; Demirkol, Dilek Odaci; Yamada, Shuhei; Endo, Takeshi; Timur, Suna; Yagci, Yusuf

    2016-07-11

    Advances in polymer chemistry resulted in substantial interest to utilize their diverse intrinsic advantages for biomedical research. Especially, studies on drug delivery for tumors have increased to a great extent. In this study, a novel fluorescent graft copolymer has been modified by a drug and targeting moiety and the resulting structure has been characterized by alterations in fluorescent intensity. The polythiophene based hybrid graft copolymer was synthesized by successive organic reactions and combination of in situ N-carboxy anhydride (NCA) ring opening and Suzuki coupling polymerization processes. Initially, targeted delivery of the graft copolymer was investigated by introducing a tumor specific ligand, anti-HER2/neu antibody, on the structure. The functionalized polymer was able to differentially indicate HER2-expressing A549 human lung carcinoma cells, whereas no signal was obtained for Vero, monkey kidney epithelial cells, and HeLa, human cervix adenocarcinoma cells. After integrating paclitaxel into the structure, cell viability, cell cycle progression, and radiosensitivity studies demonstrate HER2/neu targeting polymers were most effective to inhibit cell proliferation. Importantly, the graft copolymer used had no cytotoxic effects to cells, as evidenced by cell viability and cell cycle analysis. This work clearly confirms that a specially designed and fabricated graft copolymer with a highly complex structure is a promising theranostic agent capable of targeting tumor cells for diagnostic and therapeutic purposes. PMID:27305462

  14. Well-Defined Redox-Sensitive Polyethene Glycol-Paclitaxel Prodrug Conjugate for Tumor-Specific Delivery of Paclitaxel Using Octreotide for Tumor Targeting.

    PubMed

    Yin, Tingjie; Wu, Qu; Wang, Lei; Yin, Lifang; Zhou, Jianping; Huo, Meirong

    2015-08-01

    A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer-drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer-PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23,000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer-PTX prodrug system is promising in tumor therapy. PMID:26086430

  15. Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway.

    PubMed

    Blanco, Elvin; Sangai, Takafumi; Wu, Suhong; Hsiao, Angela; Ruiz-Esparza, Guillermo U; Gonzalez-Delgado, Carlos A; Cara, Francisca E; Granados-Principal, Sergio; Evans, Kurt W; Akcakanat, Argun; Wang, Ying; Do, Kim-Anh; Meric-Bernstam, Funda; Ferrari, Mauro

    2014-07-01

    Ongoing clinical trials target the aberrant PI3K/Akt/mammalian target of rapamycin (mTOR) pathway in breast cancer through administration of rapamycin, an allosteric mTOR inhibitor, in combination with paclitaxel. However, synergy may not be fully exploited clinically because of distinct pharmacokinetic parameters of drugs. This study explores the synergistic potential of site-specific, colocalized delivery of rapamycin and paclitaxel through nanoparticle incorporation. Nanoparticle drug loading was accurately controlled, and synergistic drug ratios established in vitro. Precise drug ratios were maintained in tumors 48 hours after nanoparticle administration to mice, at levels twofold greater than liver and spleen, yielding superior antitumor activity compared to controls. Simultaneous and preferential in vivo delivery of rapamycin and paclitaxel to tumors yielded mechanistic insights into synergy involving suppression of feedback loop Akt phosphorylation and its downstream targets. Findings demonstrate that a same time, same place, and specific amount approach to combination chemotherapy by means of nanoparticle delivery has the potential to successfully translate in vitro synergistic findings in vivo. Predictive in vitro models can be used to determine optimum drug ratios for antitumor efficacy, while nanoparticle delivery of combination chemotherapies in preclinical animal models may lead to enhanced understanding of mechanisms of synergy, ultimately opening several avenues for personalized therapy. PMID:24569835

  16. Octa-ammonium POSS-conjugated single-walled carbon nanotubes as vehicles for targeted delivery of paclitaxel

    PubMed Central

    Naderi, Naghmeh; Madani, Seyed Y.; Mosahebi, Afshin; Seifalian, Alexander M.

    2015-01-01

    Background Carbon nanotubes (CNTs) have unique physical and chemical properties. Furthermore, novel properties can be developed by attachment or encapsulation of functional groups. These unique properties facilitate the use of CNTs in drug delivery. We developed a new nanomedicine consisting of a nanocarrier, cell-targeting molecule, and chemotherapeutic drug and assessed its efficacy in vitro. Methods The efficacy of a single-walled carbon nanotubes (SWCNTs)-based nanoconjugate system is assessed in the targeted delivery of paclitaxel (PTX) to cancer cells. SWCNTs were oxidized and reacted with octa-ammonium polyhedral oligomeric silsesquioxanes (octa-ammonium POSS) to render them biocompatible and water dispersable. The functionalized SWCNTs were loaded with PTX, a chemotherapeutic agent toxic to cancer cells, and Tn218 antibodies for cancer cell targeting. The nanohybrid composites were characterized with transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and ultraviolet–visible–near-infrared (UV–Vis–NIR). Additionally, their cytotoxic effects on Colon cancer cell (HT-29) and Breast cancer cell (MCF-7) lines were assessed in vitro. Results TEM, FTIR, and UV–Vis–NIR studies confirmed side-wall functionalization of SWCNT with COOH-groups, PTX, POSS, and antibodies. Increased cell death was observed with PTX–POSS–SWCNT, PTX–POSS–Ab–SWCNT, and free PTX compared to functionalized-SWCNT (f-SWCNT), POSS–SWCNT, and cell-only controls at 48 and 72 h time intervals in both cell lines. At all time intervals, there was no significant cell death in the POSS–SWCNT samples compared to cell-only controls. Conclusion The PTX-based nanocomposites were shown to be as cytotoxic as free PTX. This important finding indicates successful release of PTX from the nanocomposites and further reiterates the potential of SWCNTs to deliver drugs directly to targeted cells and tissues. PMID:26356347

  17. Targeted delivery and controlled release of Paclitaxel for the treatment of lung cancer using single-walled carbon nanotubes.

    PubMed

    Yu, Baodan; Tan, Li; Zheng, Runhui; Tan, Huo; Zheng, Lixia

    2016-11-01

    A new type of drug delivery system (DDS) based on single-walled carbon nanotubes (SWNTs) for controlled-release of the anti-cancer drug Paclitaxel (PTX) was constructed in this study. Chitosan (CHI) was non-covalently attached to the SWNTs to improve biocompatibility. Biocompatible hyaluronan was also combined to the outer CHI layer to realise the specific targeting property. The results showed that the release of PTX was pH-triggered and was better at lower pH (pH5.5). The modified SWNTs showed a significant improvement in intracellular reactive oxygen species (ROS), which may have enhanced mitogen-activated protein kinase activation and further promoted cell apoptosis. The results of western blotting indicated that the apoptosis-related proteins were abundantly expressed in A549 cells. Lactate dehydrogenase (LDH) release assay and cell viability assay demonstrated that PTX-loaded SWNTs could destroy cell membrane integrity, thus inducing lower cell viability of the A549 cells. Thus, this targeting DDS could effectively inhibit cell proliferation and kill A549 cells, is a promising system for cancer therapy. PMID:27524057

  18. Targeted delivery of polyamidoamine-paclitaxel conjugate functionalized with anti-human epidermal growth factor receptor 2 trastuzumab

    PubMed Central

    Ma, Pengkai; Zhang, Xuemei; Ni, Ling; Li, Jinming; Zhang, Fengpu; Wang, Zheng; Lian, Shengnan; Sun, Kaoxiang

    2015-01-01

    Background Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2. Methods TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. Results Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM. Conclusion TMAB can serve as an effective targeting agent

  19. Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation.

    PubMed

    Ravar, Fatemeh; Saadat, Ebrahim; Gholami, Mehdi; Dehghankelishadi, Pouya; Mahdavi, Mehdi; Azami, Samira; Dorkoosh, Farid A

    2016-05-10

    Breast cancer is the leading cause of cancer death in women. Chemotherapy is regarded as the most essential strategy in inhibiting the proliferation of tumor cells. Paclitaxel is a widely used taxane; however, the side effects of available Cremophor-based formulations and also the limitations of passive targeting uncovered an essential need to develop tumor-specific targeted nanocarriers. A hyaluronic acid targeted liposomal formulation of paclitaxel was prepared in which, hyaluronic acid was electrostatistically attracted to the surface of liposomes. Liposomes, had a particle size of 106.4±3.2nm, a weakly negative zeta potential of -9.7±0.8mV and an acceptable encapsulation efficiency of 92.1±1.7%. The release profile of liposomes in buffer showed that 95% of PTX was released during 40h. Confocal laser scanning microscopy and flow cytometry analysis showed the greater cellular internalization of coumarin-loaded liposomes compared to free coumarin. MTT assay on 4T1 and T47D cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. Cell cycle analysis showed that cells were mainly blocked at G2/M phases after 48h treatment with liposomes. In vivo real time imaging on 4T1 tumor-bearing mice revealed that the liposomal formulation mainly accumulated in the tumor area. Liposomes also had better antitumor efficacy against Cremophor-based formulation. In conclusion, hyaluronic acid targeted paclitaxel liposome can serve as a promising targeted formulation of paclitaxel for future cancer chemotherapy. PMID:26968799

  20. Enabling Anticancer Therapeutics by Nanoparticle Carriers: The Delivery of Paclitaxel

    PubMed Central

    Liu, Yongjin; Zhang, Bin; Yan, Bing

    2011-01-01

    Anticancer drugs, such as paclitaxel (PTX), are indispensable for the treatment of a variety of malignancies. However, the application of most drugs is greatly limited by the low water solubility, poor permeability, or high efflux from cells. Nanoparticles have been widely investigated to enable drug delivery due to their low toxicity, sustained drug release, molecular targeting, and additional therapeutic and imaging functions. This review takes paclitaxel as an example and compares different nanoparticle-based delivery systems for their effectiveness in cancer chemotherapy. PMID:21845085

  1. Paclitaxel Nano-Delivery Systems: A Comprehensive Review.

    PubMed

    Ma, Ping; Mumper, Russell J

    2013-02-18

    Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

  2. Paclitaxel Nano-Delivery Systems: A Comprehensive Review

    PubMed Central

    Ma, Ping; Mumper, Russell J.

    2013-01-01

    Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

  3. The use of α-conotoxin ImI to actualize the targeted delivery of paclitaxel micelles to α7 nAChR-overexpressing breast cancer.

    PubMed

    Mei, Dong; Lin, Zhiqiang; Fu, Jijun; He, Bing; Gao, Wei; Ma, Ling; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Lu, Wanliang; Zhou, Demin; Zhang, Qiang

    2015-02-01

    Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the α7 nAChR-overexpressing tumors, herein, α-conotoxin ImI, a disulfide-rich toxin with highly affinity for α7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of α7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the α7 nAChR-targeted nanomedicines could deliver more specifically and faster into α7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca(2+) transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, α7 nAChR is also a promising target for anti-tumor drug delivery and in this case, α-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting α7 nAChR-overexpressing tumors. PMID:25542793

  4. Biodegradable Self-Assembled Nanoparticles of Galactose-Containing Amphiphilic Triblock Copolymers for Targeted Delivery of Paclitaxel to HepG2 Cells.

    PubMed

    Wang, Tieshi; Tang, Xinde; Han, Jingtian; Ding, Yuanyuan; Guo, Wenjuan; Pei, Meishan

    2016-05-01

    Biodegradable self-assembled polymeric nanoparticles (NPs) composed of poly(6-O-methacryloyl-D-galactopyranose)-b-poly(L-lactide)-b-poly(6-O-methacryloyl-D-galactopyranose) (PMAGP-b-PLA-b-PMAGP) are prepared as carriers for the hydrophobic anticancer drug paclitaxel (PTX), to achieve target delivery to hepatoma cells. PTX can be encapsulated by the NPs with various molar ratios of L-lactide (LA) and 6-O-methacryloyl-D-galactopyranose (MAGP) during the process of self-assembly, and the resulting NPs exhibit high drug loading efficacy and substantial stability in aqueous solution. The size, size distribution, and morphology of the NPs are characterized using a Zetasizer Nano ZS and transmission electron microscopy. The hemolysis assay and cell cytotoxicity assay indicate that the polymeric NPs are biocompatible and non-toxic. The cellular uptake assay demonstrates that the galactose-containing NPs can be selectively recognized and subsequently accumulate in HepG2 cells. All of these results demonstrate that galactose-containing polymeric NPs are potential carriers for hepatoma-targeted drug delivery and liver cancer therapy in clinical medicine. PMID:26833548

  5. Folate Receptor Targeted Delivery of siRNA and Paclitaxel to Ovarian Cancer Cells via Folate Conjugated Triblock Copolymer to Overcome TLR4 Driven Chemotherapy Resistance.

    PubMed

    Jones, Steven K; Lizzio, Vincent; Merkel, Olivia M

    2016-01-11

    This paper focuses on the ability of a folate-decorated triblock copolymer to deliver a targeted dose of siRNA in order to overcome chemotherapy resistance which can commonly cause complications in ovarian cancer patients. The micelleplexes that are formed upon electrostatic interaction with siRNA are used to deliver siRNA in a targeted manner to SKOV-3 ovarian cancer cells that overexpress folate receptor-α (FRα). The triblock copolymer consists of polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol). In this work, polymers of different molecular weights of PEG, as well as different grafting degrees of the (g-PCL-b-PEG-Fol) chains to PEI, were analyzed to optimize targeted siRNA delivery. The polymers, their micelleplexes, and the in vitro performance of the latter were characterized by nuclear magnetic resonance, dynamic light scattering, transmission electron microscopy, flow cytrometry, western blot, confocal microscopy, and in luciferase assays. The different PEI-g-PCL-b-PEG-Fol conjugates showed suitable sizes below 260 nm, especially at N/P 5, which also allowed for full siRNA condensation. Furthermore, flow cytometry and Western blot analysis demonstrated that our best polymer was able to effectively deliver siRNA and that siRNA delivery resulted in efficient protein knockdown of toll-like receptor 4 (TLR4). Consequently, TLR4 knock down within SKOV-3 cells resensitized them toward paclitaxel (PTX) treatment, and apoptotic events increased. This study demonstrates that PEI-g-PCL-b-PEG-Fol conjugates are a reliable delivery system for siRNA and are able to mediate therapeutic protein knockdown within ovarian cancer cells. Additionally, this study provides further evidence to link TLR4 levels to chemotherapy resistance. PMID:26636884

  6. Paclitaxel loaded fibrinogen coated CdTe/ZnTe core shell nanoparticles for targeted imaging and drug delivery to breast cancer cells.

    PubMed

    Rejinold, N Sanoj; Baby, Thejus; Nair, Shantikumar V; Jayakumar, R

    2013-10-01

    The study aims at the targeted imaging using CdTe/ZnTe core shell QDs and delivery of paclitaxel (PTX) loaded fibrinogen coated yellow-QDs (PTX-fib-yellow-QDs) towards breast cancer cells via the alpha5Beta1-integrins. We developed fibrinogen coated different sized CdTe/ZnTe core shell quantum dots of 2-10 nm size, which have been prepared by one-pot aqueous-phase approach. The fib-coated-QDs (fib-coated-QDs) and PTX-fib-yellow-QDs were prepared by two-step coacervation technique using CaCl2 as cross-linker. Particle size of fib-coated-QDs was in between 60-220 nm while PTX-fib-yellow-QDs showed 180 +/- 40 nm. The MTT assay confirmed cytocompatibility of fib-coated-QDs on L929 and MCF-7 than bare QDs, whereas significant toxicity toward MCF-7 by PTX-fib-yellow-QDs was observed. The hemocompatible fib-coated-QDs showed enhanced localization and retention toward alpha5beta1-integrins +ve MCF-7 compared to alpha5beta1-integrins -ve L929 cells. The specific binding of fib-coated-yellow-QDs was further confirmed with alpha5beta1-integrins +ve HeLa and alpha5/beta1-integrins -ve HT29 cells. Cellular uptake studies revealed localization of PTX-fib-coated-yellow-QDs inside MCF-7 cells compared to the normal L929 cells. These results indicated that fib-coated-QDs could be used for targeted imaging and as a suitable "nanocarrier" aiming breast cancer cells. PMID:24015495

  7. Poly-paclitaxel/cyclodextrin-SPION nano-assembly for magnetically guided drug delivery system.

    PubMed

    Jeon, Hyeonjeong; Kim, Jihoon; Lee, Yeong Mi; Kim, Jinhwan; Choi, Hyung Woo; Lee, Junseok; Park, Hyeongmok; Kang, Youngnam; Kim, In-San; Lee, Byung-Heon; Hoffman, Allan S; Kim, Won Jong

    2016-06-10

    This work demonstrates the development of magnetically guided drug delivery systems and its potential on efficient anticancer therapy. The magnetically guided drug delivery system was successfully developed by utilizing superparamagnetic iron oxide nanoparticle, β-cyclodextrin, and polymerized paclitaxel. Multivalent host-guest interactions between β-cyclodextrin-conjugated superparamagnetic iron oxide nanoparticle and polymerized paclitaxel allowed to load the paclitaxel and the nanoparticle into the nano-assembly. Clusterized superparamagnetic iron oxide nanoparticles in the nano-assembly permitted the rapid and efficient targeted drug delivery. Compared to the control groups, the developed nano-assembly showed the enhanced anticancer effects in vivo as well as in vitro. Consequently, the strategy of the use of superparamagnetic nanoparticles and multivalent host-guest interactions has a promising potential for developing the efficient drug delivery systems. PMID:26780174

  8. A mucoadhesive in situ gel delivery system for paclitaxel.

    PubMed

    Jauhari, Saurabh; Dash, Alekha K

    2006-01-01

    MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen's phosphate buffer (pH 7.4) at 37 degrees C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61% +/- 0.19%, 12.0% +/- 0.98%, 31.7% +/- 0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drug-loaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1% +/- 4.35%, 44.2% +/- 6.35%, and 97.1% +/- 1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell. PMID:16796370

  9. Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors.

    PubMed

    Wang, Jie; Lu, Ze; Wang, Junfeng; Cui, Minjian; Yeung, Bertrand Z; Cole, David J; Wientjes, M Guillaume; Au, Jessie L-S

    2015-10-28

    The major barrier for using small interfering RNA (siRNA) as cancer therapeutics is the inadequate delivery and transfection in solid tumors. We have previously shown that paclitaxel tumor priming, by inducing apoptosis, expands the tumor interstitial space, improves the penetration and dispersion of nanoparticles and siRNA-lipoplexes in 3-dimensional tumor histocultures, and promotes the delivery and transfection efficiency of siRNA-lipoplexes under the locoregional setting in vivo (i.e., intraperitoneal treatment of intraperitoneal tumors). The current study evaluated whether tumor priming is functional for systemically delivered siRNA via intravenous injection, which would subject siRNA to several additional delivery barriers and elimination processes. We used the same pegylated cationic (PCat)-siRNA lipoplexes as in the intraperitoneal study to treat mice bearing subcutaneous human pancreatic Hs766T xenograft tumors. The target gene was survivin, an inducible chemoresistance gene. The results show single agent paclitaxel delayed tumor growth but also significantly induced the survivin protein level in residual tumors, whereas addition of PCat-siSurvivin completely reversed the paclitaxel-induced survivin and enhanced the paclitaxel activity (p<0.05). In comparison, PCat-siSurvivin alone did not yield survivin knockdown or antitumor activity, indicating the in vivo effectiveness of intravenous siRNA-mediated gene silencing requires paclitaxel cotreatment. Additional in vitro studies showed that paclitaxel promoted the cytoplasmic release of siGLO, a 22 nucleotide double-stranded RNA that has no mRNA targets, from its PCat lipoplex and/or endosomes/lysosomes. Taken together, our earlier and current data show paclitaxel tumor priming, by promoting the interstitial transport and cytoplasmic release, is critical to promote the delivery and transfection of siRNA in vivo. In addition, because paclitaxel has broad spectrum activity and is used to treat multiple types

  10. The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors

    PubMed Central

    Sarisozen, Can; Abouzeid, Abraham H.; Torchilin, Vladimir P.

    2014-01-01

    Multicellular 3D cancer cell culture (spheroids) resemble to in vivo tumors in terms of shape, cell morphology, growth kinetics, gene expression and drug response. However, these characteristics cause very limited drug penetration into deeper parts of the spheroids. In this study, we used multi drug resistant (MDR) ovarian cancer cell spheroid and in vivo tumor models to evaluate the co-delivery of paclitaxel (PCL) and a potent NF-κB inhibitor curcumin (CUR). PCL and CUR were co-loaded into the polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) based polymeric micelles modified with Transferrin (TF) as the targeting ligand. Cytotoxicity, cellular association and accumulation into the deeper layers were investigated in the spheroids and compared with the monolayer cell culture. Comparing to non-targeted micelles, flow cytometry and confocal imaging proved significantly deeper and higher micelle penetration into the spheroids with TF-targeting. Both in monolayers and spheroids, PCL cytotoxicity was significantly increased when co-delivered with CUR in non-targeted micelles or as single agent in TF-targeted micelles, whereas TF-modification of co-loaded micelles did not further enhance the cytotoxicity. In vivo tumor inhibition studies showed good correlation with the 3D cell culture experiments, which suggests the current spheroid model can be used as an intermediate model for evaluation of co-delivery of anticancer compounds in targeted micelles. PMID:25016976

  11. Designing Paclitaxel Drug Delivery Systems Aimed at Improved Patient Outcomes: Current Status and Challenges

    PubMed Central

    Surapaneni, Madhu S.; Das, Sudip K.; Das, Nandita G.

    2012-01-01

    Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01 mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper. PMID:22934190

  12. Targeted chemotherapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in metastatic breast cancer: which benefit for which patients?

    PubMed Central

    Palumbo, Raffaella; Sottotetti, Federico; Bernardo, Antonio

    2016-01-01

    The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m2, but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific ‘difficult-to-treat’ patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, ‘real life’ available experiences are also discussed with the aim of providing an update for daily clinical practice. PMID:27239239

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

    NASA Astrophysics Data System (ADS)

    Zubris, Kimberly Ann Veronica

    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

  14. Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

    PubMed Central

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

    2016-01-01

    The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery. PMID:26759029

  15. Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol.

    PubMed

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

    2016-01-01

    The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery. PMID:26759029

  16. Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer

    PubMed Central

    Xing, Lingxi; Shi, Qiusheng; Zheng, Kailiang; Shen, Ming; Ma, Jing; Li, Fan; Liu, Yang; Lin, Lizhou; Tu, Wenzhi; Duan, Yourong; Du, Lianfang

    2016-01-01

    Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer. PMID:27446491

  17. Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer.

    PubMed

    Xing, Lingxi; Shi, Qiusheng; Zheng, Kailiang; Shen, Ming; Ma, Jing; Li, Fan; Liu, Yang; Lin, Lizhou; Tu, Wenzhi; Duan, Yourong; Du, Lianfang

    2016-01-01

    Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer. PMID:27446491

  18. Photoimmunotherapy of hepatocellular carcinoma-targeting Glypican-3 combined with nanosized albumin-bound paclitaxel

    PubMed Central

    Hanaoka, Hirofumi; Nakajima, Takahito; Sato, Kazuhide; Watanabe, Rira; Phung, Yen; Gao, Wei; Harada, Toshiko; Kim, Insook; Paik, Chang H; Choyke, Peter L; Ho, Mitchell; Kobayashi, Hisataka

    2015-01-01

    Aim Effectiveness of Glypican-3 (GPC3)-targeted photoimmunotherapy (PIT) combined with the nanoparticle albumin-bound paclitaxel (nab-paclitaxel) for hepatocellular carcinoma was evaluated. Materials & methods GPC3 expressing A431/G1 cells were incubated with a phthalocyanine-derivative, IRDye700DX (IR700), conjugated to an anti-GPC3 antibody, IR700-YP7 and exposed to near-infrared light. Therapeutic experiments combining GPC3-targeted PIT with nab-paclitaxel were performed in A431/G1 tumor-bearing mice. Results IR700-YP7 bound to A431/G1 cells and induced rapid target-specific necrotic cell death by near-infrared light exposure in vitro. IR700-YP7 accumulated in A431/G1 tumors. Tumor growth was inhibited by PIT compared with nontreated control. Additionally, PIT dramatically increased nabpaclitaxel delivery and enhanced the therapeutic effect. Conclusion PIT targeting GPC3 combined with nab-paclitaxel is a promising method for treating hepatocellular carcinoma. PMID:25929570

  19. c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma.

    PubMed

    Huang, YuKun; Liu, Wenchao; Gao, Feng; Fang, Xiaoling; Chen, Yanzuo

    2016-01-01

    Brain glioma therapy is an important challenge in oncology. Here, doxorubicin (DOX) and paclitaxel (PTX)-loaded cyclic arginine-glycine-aspartic acid peptide (c(RGDyK))-decorated Pluronic micelles (cyclic arginine-glycine-aspartic acid peptide-decorated Pluronic micelles loaded with doxorubicin and paclitaxel [RGD-PF-DP]) were designed as a potential targeted delivery system to enhance blood-brain barrier penetration and improve drug accumulation via integrin-mediated transcytosis/endocytosis and based on integrin overexpression in blood-brain barrier and glioma cells. The physicochemical characterization of RGD-PF-DP revealed a satisfactory size of 28.5±0.12 nm with uniform distribution and core-shell structure. The transport rates across the in vitro blood-brain barrier model, cellular uptake, cytotoxicity, and apoptosis of U87 malignant glioblastoma cells of RGD-PF-DP were significantly greater than those of non-c(RGDyK)-decorated Pluronic micelles. In vivo fluorescence imaging demonstrated the specificity and efficacy of intracranial tumor accumulation of RGD-PF-DP. RGD-PF-DP displayed an extended median survival time of 39 days, with no serious body weight loss during the regimen. No acute toxicity to major organs was observed in mice receiving treatment doses via intravenous administration. In conclusion, RGD-PF-DP could be a promising vehicle for enhanced doxorubicin and paclitaxel delivery in patients with brain glioma. PMID:27143884

  20. c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma

    PubMed Central

    Huang, YuKun; Liu, Wenchao; Gao, Feng; Fang, Xiaoling; Chen, Yanzuo

    2016-01-01

    Brain glioma therapy is an important challenge in oncology. Here, doxorubicin (DOX) and paclitaxel (PTX)-loaded cyclic arginine-glycine-aspartic acid peptide (c(RGDyK))-decorated Pluronic micelles (cyclic arginine-glycine-aspartic acid peptide-decorated Pluronic micelles loaded with doxorubicin and paclitaxel [RGD-PF-DP]) were designed as a potential targeted delivery system to enhance blood–brain barrier penetration and improve drug accumulation via integrin-mediated transcytosis/endocytosis and based on integrin overexpression in blood–brain barrier and glioma cells. The physicochemical characterization of RGD-PF-DP revealed a satisfactory size of 28.5±0.12 nm with uniform distribution and core-shell structure. The transport rates across the in vitro blood–brain barrier model, cellular uptake, cytotoxicity, and apoptosis of U87 malignant glioblastoma cells of RGD-PF-DP were significantly greater than those of non-c(RGDyK)-decorated Pluronic micelles. In vivo fluorescence imaging demonstrated the specificity and efficacy of intracranial tumor accumulation of RGD-PF-DP. RGD-PF-DP displayed an extended median survival time of 39 days, with no serious body weight loss during the regimen. No acute toxicity to major organs was observed in mice receiving treatment doses via intravenous administration. In conclusion, RGD-PF-DP could be a promising vehicle for enhanced doxorubicin and paclitaxel delivery in patients with brain glioma. PMID:27143884

  1. iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes.

    PubMed

    Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo; Gaitzsch, Jens; Kotamraju, Venkata Ramana; Sugahara, Kazuki N; Tammik, Olav; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet

    2016-10-01

    Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis. PMID:27472162

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

    PubMed

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

    2013-07-01

    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

  3. Covalent linkage of nanodiamond-paclitaxel for drug delivery and cancer therapy

    NASA Astrophysics Data System (ADS)

    Liu, Kuang-Kai; Zheng, Wen-Wei; Wang, Chi-Ching; Chiu, Yu-Chung; Cheng, Chia-Liang; Lo, Yu-Shiu; Chen, Chinpiao; Chao, Jui-I.

    2010-08-01

    A nanoparticle-conjugated cancer drug provides a novel strategy for cancer therapy. In this study, we manipulated nanodiamond (ND), a carbon nanomaterial, to covalently link paclitaxel for cancer drug delivery and therapy. Paclitaxel was bound to the surface of 3-5 nm sized ND through a succession of chemical modifications. The ND-paclitaxel conjugation was measured by atomic force microscope and nuclear magnetic resonance spectroscopy, and confirmed with infrared spectroscopy by the detection of deuterated paclitaxel. Treatment with 0.1-50 µg ml - 1 ND-paclitaxel for 48 h significantly reduced the cell viability in the A549 human lung carcinoma cells. ND-paclitaxel induced both mitotic arrest and apoptosis in A549 cells. However, ND alone or denatured ND-paclitaxel (after treatment with strong alkaline solution, 1 M NaOH) did not induce the damage effects on A549 cells. ND-paclitaxel was taken into lung cancer cells in a concentration-dependent manner using flow cytometer analysis. The ND-paclitaxel particles were located in the microtubules and cytoplasm of A549 cells observed by confocal microscopy. Furthermore, ND-paclitaxel markedly blocked the tumor growth and formation of lung cancer cells in xenograft SCID mice. Together, we provide a functional covalent conjugation of ND-paclitaxel, which can be delivered into lung carcinoma cells and preserves the anticancer activities on the induction of mitotic blockage, apoptosis and anti-tumorigenesis.

  4. Hydrophobically modified inulin as an amphiphilic carbohydrate polymer for micellar delivery of paclitaxel for intravenous route.

    PubMed

    Muley, Pratik; Kumar, Sunny; El Kourati, Fadoua; Kesharwani, Siddharth S; Tummala, Hemachand

    2016-03-16

    Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate 'core-shell' delivery system for drug targeting. Recently, hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1(®) (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37±10.45nm with excellent drug encapsulation efficiency (95.66±2.25%) and loading (8.69±0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel. PMID:26792170

  5. A review of the ligands and related targeting strategies for active targeting of paclitaxel to tumours.

    PubMed

    Li, Juan; Wang, Fengshan; Sun, Deqing; Wang, Rongmei

    2016-08-01

    It has been 30 years since the discovery of the anti-tumour property of paclitaxel (PTX), which has been successfully applied in clinic for the treatment of carcinomas of the lungs, breast and ovarian. However, PTX is poorly soluble in water and has no targeting and selectivity to tumour tissue. Recent advances in active tumour targeting of PTX delivery vehicles have addressed some of the issues related to lack of solubility in water and non-specific toxicities associated with PTX. These PTX delivery vehicles are designed for active targeting to specific cancer cells by the addition of ligands for recognition by specific receptors/antigens on cancer cells. This article will focus on various ligands and related targeting strategies serving as potential tools for active targeting of PTX to tumour tissues, illustrating their use in different tumour models. This review also highlights the need of further studies on the discovery of receptors in different cells of specific organ and ligands with binding efficiency to these specific receptors. PMID:26878228

  6. Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance.

    PubMed

    Khongkow, P; Gomes, A R; Gong, C; Man, E P S; Tsang, J W-H; Zhao, F; Monteiro, L J; Coombes, R C; Medema, R H; Khoo, U S; Lam, E W-F

    2016-02-25

    FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7Tax(R) cells. KIF20A depletion also renders MCF-7 and MCF-7Tax(R) cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance. PMID:25961928

  7. Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance

    PubMed Central

    Khongkow, P; Gomes, A R; Gong, C; Man, E P S; Tsang, J W-H; Zhao, F; Monteiro, L J; Coombes, R C; Medema, R H; Khoo, U S; Lam, E W-F

    2016-01-01

    FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7TaxR cells. KIF20A depletion also renders MCF-7 and MCF-7TaxR cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance. PMID:25961928

  8. Paclitaxel-loaded phosphonated calixarene nanovesicles as a modular drug delivery platform

    PubMed Central

    Mo, Jingxin; Eggers, Paul K.; Yuan, Zhi-xiang; Raston, Colin L.; Lim, Lee Yong

    2016-01-01

    A modular p-phosphonated calix[4]arene vesicle (PCV) loaded with paclitaxel (PTX) and conjugated with folic acid as a cancer targeting ligand has been prepared using a thin film-sonication method. It has a pH-responsive capacity to trigger the release of the encapsulated PTX payload under mildly acidic conditions. PTX-loaded PCV conjugated with alkyne-modified PEG-folic acid ligands prepared via click ligation (fP-PCVPTX) has enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumour cells over FR-negative A549 lung tumour cells. Moreover, fP-PCVPTX is also four times more potent than the non-targeting PCVPTX platform towards SKOV-3 cells. Overall, as a delivery platform the PCVs have the potential to enhance efficacy of anticancer drugs by targeting a chemotherapeutic payload specifically to tumours and triggering the release of the encapsulated drug in the vicinity of cancer cells. PMID:27009430

  9. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

    PubMed Central

    Brunetti, Jlenia; Pillozzi, Serena; Falciani, Chiara; Depau, Lorenzo; Tenori, Eleonora; Scali, Silvia; Lozzi, Luisa; Pini, Alessandro; Arcangeli, Annarosa; Menichetti, Stefano; Bracci, Luisa

    2015-01-01

    Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. PMID:26626158

  10. Pegylated polyelectrolyte nanoparticles containing paclitaxel as a promising candidate for drug carriers for passive targeting.

    PubMed

    Szczepanowicz, Krzysztof; Bzowska, Monika; Kruk, Tomasz; Karabasz, Alicja; Bereta, Joanna; Warszynski, Piotr

    2016-07-01

    Targeted drug delivery systems are of special importance in cancer therapies, since serious side effects resulting from unspecific accumulation of highly toxic chemotherapeutics in healthy tissues can restrict effectiveness of the therapy. In this work we present the method of preparing biocompatible, polyelectrolyte nanoparticles containing the anticancer drug that may serve as a vehicle for passive tumor targeting. The nanoparticles were prepared via direct encapsulation of emulsion droplets in a polyelectrolyte multilayer shell. The oil cores that contained paclitaxel were stabilized by docusate sodium salt/poly-l-lysine surface complex (AOT/PLL) and were encapsulated in shells formed by the LbL adsorption of biocompatible polyelectrolytes, poly-L-glutamic acid (PGA) and PLL up to 5 or 6 layers. The surface of the nanoparticles was pegylated through the adsorption of the pegylated polyelectrolyte (PGA-g-PEG) as the outer layer to prolong the persistence of the nanocarriers in the circulation. The synthesized nanoparticles were stable in cell culture medium containing serum and their average size was 100nm, which makes them promising candidates for passive targeted drug delivery. This notion was further confirmed by the results of studying the biological effects of nanoformulations on two tumor cell lines: mouse colon carcinoma cell line CT26-CEA and the mouse mammary carcinoma cell line 4T1. The empty polyelectrolyte nanoparticles did not affect the viability of the tested cells, whereas encapsulated paclitaxel retained its strong cytotoxic/cytostatic activity. PMID:27037784

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

    NASA Astrophysics Data System (ADS)

    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

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

    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.

  13. Vaginal delivery of paclitaxel via nanoparticles with non-mucoadhesive surfaces suppresses cervical tumor growth

    PubMed Central

    Yang, Ming; Yu, Tao; Wang, Ying-Ying; Lai, Samuel K.; Zeng, Qi; Miao, Bolong; Tang, Benjamin C.; Simons, Brian W.; Ensign, Laura; Liu, Guanshu; Chan, Kannie W. Y.; Juang, Chih-Yin; Mert, Olcay; Wood, Joseph; Fu, Jie; McMahon, Michael T.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early stage cervical cancer. We hypothesize drug-loaded nanoparticles must rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract to effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner. We develop paclitaxel-loaded nanoparticles, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. We further employ a mouse model with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles , or CP) and similar particles coated with Pluronic® F127 (mucus-penetrating particles , or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared to free paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate for the first time the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface. PMID:24339398

  14. PEG-derivatized octacosanol as micellar carrier for paclitaxel delivery.

    PubMed

    Chu, Bingyang; Qu, Ying; Huang, Yixing; Zhang, Lan; Chen, Xiaoxin; Long, Chaofeng; He, Yunqi; Ou, Caiwen; Qian, Zhiyong

    2016-03-16

    In this study, PEG-derivatized octacosanol copolymer was successfully developed to improve the anti-tumor activity and eliminate toxicity of the commercial formulation of paclitaxel (PTX). MPEG2K-C28, the conjugation of monomethoxy Poly(ethylene glycol) 2000 and octacosanol, was readily soluble in aqueous solution and self-assembled to form micelles with small sizes (< 20 nm) that are efficient in encapsulating PTX with a drug loading of 9.38 ± 0.18% and an encapsulation efficiency of 93.90 ± 2.12%. Meanwhile, octacosanol is very safe for humans and amazingly exhibits antitumor activity through inhibition activity of matrix metalloproteinases (MMPs) and translocation of the transcription factor (nuclear factor-kappa B, NF-κB) to the nucleus, which may be able to promote synergistic effects with PTX. A sustained and slower in vitro release behavior was observed in the (PTX micelles) than that of Taxol. PTX micelles exhibited more potent cytotoxicity than Taxol in the 4T1 breast cancer cell line. More interestingly, MPEG2K-C28 selectively inhibited the growth of 4T1 cells rather than the normal cells (HEK293 and L929 cell lines), indicating the antitumor activity of octacosanol remained after conjugation with MPEG. Acute toxicity evaluations indicated that MPEG2K-C28 was a safe drug carrier. Pharmacokinetic study revealed that PTX micelles improved the T1/2 and AUC of PTX (compared with Taxol) from 1.910 ± 0.139 h and 13.999 ± 1.109 mg/l × h to 2.876 ± 0.532 h and 76.462 ± 8.619 mg/l × h in vivo, respectively. The maximal tolerated dose (MTD) for PTX micelles (ca. 120 mg PTX/kg) in mice was significantly higher than that for Taxol (ca. 20mg PTX/kg). PTX micelles exhibited slightly better antitumor activity than Taxol but safer in 4T1 breast cancer model in vivo. The cell apoptosis in the immunofluorescent studies and the cell proliferation in the immunohistochemical studies also proved the results. In conclusion, MPEG2K-C28 is a simple, safe and effective

  15. Hemocompatibility of folic-acid-conjugated amphiphilic PEG-PLGA copolymer nanoparticles for co-delivery of cisplatin and paclitaxel: treatment effects for non-small-cell lung cancer.

    PubMed

    He, Zelai; Shi, Zengfang; Sun, Wenjie; Ma, Jing; Xia, Junyong; Zhang, Xiangyu; Chen, Wenjun; Huang, Jingwen

    2016-06-01

    In this study, we used folic-acid-modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) to encapsulate cisplatin and paclitaxel (separately or together), and evaluated their antitumor effects against lung cancer; this study was conducted in order to investigate the antitumor effects of the co-delivery of cisplatin and paclitaxel by a targeted drug delivery system. Blood compatibility assays and complement activation tests revealed that FA-PEG-PLGA nanoparticles did not induce blood hemolysis, blood clotting, or complement activation. The results also indicated that FA-PEG-PLGA nanoparticles had no biotoxic effects, the drug delivery system allowed controlled release of the cargo molecules, and the co-delivery of cisplatin and paclitaxel efficiently induces cancer cell apoptosis and cell cycle retardation. In addition, co-delivery of cisplatin and paclitaxel showed the ability to suppress xenograft lung cancer growth and prolong the survival time of xenografted mice. These results implied that FA-PEG-PLGA nanoparticles can function as effective carriers of cisplatin and paclitaxel, and that co-delivery of cisplatin and paclitaxel by FA-PEG-PLGA nanoparticles results in more effective antitumor effects than the combination of free-drugs or single-drug-loaded nanoparticles. PMID:26695149

  16. In vitro and in vivo targeting effect of folate decorated paclitaxel loaded PLA–TPGS nanoparticles

    PubMed Central

    Thu, Ha Phuong; Nam, Nguyen Hoai; Quang, Bui Thuc; Son, Ho Anh; Toan, Nguyen Linh; Quang, Duong Tuan

    2015-01-01

    Paclitaxel is one of the most effective chemotherapeutic agents for treating various types of cancer. However, the clinical application of paclitaxel in cancer treatment is considerably limited due to its poor water solubility and low therapeutic index. Thus, it requires an urgent solution to improve therapeutic efficacy of paclitaxel. In this study, folate decorated paclitaxel loaded PLA–TPGS nanoparticles were prepared by a modified emulsification/solvent evaporation method. The obtained nanoparticles were characterized by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR) and Dynamic Light Scattering (DLS) method. The spherical nanoparticles were around 50 nm in size with a narrow size distribution. Targeting effect of nanoparticles was investigated in vitro on cancer cell line and in vivo on tumor bearing nude mouse. The results indicated the effective targeting of folate decorated paclitaxel loaded copolymer nanoparticles on cancer cells both in vitro and in vivo. PMID:26702264

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

    PubMed

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

    2014-06-01

    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

  18. Efficient drug delivery of Paclitaxel glycoside: a novel solubility gradient encapsulation into liposomes coupled with immunoliposomes preparation.

    PubMed

    Shigehiro, Tsukasa; Kasai, Tomonari; Murakami, Masaharu; Sekhar, Sreeja C; Tominaga, Yuki; Okada, Masashi; Kudoh, Takayuki; Mizutani, Akifumi; Murakami, Hiroshi; Salomon, David S; Mikuni, Katsuhiko; Mandai, Tadakatsu; Hamada, Hiroki; Seno, Masaharu

    2014-01-01

    Although the encapsulation of paclitaxel into liposomes has been extensively studied, its significant hydrophobic and uncharged character has generated substantial difficulties concerning its efficient encapsulation into the inner water core of liposomes. We found that a more hydrophilic paclitaxel molecule, 7-glucosyloxyacetylpaclitaxel, retained tubulin polymerization stabilization activity. The hydrophilic nature of 7-glucosyloxyacetylpaclitaxel allowed its efficient encapsulation into the inner water core of liposomes, which was successfully accomplished using a remote loading method with a solubility gradient between 40% ethylene glycol and Cremophor EL/ethanol in PBS. Trastuzumab was then conjugated onto the surface of liposomes as immunoliposomes to selectively target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells. In vitro cytotoxicity assays revealed that the immunoliposomes enhanced the toxicity of 7-glucosyloxyacetylpaclitaxel in HER2-overexpressing cancer cells and showed more rapid suppression of cell growth. The immunoliposomes strongly inhibited the tumor growth of HT-29 cells xenografted in nude mice. Notably, mice survived when treated with the immunoliposomes formulation, even when administered at a lethal dose of 7-glucosyloxyacetylpaclitaxel in vivo. This data successfully demonstrates immunoliposomes as a promising candidate for the efficient delivery of paclitaxel glycoside. PMID:25264848

  19. Efficient Drug Delivery of Paclitaxel Glycoside: A Novel Solubility Gradient Encapsulation into Liposomes Coupled with Immunoliposomes Preparation

    PubMed Central

    Murakami, Masaharu; Sekhar, Sreeja C.; Tominaga, Yuki; Okada, Masashi; Kudoh, Takayuki; Mizutani, Akifumi; Murakami, Hiroshi; Salomon, David S.; Mikuni, Katsuhiko; Mandai, Tadakatsu; Hamada, Hiroki; Seno, Masaharu

    2014-01-01

    Although the encapsulation of paclitaxel into liposomes has been extensively studied, its significant hydrophobic and uncharged character has generated substantial difficulties concerning its efficient encapsulation into the inner water core of liposomes. We found that a more hydrophilic paclitaxel molecule, 7-glucosyloxyacetylpaclitaxel, retained tubulin polymerization stabilization activity. The hydrophilic nature of 7-glucosyloxyacetylpaclitaxel allowed its efficient encapsulation into the inner water core of liposomes, which was successfully accomplished using a remote loading method with a solubility gradient between 40% ethylene glycol and Cremophor EL/ethanol in PBS. Trastuzumab was then conjugated onto the surface of liposomes as immunoliposomes to selectively target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells. In vitro cytotoxicity assays revealed that the immunoliposomes enhanced the toxicity of 7-glucosyloxyacetylpaclitaxel in HER2-overexpressing cancer cells and showed more rapid suppression of cell growth. The immunoliposomes strongly inhibited the tumor growth of HT-29 cells xenografted in nude mice. Notably, mice survived when treated with the immunoliposomes formulation, even when administered at a lethal dose of 7-glucosyloxyacetylpaclitaxel in vivo. This data successfully demonstrates immunoliposomes as a promising candidate for the efficient delivery of paclitaxel glycoside. PMID:25264848

  20. Wheat germ agglutinin-conjugated PLGA nanoparticles for enhanced intracellular delivery of paclitaxel to colon cancer cells.

    PubMed

    Wang, Chunxia; Ho, Paul C; Lim, Lee Yong

    2010-11-15

    The purpose of this study was to investigate the potentiation of the anticancer activity and enhanced cellular retention of paclitaxel-loaded PLGA nanoparticles after surface conjugation with wheat germ agglutinin (WGA) against colon cancer cells. Glycosylation patterns of representative colon cancer cells confirmed the higher expression levels of WGA-binding glycoproteins in the Caco-2 and HT-29 cells, than in the CCD-18Co cells. Cellular uptake and in vitro cytotoxicity of WNP (final formulation) against colon cell lines was evaluated alongside control formulations. Confocal microscopy and quantitative analysis of intracellular paclitaxel were used to monitor the endocytosis and retention of nanoparticles inside the cells. WNP showed enhanced anti-proliferative activity against Caco-2 and HT-29 cells compared to corresponding nanoparticles without WGA conjugation (PNP). The greater efficacy of WNP was associated with higher cellular uptake and sustained intracellular retention of paclitaxel, which in turn was attributed to the over-expression of N-acetyl-D-glucosamine-containing glycoprotein on the colon cell membrane. WNP also demonstrated increased intracellular retention in the Caco-2 (30% of uptake) and HT-29 (40% of uptake) cells, following post-uptake incubation with fresh medium, compared to the unconjugated PNP nanoparticles (18% in Caco-2) and (27% in HT-29), respectively. Cellular trafficking study of WNP showed endocytosed WNP could successful escape from the endo-lysosome compartment and release into the cytosol with increasing incubation time. It may be concluded that WNP has the potential to be applied as a targeted delivery platform for paclitaxel in the treatment of colon cancer. PMID:20804835

  1. Stable and efficient Paclitaxel nanoparticles for targeted glioblastoma therapy.

    PubMed

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K; Wang, Kui; Press, Oliver W; Zhang, Miqin

    2015-06-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, the development of a NP formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy is reported. This multifunctional NP is composed of a polyethylene glycol-coated magnetic iron oxide NP conjugated with cyclodextrin and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL are characterized by transmission electron microscope, dynamic light scattering, and high-performance liquid chromatography. The cellular uptake of NPs is studied using flow cytometry and confocal microscopy. Cell viability and apoptosis are assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ≈44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers. PMID:25761648

  2. Stable and Efficient Paclitaxel Nanoparticles for Targeted Glioblastoma Therapy

    PubMed Central

    Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan; Patton, Victoria K.; Wang, Kui; Press, Oliver W.

    2015-01-01

    Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, we report the development of a nanoparticle formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy. This multifunctional nanoparticle is composed of a polyethylene glycol (PEG) coated magnetic iron oxide NP conjugated with cyclodextrin (CD) and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL were characterized by TEM, dynamic light scattering (DLS), and HPLC. The cellular uptake of NPs was studied using flow cytometry and confocal microscopy. Cell viability and apoptosis were assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ~44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL has demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers. PMID:25761648

  3. Paclitaxel Loaded Nanoliposomes in Thermosensitive Hydrogel: A Dual Approach for Sustained and Localized Delivery.

    PubMed

    Mahajan, Mohit; Utreja, Puneet; Jain, Subheet Kumar

    2016-01-01

    In an attempt to improve the localized paclitaxel delivery, carrier based thermoresponsive chitosan hydrogel was exploited in the present study. Nanoliposomes as carrier for paclitaxel were prepared and optimized in strength of 6 mg/ml similar to marketed paclitaxel formulation. The chitosan solution (2% w/v) mixed with different concentrations of dibasic sodium phosphate (DSP) was evaluated as thermoresponsive systems in terms of gelling temperature and time. Finally, the drug loaded nanoliposomes were incorporated in optimized chitosan- DSP hydrogel base to form nanoliposomal in situ thermosensitive hydrogel formulations having dual mechanism of protection and release. The optimal formulation containing DSP was selected on the basis of minimal gelation temperature (37±0.8 ºC) and time (6.7±0.3 min). In vitro drug release experiment illustrated that developed formulation manifested sustained release action in which drug release was extended for more than 72 h compared to marketed formulation. In addition, optimized nanoliposomal hydrogel demonstrated enhanced biological half-life of 15.7±1.5h, depicting maintenance of constant plasma concentration in contrast to marketed formulation that showed the half-life (t1/2) of 3.6±0.4h. The in vivo anti tumor activity tested using EAC model also corroborated the above findings that developed formulation was having significant higher anti-tumor activity and reduced toxicity than the marketed formulation. Tumor volume was found to reduce upto 89.1±3.5% by treatment with in situ hydrogel formulation. The histopathological study of tumor also demonstrated the better safety and efficacy of developed formulation in comparison to marketed paclitaxel formulation. Our results suggest that carrier based chitosan hydrogel could be an efficacious vehicle for sustained and localized delivery of paclitaxel. PMID:26255673

  4. Preparation and characterization of amphiphilic calixarene nanoparticles as delivery carriers for paclitaxel.

    PubMed

    Zhao, Zi-Ming; Wang, Yu; Han, Jin; Zhu, Hui-Dong; An, Lin

    2015-01-01

    Two types of amphoteric calix[n]arene carboxylic acid (CnCA) derivative, i.e., calix[6]arene hexa-carboxylic acid (C6HCA) and calix[8]arene octo-carboxylic acid (C8OCA), were synthesized by introducing acetoxyls into the hydroxyls of calix[n]arene (n=6, 8). C6HCA and C8OCA nanoparticles (NPs) were prepared successfully using the dialysis method. CnCA NPs had regular spherical shapes with an average diameter of 180-220 nm and possessed negative charges of greater than -30 mV. C6HCA and C8OCA NPs were stable in 4.5% bovine serum albumin solutions and buffers (pH 5-9), with a low critical aggregation concentration value of 5.7 mg·L(-1) and 4.0 mg·L(-1), respectively. C6HCA and C8OCA NPs exhibited good paclitaxel (PTX) loading capacity, with drug loading contents of 7.5% and 8.3%, respectively. The overall in vitro release behavior of PTX from the CnCA NPs was sustained, and C8OCA NPs had a slower release rate compared with C6HCA NPs. These favorable properties of CnCA NPs make them promising nanocarriers for tumor-targeted drug delivery. PMID:25757488

  5. SPARC-Independent Delivery of Nab-Paclitaxel without Depleting Tumor Stroma in Patient-Derived Pancreatic Cancer Xenografts.

    PubMed

    Kim, Harrison; Samuel, Sharon; Lopez-Casas, Pedro; Grizzle, William; Hidalgo, Manuel; Kovar, Joy; Oelschlager, Denise; Zinn, Kurt; Warram, Jason; Buchsbaum, Donald

    2016-04-01

    The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the antistromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC-positive and -negative mice bearing Panc02 tumor xenografts (n = 5-6/group) were injected with IRDye 800CW (IR800)-labeled nab-paclitaxel. After 24 hours, tumors were collected and stained with DL650-labeled anti-SPARC antibody, and the correlation between nab-paclitaxel and SPARC distributions was examined. Eight groups of mice bearing either Panc039 or Panc198 patient-derived xenografts (PDX; 4 groups/model, 5 animals/group) were untreated (served as control) or treated with gemcitabine (100 mg/kg body weight, i.p., twice per week), nab-paclitaxel (30 mg/kg body weight, i.v., for 5 consecutive days), and these agents in combination, respectively, for 3 weeks, and tumor volume and perfusion changes were assessed using T2-weighted MRI and dynamic contrast-enhanced (DCE) MRI, respectively. All tumors were collected and stained with Masson's Trichrome Stain, followed by a blinded comparative analysis of tumor stroma density. IR800-nab-paclitaxel was mainly distributed in tumor stromal tissue, but nab-paclitaxel and SPARC distributions were minimally correlated in either SPARC-positive or -negative animals. Nab-paclitaxel treatment neither decreased tumor stroma nor increased tumor vascular perfusion in either PDX model when compared with control groups. These data suggest that the specific tumor delivery of nab-paclitaxel is not directly related to SPARC expression, and nab-paclitaxel does not deplete tumor stroma in general. Mol Cancer Ther; 15(4); 680-8. ©2016 AACR. PMID:26832793

  6. Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel.

    PubMed

    Luan, Xin; Guan, Ying-Yun; Lovell, Jonathan F; Zhao, Mei; Lu, Qin; Liu, Ya-Rong; Liu, Hai-Jun; Gao, Yun-Ge; Dong, Xiao; Yang, Si-Cong; Zheng, Lin; Sun, Peng; Fang, Chao; Chen, Hong-Zhuan

    2016-07-01

    Normalization of the tumor microenvironment is a promising approach to render conventional chemotherapy more effective. Although passively targeted drug nanocarriers have been investigated to this end, actively targeted tumor priming remains to be explored. In this work, we demonstrate an effective tumor priming strategy using metronomic application of nanoparticles actively targeted to tumor neovasculature. F56 peptide-conjugated paclitaxel-loaded nanoparticles (F56-PTX-NP) were formulated from PEGylated polylactide using an oil in water emulsion approach. Metronomic F56-PTX-NP specifically targeted tumor vascular endothelial cells (ECs), pruned vessels with strong antiangiogenic activity and induced thrombospondin-1 (TSP-1) secretion from ECs. The treatment induced tumor vasculature normalization as evidenced by significantly increased coverage of basement membrane and pericytes. The tumor microenvironment was altered with enhanced pO2, lower interstitial fluid pressure, and enhanced vascular perfusion and doxorubicin delivery. A "normalization window" of at least 9 days was induced, which was longer than other approaches using antiangiogenic agents. Together, these results show that metronomic, actively-targeted nanomedicine can induce tumor vascular normalization and modulate the tumor microenvironment, opening a window of opportunity for effective combination chemotherapies. PMID:27130953

  7. Polymerizable disulfide paclitaxel prodrug for controlled drug delivery.

    PubMed

    Ding, Yi; Chen, Wulian; Hu, Jianhua; Du, Ming; Yang, Dong

    2014-11-01

    A polymerizable disulfide paclitaxel (PTX) prodrug was synthesized by the consequential esterification reactions of 3,3'-dithiodipropionic acid (DTPA), a disulfide compound containing two active carboxyl groups, with 2-hydroxyethyl methacrylate (HEMA) and PTX. The structure of the prodrug was confirmed by (1)H NMR characterization. Then, the polymerizable prodrug was copolymerized with poly(ethylene glycol) methyl ether methacrylate (PEGMEA) to obtain a copolymer with hydrophilic PEG side chains and PTX covalently linked onto the backbone via disulfide bonds. The loading content of PTX was 23%. In aqueous solution, this copolymer prodrug could self-assemble into micelles, with hydrophobic PTX as the cores and hydrophilic PEG-segment as the shells. In vitro cell assay demonstrated that this copolymer prodrug showed more apparent cytotoxicity to cancer cells than to human normal cells. After incubation for 48 h, the cell viability of HEK-293 cells (human embryo kidney cells) at 0.1 μg/mL PTX still remained more than 90%, however, that of HeLa cells (human cervical cancer cells) decreased to 52%. PMID:25280719

  8. Thermosensitive and Mucoadhesive Sol-Gel Composites of Paclitaxel/Dimethyl-β-Cyclodextrin for Buccal Delivery

    PubMed Central

    Kang, Bong-Seok; Ng, Choon Lian; Davaa, Enkhzaya; Park, Jeong-Sook

    2014-01-01

    The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O-methyl)-β-cyclodextrin (DMβCD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4°C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37°C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127-based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel. PMID:25275485

  9. Double layer paclitaxel delivery systems based on bioresorbable terpolymer with shape memory properties.

    PubMed

    Musiał-Kulik, Monika; Kasperczyk, Janusz; Smola, Anna; Dobrzyński, Piotr

    2014-04-25

    The growing interest in the bioresorbable polymers contributed to developing a number of commercially available controlled drug delivery systems. Due to a variety of drugs and their physicochemical properties, there is a necessity of choosing an appropriate drug carrier. Terpolymer with shape memory properties was used to obtain double layer matrices composed of drug free matrix and paclitaxel containing layer. The in vitro degradation and drug release study were conducted at 37 °C in PBS (pH 7.4). The investigated materials were characterized by GPC (gel permeation chromatography) and DSC (differential scanning calorimetry). HPLC (high-pressure liquid chromatography) was applied to analyze the amount of released paclitaxel. The main purpose of this work was to determine the usefulness of the studied terpolymer as an anti-restenotic drug vehicle. Based on the obtained results it was established that polymer's degradation proceeded regularly and provided even paclitaxel release profiles. Double layer systems allowed to modify the amount of released drug which may be considered while developing the self-expanding drug-eluting stents tailoring different clinical indications. PMID:24491529

  10. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles.

    PubMed

    Chan, Juliana M; Rhee, June-Wha; Drum, Chester L; Bronson, Roderick T; Golomb, Gershon; Langer, Robert; Farokhzad, Omid C

    2011-11-29

    Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD. PMID:22087004

  11. Development of chitosan graft pluronic®F127 copolymer nanoparticles containing DNA aptamer for paclitaxel delivery to treat breast cancer cells

    NASA Astrophysics Data System (ADS)

    Thach Nguyen, Kim; Le, Duc Vinh; Do, Dinh Ho; Huan Le, Quang

    2016-06-01

    HER-2/ErbB2/Neu(HER-2), a member of the epidermal growth factor receptor family, is specifically overexpressed on the surface of breast cancer cells and serves a therapeutic target for breast cancer. In this study, we aimed to isolate DNA aptamer (Ap) that specifically bind to a HER-2 overexpressing SK-BR-3 human breast cancer cell line, using SELEX strategy. We developed a novel multifunctional composite micelle with surface modification of Ap for targeted delivery of paclitaxel. This binary mixed system consisting of Ap modified pluronic®F127 and chitosan could enhance PTX loading capacity and increase micelle stability. Polymeric micelles had a spherical shape and were self-assemblies of block copolymers of approximately 86.22 ± 1.45 nm diameter. PTX could be loaded with high encapsulation efficiency (83.28 ± 0.13%) and loading capacity (9.12 ± 0.34%). The release profile were 29%–35% in the first 12 h and 85%–93% after 12 d at pH 7.5 of receiving media. The IC50 doses by MTT assay showed the greater activity of nanoparticles loaded paclitaxel over free paclitaxel and killed cells up to 95% after 6 h. These results demonstrated unique assembly with the capacity to function as an efficient detection and delivery vehicle in the biological living system.

  12. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles

    PubMed Central

    Zhu, Xu; Guo, Jun; He, Cancan; Geng, Huaxiao; Yu, Gengsheng; Li, Jinqing; Zheng, Hairong; Ji, Xiaojuan; Yan, Fei

    2016-01-01

    Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis. PMID:26899550

  13. Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

    NASA Astrophysics Data System (ADS)

    Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

    2016-01-01

    Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

  14. Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

    PubMed Central

    Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

    2016-01-01

    Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues. PMID:26740245

  15. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting

    NASA Astrophysics Data System (ADS)

    Jin, Zhu; Lv, Yaqi; Cao, Hui; Yao, Jing; Zhou, Jianping; He, Wei; Yin, Lifang

    2016-06-01

    Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Herein, core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. Improved in vitro and in vivo tumor targeting and penetration were observed with NCs and iRGD-NCs; the latter exhibited better antitumor activity because iRGD enhanced the accumulation and penetration of NCs in tumors. The NCs were cytocompatible, histocompatible, and non-toxic to other healthy tissues. The endocytosis of NCs was mediated by lipid rafts in an energy-dependent manner, leading to better cytotoxicity of PTX against cancer cells. In contrast with commercial product, PTX-loaded NCs (PTX-NCs) increased area under concentration-time curve (AUC) by about 4-fold, prolonged mean resident time (MRT) by more than 8-fold and reduced the elimination rate constant by greater than 68-fold. In conclusion, the present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy.

  16. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting

    PubMed Central

    Jin, Zhu; Lv, Yaqi; Cao, Hui; Yao, Jing; Zhou, Jianping; He, Wei; Yin, Lifang

    2016-01-01

    Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Herein, core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. Improved in vitro and in vivo tumor targeting and penetration were observed with NCs and iRGD-NCs; the latter exhibited better antitumor activity because iRGD enhanced the accumulation and penetration of NCs in tumors. The NCs were cytocompatible, histocompatible, and non-toxic to other healthy tissues. The endocytosis of NCs was mediated by lipid rafts in an energy-dependent manner, leading to better cytotoxicity of PTX against cancer cells. In contrast with commercial product, PTX-loaded NCs (PTX-NCs) increased area under concentration-time curve (AUC) by about 4-fold, prolonged mean resident time (MRT) by more than 8-fold and reduced the elimination rate constant by greater than 68-fold. In conclusion, the present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy. PMID:27278751

  17. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting.

    PubMed

    Jin, Zhu; Lv, Yaqi; Cao, Hui; Yao, Jing; Zhou, Jianping; He, Wei; Yin, Lifang

    2016-01-01

    Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Herein, core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. Improved in vitro and in vivo tumor targeting and penetration were observed with NCs and iRGD-NCs; the latter exhibited better antitumor activity because iRGD enhanced the accumulation and penetration of NCs in tumors. The NCs were cytocompatible, histocompatible, and non-toxic to other healthy tissues. The endocytosis of NCs was mediated by lipid rafts in an energy-dependent manner, leading to better cytotoxicity of PTX against cancer cells. In contrast with commercial product, PTX-loaded NCs (PTX-NCs) increased area under concentration-time curve (AUC) by about 4-fold, prolonged mean resident time (MRT) by more than 8-fold and reduced the elimination rate constant by greater than 68-fold. In conclusion, the present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy. PMID:27278751

  18. IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel.

    PubMed

    Wee, Zhen Ning; Yatim, Siti Maryam J M; Kohlbauer, Vera K; Feng, Min; Goh, Jian Yuan; Bao, Yi; Yi, Bao; Lee, Puay Leng; Zhang, Songjing; Wang, Pan Pan; Lim, Elgene; Tam, Wai Leong; Cai, Yu; Ditzel, Henrik J; Hoon, Dave S B; Tan, Ern Yu; Yu, Qiang

    2015-01-01

    Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-κB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance. PMID:26503059

  19. Delivery of baicalein and paclitaxel using self-assembled nanoparticles: synergistic antitumor effect in vitro and in vivo

    PubMed Central

    Wang, Wei; Xi, Mei; Duan, Xuezhong; Wang, Yong; Kong, Fansheng

    2015-01-01

    Purpose Combination anticancer therapy is promising to generate synergistic anticancer effects to maximize the treatment effect and overcome multidrug resistance. The aim of the study reported here was to develop multifunctional, dual-ligand, modified, self-assembled nanoparticles (NPs) for the combination delivery of baicalein (BCL) and paclitaxel (PTX) prodrugs. Methods Prodrug of PTX and prodrug of BCL, containing dual-targeted ligands of folate (FA) and hyaluronic acid (HA), were synthesized. Multifunctional self-assembled NPs for combination delivery of PTX prodrug and BCL prodrug (PTX-BCL) were prepared and the synergistic antitumor effect was evaluated in vitro and in vivo. The in vitro transfection efficiency of the novel modified vectors was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/PTX cells. The in vivo antitumor efficiency and systemic toxicity of different formulations were further investigated in mice bearing A549/PTX drug-resistant human lung cancer xenografts. Results The size of the PTX-BCL NPs was approximately 90 nm, with a positive zeta potential of +3.3. The PTX-BCL NPs displayed remarkably better antitumor activity over a wide range of drug concentrations, and showed an obvious synergism effect with CI50 values of 0.707 and 0.513, indicating that double-ligand modification and the co-delivery of PTX and BCL prodrugs with self-assembled NPs had remarkable superiority over other formulations. Conclusion The prepared PTX-BCL NP drug-delivery system was proven efficient by its targeting of drug-resistant human lung cancer cells and delivering of BCL and PTX prodrugs. Enhanced synergistic anticancer effects were achieved by PTX-BCL NPs, and multidrug resistance of PTX was overcome by this promising targeted nanomedicine. PMID:26045664

  20. Targeting HDAC with a novel inhibitor effectively reverses paclitaxel resistance in non-small cell lung cancer via multiple mechanisms

    PubMed Central

    Wang, L; Li, H; Ren, Y; Zou, S; Fang, W; Jiang, X; Jia, L; Li, M; Liu, X; Yuan, X; Chen, G; Yang, J; Wu, C

    2016-01-01

    Chemotherapy paclitaxel yields significant reductions in tumor burden in the majority of advanced non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits its clinical use. Here we demonstrated that the histone deacetylase (HDAC) was activated in paclitaxel-resistant NSCLC cells, and its activation promoted proliferation and tumorigenesis of paclitaxel-resistant NSCLC cells in vitro and in vivo. By contrast, knockdown of HDAC1, a primary isoform of HDAC, sensitized resistant cells to paclitaxel in vitro. Furthermore, we observed that overexpression of HDAC1 was associated with the downregulation of p21, a known HDAC target, in advanced NSCLC patients with paclitaxel treatment, and predicted chemotherapy resistance and bad outcome. In addition, we also identified a novel HDACs inhibitor, SNOH-3, which inhibited HDAC expression and activity, induced cell apoptosis, and suppressed cell migration, invasion and angiogenesis. Notably, co-treatment with SNOH-3 and paclitaxel overcome paclitaxel resistance through inhibiting HDAC activity, leading to the induction of apoptosis and suppression of angiogenesis in vitro and in preclinical model. In summary, our data demonstrate a role of HDAC in paclitaxel-resistant NSCLC and provide a promising therapeutic strategy to overcome paclitaxel-acquired resistance. PMID:26794658

  1. Dual Targeting Biomimetic Liposomes for Paclitaxel/DNA Combination Cancer Treatment

    PubMed Central

    Liu, Guo-Xia; Fang, Gui-Qing; Xu, Wei

    2014-01-01

    Combinations of chemotherapeutic drugs with nucleic acid has shown great promise in cancer therapy. In the present study, paclitaxel (PTX) and DNA were co-loaded in the hyaluronic acid (HA) and folate (FA)-modified liposomes (HA/FA/PPD), to obtain the dual targeting biomimetic nanovector. The prepared HA/FA/PPD exhibited nanosized structure and narrow size distributions (247.4 ± 4.2 nm) with appropriate negative charge of −25.40 ± 2.7 mV. HA/FA/PD (PTX free HA/FA/PPD) showed almost no toxicity on murine malignant melanoma cell line (B16) and human hepatocellular carcinoma cell line (HepG2) (higher than 80% cell viability), demonstrating the safety of the blank nanovector. In comparison with the FA-modified PTX/DNA co-loaded liposomes (FA/PPD), HA/FA/PPD showed significant superiority in protecting the nanoparticles from aggregation in the presence of plasma and degradation by DNase I. Moreover, HA/FA/PPD could also significantly improve the transfection efficiency and cellular internalization rates on B16 cells comparing to that of FA/PPD (p < 0.05) and PPD (p < 0.01), demonstrating the great advantages of dual targeting properties. Furthermore, fluorescence microscope and flow cytometry results showed that PTX and DNA could be effectively co-delivered into the same tumor cell via HA/FA/PPD, contributing to PTX/DNA combination cancer treatment. In conclusion, the obtained HA/FA/PPD in the study could effectively target tumor cells, enhance transfection efficiency and subsequently achieve the co-delivery of PTX and DNA, displaying great potential for optimal combination therapy. PMID:25177862

  2. Telodendrimer nanocarrier for co-delivery of paclitaxel and cisplatin: A synergistic combination nanotherapy for ovarian cancer treatment.

    PubMed

    Cai, Liqiong; Xu, Gaofei; Shi, Changying; Guo, Dandan; Wang, Xu; Luo, Juntao

    2015-01-01

    Cisplatin (CDDP) and paclitaxel (PTX) are two established chemotherapeutic drugs used in combination for the treatment of many cancers, including ovarian cancer. We have recently developed a three-layered linear-dendritic telodendrimer micelles (TM) by introducing carboxylic acid groups in the adjacent layer via "thio-ene" click chemistry for CDDP complexation and conjugating cholic acids via peptide chemistry in the interior layer of telodendrimer for PTX encapsulation. We hypothesize that the co-delivery of low dosage PTX with CDDP could act synergistically to increase the treatment efficacy and reduce their toxic side effects. This design allowed us to co-deliver PTX and CDDP at various drug ratios to ovarian cancer cells. The in vitro cellular assays revealed strongest synergism in anti-tumor effects when delivered at a 1:2 PTX/CDDP loading ratio. Using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrate that our co-encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and stronger anti-tumor effect, when compared with free drug combination or the single loading TM formulations. PMID:25453973

  3. Programmed co-delivery of paclitaxel and doxorubicin boosted by camouflaging with erythrocyte membrane

    NASA Astrophysics Data System (ADS)

    Fu, Qiang; Lv, Piping; Chen, Zhongke; Ni, Dezhi; Zhang, Lijun; Yue, Hua; Yue, Zhanguo; Wei, Wei; Ma, Guanghui

    2015-02-01

    Combination chemotherapy has been proven promising for cancer treatment, but unsatisfactory therapeutic data and increased side effects slow down the development in the clinic. In this study, we develop an effective approach to co-encapsulate a hydrophilic-hydrophobic chemotherapeutic drug pair (paclitaxel and doxorubicin) into magnetic O-carboxymethyl-chitosan nanoparticles. To endow them with the ability of programmed delivery, these carriers are further camouflaged with an Arg-Gly-Asp anchored erythrocyte membrane. Compared with the traditional polyethylene glycol coating method, this biomimetic decoration strategy is demonstrated to be superior in prolonging circulation time, improving tumor accumulation, facilitating tumor uptake, and tuning intracellular fate. These outstanding properties enable the as-designed nanodevice to exhibit greater tumor growth inhibition ability and much lower side effects than the combined use of commercial formulations.Combination chemotherapy has been proven promising for cancer treatment, but unsatisfactory therapeutic data and increased side effects slow down the development in the clinic. In this study, we develop an effective approach to co-encapsulate a hydrophilic-hydrophobic chemotherapeutic drug pair (paclitaxel and doxorubicin) into magnetic O-carboxymethyl-chitosan nanoparticles. To endow them with the ability of programmed delivery, these carriers are further camouflaged with an Arg-Gly-Asp anchored erythrocyte membrane. Compared with the traditional polyethylene glycol coating method, this biomimetic decoration strategy is demonstrated to be superior in prolonging circulation time, improving tumor accumulation, facilitating tumor uptake, and tuning intracellular fate. These outstanding properties enable the as-designed nanodevice to exhibit greater tumor growth inhibition ability and much lower side effects than the combined use of commercial formulations. Electronic supplementary information (ESI) available. See DOI

  4. 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...

  5. Multifunctional mesoporous silica nanoparticles mediated co-delivery of paclitaxel and tetrandrine for overcoming multidrug resistance.

    PubMed

    Jia, Lejiao; Li, Zhenyu; Shen, Jingyi; Zheng, Dandan; Tian, Xiaona; Guo, Hejian; Chang, Ping

    2015-07-15

    The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR. PMID:25956050

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

    PubMed Central

    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

    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. PMID:20681596

  7. Integrin Targeted Delivery of Chemotherapeutics

    PubMed Central

    Chen, Kai; Chen, Xiaoyuan

    2011-01-01

    Targeted delivery of chemotherapeutics is defined in the sense, that is, to maximize the therapeutic index of a chemotherapeutic agent by strictly localizing its pharmacological activity to the site or tissue of action. Integrins are a family of heterodimeric transmembrane glycoproteins involved in a wide range of cell-to-extracellular matrix (ECM) and cell-to-cell interactions. As cell surface receptors, integrins readily interact with extracellular ligands and play a vital role in angiogenesis, leukocytes function and tumor development, which sets up integrins as an excellent target for chemotherapy treatment. The peptide ligands containing the arginine-glycine-aspartic acid (RGD), which displays a strong binding affinity and selectivity to integrins, particularly to integrin αvβ3, have been developed to conjugate with various conventional chemotherapeutic agents, such as small molecules, peptides and proteins, and nanoparticle-carried drugs for integtrin targeted therapeutic studies. This review highlights the recent advances in integrin targeted delivery of chemotherapeutic agents with emphasis on target of integrin αvβ3, and describes the considerations for the design of the diverse RGD peptide-chemotherapeutics conjugates and their major applications. PMID:21547159

  8. Micro RNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR

    PubMed Central

    He, Yuan; Fu, Xing; Fu, Liya; Zhu, Zhengmao; Fu, Li; Dong, Jin-Tang

    2016-01-01

    Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment. PMID:26744318

  9. Aptamers for Targeted Drug Delivery

    PubMed Central

    Ray, Partha; White, Rebekah R.

    2010-01-01

    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.

  10. Dendritic polyglycerol sulfate as a novel platform for paclitaxel delivery: pitfalls of ester linkage

    NASA Astrophysics Data System (ADS)

    Sousa-Herves, Ana; Würfel, Patrick; Wegner, Nicole; Khandare, Jayant; Licha, Kai; Haag, Rainer; Welker, Pia; Calderón, Marcelo

    2015-02-01

    In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non-sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by 1H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These observations suggest a fast ester hydrolysis and premature drug release, as confirmed by HPLC measurements in the presence of plasma enzymes.In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non-sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by 1H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These

  11. Hypocrellin B and paclitaxel-encapsulated hyaluronic acid-ceramide nanoparticles for targeted photodynamic therapy in lung cancer.

    PubMed

    Chang, Ji-Eun; Cho, Hyun-Jong; Yi, Eunjue; Kim, Dae-Duk; Jheon, Sanghoon

    2016-05-01

    To increase the therapeutic efficacy of photodynamic therapy (PDT) in treating lung cancer, we developed both photosensitizer and anticancer drug encapsulated hyaluronic acid-ceramide nanoparticles. Based on our previous study, a co-delivery system of photosensitizers and anticancer agents greatly improves the therapeutic effect of PDT. Furthermore, hyaluronic acid-ceramide-based nanoparticles are ideal targeting carriers for lung cancer. In vitro phototoxicity in A549 (human lung adenocarcinoma) cells and in vivo antitumor efficacy in A549 tumor-bearing mice treated with hypocrellin B (HB)-loaded nanoparticles (HB-NPs) or hypocrellin B and paclitaxel loaded nanoparticles (HB-P-NPs) were evaluated. Cell viability assay, microscopic analysis and FACS analysis were performed for the in vitro studies and HB-P-NPs showed enhanced phototoxicity compared with HB-NPs. In the animal study, the tumor volume change and the histological analysis was studied and the anticancer efficacy improved in the order of free HBtargeted delivery improved the effects of PDT in lung cancer in mice. PMID:26967521

  12. Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy

    PubMed Central

    Shan, Lingling; Liu, Ming; Wu, Chao; Zhao, Liang; Li, Siwen; Xu, Lisheng; Cao, Wengen; Gao, Guizhen; Gu, Yueqing

    2015-01-01

    In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX) as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6)-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX) and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX), composed of folic acid (FA, target), amino acids (Arg or Glu, linker), and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo) in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems. PMID:26366078

  13. Aptamers and aptamer targeted delivery

    PubMed Central

    Yan, Amy C.; Levy, Matthew

    2014-01-01

    When aptamers first emerged almost two decades ago, most were RNA species that bound and tagged or inhibited simple target ligands. Very soon after, the ‘selectionologists’ developing aptamer technology quickly realized more potential for the aptamer. In recent years, advances in aptamer techniques have enabled the use of aptamers as small molecule inhibitors, diagnostic tools and even therapeutics. Aptamers are now being employed in novel applications. We review, herein, some of the recent and exciting applications of aptamers in cell-specific recognition and delivery. PMID:19458497

  14. Targeting delivery in Parkinson's disease.

    PubMed

    Newland, Ben; Dunnett, Stephen B; Dowd, Eilís

    2016-08-01

    Disease-modifying therapies for Parkinson's disease (PD), with the potential to halt the neurodegenerative process and to stimulate the protection, repair, and regeneration of dopaminergic neurons, remain a vital but unmet clinical need. Targeting the delivery of current and new therapeutics directly to the diseased brain region (in particular the nigrostriatal pathway) could result in greater improvements in the motor functions that characterise PD. Here, we highlight some of the opportunities and challenges facing the development of the next generation of therapies for patients with PD. PMID:27312875

  15. Dendritic polyglycerol sulfate as a novel platform for paclitaxel delivery: pitfalls of ester linkage.

    PubMed

    Sousa-Herves, Ana; Würfel, Patrick; Wegner, Nicole; Khandare, Jayant; Licha, Kai; Haag, Rainer; Welker, Pia; Calderón, Marcelo

    2015-03-01

    In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non-sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by (1)H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These observations suggest a fast ester hydrolysis and premature drug release, as confirmed by HPLC measurements in the presence of plasma enzymes. PMID:25516353

  16. Solid lipid nanoparticles of paclitaxel strengthened by hydroxypropyl-β-cyclodextrin as an oral delivery system.

    PubMed

    Baek, Jong-Suep; So, Jae-Woo; Shin, Sang-Chul; Cho, Cheong-Weon

    2012-10-01

    The objective of this study was to evaluate the potential of surface-modified paclitaxel (PTX)-incorporated solid lipid nanoparticles with hydroxypropyl-β-cyclodextrin (smPSH). The smPSH released 89.70 ± 3.99% of its entrapped PTX within 24 h when placed in dissolution medium containing sodium lauryl sulfate. The cellular uptake of PTX from smPSH in Caco-2 cells was 5.3-fold increased compared to a PTX solution based on a Taxol formulation. Moreover, smPSH showed an increased cytotoxicity compared to PTX solution. In addition, AUC (5.43 µg•h/ml) and Cmax (1.44 µg/ml) of smPSH were higher than those (1.81 µg•h/ml and 0.73 µg/ml) of PTX solution. The drug concentration of smPSH (11.12 ± 4.45 ng/mg of lymph tissue) in lymph nodes was higher than that of the PTX solution (0.89 ± 0.75 ng/mg of lymph tissue), suggesting that more PTX was transported to the lymphatic vessels in the form of smPSH. In conclusion, smPSH have a potential as an alternative delivery system for oral administration of PTX. PMID:22859311

  17. Liposomal formulation for co-delivery of paclitaxel and lapatinib, preparation, characterization and optimization.

    PubMed

    Ravar, Fatemeh; Saadat, Ebrahim; Kelishadi, Pouya Dehghan; Dorkoosh, Farid A

    2016-09-01

    Paclitaxel (PTX) is one of the most promising natural anticancer agents with a wide therapeutic range which is limited by its hydrophobic nature, low therapeutic index and more importantly, the emergence of multidrug resistance (MDR). Lapatinib (LPT) is a dual tyrosine kinase inhibitor with a significant potential to inhibit p-glycoproteins which form one of the main groups of proteins responsible for efflux pump mediated MDR. To overcome the PTX related MDR, a novel liposomal formulation was optimized for co-delivery of PTX and LPT by applying the D-optimal response surface methodology. The encapsulation efficiency (EE%) of the optimized formulation for LPT and PTX was 52 ± 3% and 68 ± 5, respectively. The optimized formulation showed a narrow size distribution with the average of 235 ± 12 nm. The transmission electron microscopy image showed that liposomes were round in shape and discrete. The release profile exhibited 93% and 71% drug release for PTX and LPT after 40 h in the sink condition. The differential scanning calorimetry analysis indicated the conversion of both drugs from crystalline state to molecular state in the optimized lyophilized formulation. The cytotoxicity of the prepared formulation was studied against 4T1 murine mammary cells. The liposomal formulation showed better cytotoxicity in comparison to the binary mixture of free drugs. PMID:26266828

  18. The ClC-3 chloride channel associated with microtubules is a target of paclitaxel in its induced-apoptosis

    PubMed Central

    Zhang, Haifeng; Li, Huarong; Yang, Lili; Deng, Zhiqin; Luo, Hai; Ye, Dong; Bai, Zhiquan; Zhu, Linyan; Ye, Wencai; Wang, Liwei; Chen, Lixin

    2013-01-01

    Recent evidences show that cationic fluxes play a pivotal role in cell apoptosis. In this study, the roles of Cl− channels in paclitaxel-induced apoptosis were investigated in nasopharyngeal carcinoma CNE-2Z cells. Chloride current and apoptosis were induced by paclitaxel and inhibited by chloride channel blockers. Paclitaxel-activated current possessed similar properties to volume-activated chloride current. After ClC-3 was knocked-down by ClC-3-siRNA, hypotonicity-activated and paclitaxel-induced chloride currents were obviously decreased, indicating that the chloride channel involved in paclitaxel-induced apoptosis may be ClC-3. In early apoptotic cells, ClC-3 was up-regulated significantly; over-expressed ClC-3 was accumulated in cell membrane to form intercrossed filaments, which were co-localized with α-tubulins; changes of ultrastructures and decrease of flexibility in cell membrane were detected by atomic force microscopy. These suggest that ClC-3 is a critical target of paclitaxel and the involvement of ClC-3 in apoptosis may be associated with its accumulation with membrane microtubules and its over activation. PMID:24026363

  19. Co-delivery of hydrophobic paclitaxel and hydrophilic AURKA specific siRNA by redox-sensitive micelles for effective treatment of breast cancer.

    PubMed

    Yin, Tingjie; Wang, Lei; Yin, Lifang; Zhou, Jianping; Huo, Meirong

    2015-08-01

    In this study, a novel redox-sensitive micellar system constructed from a hyaluronic acid-based amphiphilic conjugate (HA-ss-(OA-g-bPEI), HSOP) was successfully developed for tumor-targeted co-delivery of paclitaxel (PTX) and AURKA specific siRNA (si-AURKA). HSOP exhibited excellent loading capacities for both PTX and siRNA with adjustable dosing ratios and desirable redox-sensitivity independently verified by morphological changes of micelles alongside in vitro release of both drugs in different reducing environments. Moreover, flow cytometry and confocal microscopy analysis confirmed that HSOP micelles were capable of simultaneously delivering PTX and siRNA into MDA-MB-231 breast cancer cells via HA-receptor mediated endocytosis followed by rapid transport of cargoes into the cytosol. Successful delivery and transport amplified the synergistic effects between the drugs while leading to substantially greater antitumor efficacy when compared with single drug-loaded micelles and non-sensitive co-loaded micelles. In vivo investigation demonstrated that HSOP micelles could effectively accumulate in tumor sites and possessed the greatest antitumor efficacy over non-sensitive co-delivery control and redox-sensitive single-drug controls. These findings indicated that redox-sensitive HSOP co-delivery system holds great promise for combined drug/gene treatment for targeted cancer therapy. PMID:25996409

  20. Ultrasound-Mediated Destruction of LHRHa Targeted and Paclitaxel Loaded Lipid Microbubbles for the Treatment of Intraperitoneal Ovarian Cancer Xenografts

    PubMed Central

    Chang, Shufang; Liu, Hongxia; Zhu, Yi; Wang, Zhigang; Xu, Ronald X.

    2014-01-01

    Ultrasound-targeted microbubble destruction (UTMD) is a promising technique to facilitate the delivery of chemotherapy in cancer treatment. However, the process typically uses non-specific microbubbles, leading to low tumor-to-normal tissue uptake ratio and adverse side effects. In this study, we synthesized the LHRH receptor targeted and paclitaxel (PTX) loaded lipid microbubbles (TPLMBs) for tumor-specific binding and enhanced therapeutic effect at the tumor site. An ovarian cancer xenograft model was established by injecting A2780/DDP cells intraperitoneally in BALB/c nude mice. Microscopic imaging of tumor sections after intraperitoneal injection of TPLMBs showed effective binding of the microbubbles with cancer cells. Ultrasound mediated destruction of the intraperitoneally injected TPLMBs yielded a superior therapeutic outcome in comparison with other treatment options. Immunohistochemical analyses of the dissected tumor tissue further confirmed the increased tumor apoptosis and reduced angiogenesis. Our experiment suggests that ultrasound mediated intraperitoneal administration of the targeted drug-loaded microbubbles may be a useful method for the treatment of ovarian cancer. PMID:24237050

  1. Improved Biochemical Strategies for Targeted Delivery of Taxoids

    PubMed Central

    Ganesh, Thota

    2008-01-01

    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. PMID:17419065

  2. A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

    PubMed Central

    Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

    2015-01-01

    Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic

  3. Targeted drug delivery nanosystems based on copolymer poly(lactide)-tocopheryl polyethylene glycol succinate for cancer treatment

    NASA Astrophysics Data System (ADS)

    Thu Ha, Phuong; Nguyen, Hoai Nam; Doan Do, Hai; Thong Phan, Quoc; Nguyet Tran Thi, Minh; Phuc Nguyen, Xuan; Nhung Hoang Thi, My; Huong Le, Mai; Nguyen, Linh Toan; Quang Bui, Thuc; Hieu Phan, Van

    2016-03-01

    Along with the development of nanotechnology, drug delivery nanosystems (DDNSs) have attracted a great deal of concern among scientists over the world, especially in cancer treatment. DDNSs not only improve water solubility of anticancer drugs but also increase therapeutic efficacy and minimize the side effects of treatment methods through targeting mechanisms including passive and active targeting. Passive targeting is based on the nano-size of drug delivery systems while active targeting is based on the specific bindings between targeting ligands attached on the drug delivery systems and the unique receptors on the cancer cell surface. In this article we present some of our results in the synthesis and testing of DDNSs prepared from copolymer poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS), which carry anticancer drugs including curcumin, paclitaxel and doxorubicin. In order to increase the targeting effect to cancer cells, active targeting ligand folate was attached to the DDNSs. The results showed copolymer PLA-TPGS to be an excellent carrier for loading hydrophobic drugs (curcumin and paclitaxel). The fabricated DDNSs had a very small size (50-100 nm) and enhanced the cellular uptake and cytotoxicity of drugs. Most notably, folate-decorated paclitaxel-loaded copolymer PLA-TPGS nanoparticles (Fol/PTX/PLA-TPGS NPs) were tested on tumor-bearing nude mice. During the treatment time, Fol/PTX/PLA-TPGS NPs always exhibited the best tumor growth inhibition compared to free paclitaxel and paclitaxel-loaded copolymer PLA-TPGS nanoparticles. All results evidenced the promising potential of copolymer PLA-TPGS in fabricating targeted DDNSs for cancer treatment.

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

    PubMed

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

    2013-06-01

    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

  5. Self-assembly PEGylation assists SLN-paclitaxel delivery inducing cancer cell apoptosis upon internalization.

    PubMed

    Arranja, Alexandra; Gouveia, Luís F; Gener, Petra; Rafael, Diana F; Pereira, Carolina; Schwartz, Simó; Videira, Mafalda A

    2016-03-30

    In past years, a considerable progress has been made in the conversion of conventional chemotherapy into potent and safe nanomedicines. The ultimate goal is to improve the therapeutic window of current chemotherapeutics by reducing systemic toxicities and to deliver higher concentrations of the chemotherapeutic agents to malignant cells. In this work, we report that PEGylation of the nanocarriers increases drug intracellular bioavailability leading therefore to higher therapeutic efficacy. The surface of the already patented solid lipid nanoparticles (SLN) loaded with paclitaxel (SLN-PTX) was coated with a PEG layer (SLN-PTX_PEG) through an innovative process to provide stable and highly effective nanoparticles complying with the predefined pharmaceutical quality target product profile. We observed that PEGylation not only stabilizes the SLN, but also modulates their cellular uptake kinetics. As a consequence, the intracellular concentration of chemotherapeutics delivered by SLN-PTX_PEG increases. This leads to the increase of efficacy and thus it is expected to significantly circumvent cancer cell resistance and increase patient survival and cure. PMID:26853316

  6. Aptamer-targeted Antigen Delivery

    PubMed Central

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

    2014-01-01

    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 CD8α+ 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)-γ 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. PMID:24682172

  7. Poly(ethylene oxide)-block-polyphosphoester-graft-paclitaxel Conjugates with Acid-labile Linkages as a pH-Sensitive and Functional Nanoscopic Platform for Paclitaxel Delivery

    PubMed Central

    Zou, Jiong; Zhang, Fuwu; Zhang, Shiyi; Pollack, Stephanie F.; Elsabahy, Mahmoud; Fan, Jingwei; Wooley, Karen L.

    2013-01-01

    There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile, polyphosphoester-based degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading has been improved significantly, in this second generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive β-thiopropionate linkage. The results for this system indicate that it has great potential as an effective anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-graft-PTX drug conjugate (PEO-b-PPE-g-PTX G2) was synthesized by organocatalyst-promoted ring-opening polymerization of 2-(but-3-en-1-yloxy)-1,3,2-dioxaphospholane-2-oxide from a PEO macroinitiator, followed by thermo-promoted thiolene click conjugation of a thiol-functionalized PTX prodrug to the pendant alkene groups of the block copolymer. The PEO-b-PPE-g-PTX G2 formed well-defined nanoparticles in aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 114 ± 31 nm. The conjugate had PTX loading capacity as high as 53 wt%, and a maximum PTX concentration of 0.68 mg/mL in water (vs. 1.7 μg/mL for free PTX). Although the PTX concentration is ca. 10× less than for our first generation material, its accelerated release allowed for similar free PTX concentrations vs. time. The PEO-b-PPE-g-PTX G2 exhibited accelerated drug release under acidic conditions (~50 wt% PTX released in 8 d) compared to neutral conditions (~20 wt% PTX released in 8 d) and compared to the first generation analog that contained ester linkages between PTX and the polymer backbone (<5 wt% PTX released in 4 d), due to their acid-sensitive hydrolytically-labile β-thiopropionate linkages between PTX molecules and the polymer backbone. The positive cell-killing activity of PEO-b-PPE-g-PTX G2 against two cancer cell

  8. Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery.

    PubMed

    Groo, Anne-Claire; Saulnier, Patrick; Gimel, Jean-Christophe; Gravier, Julien; Ailhas, Caroline; Benoit, Jean-Pierre; Lagarce, Frederic

    2013-01-01

    The bioavailability of paclitaxel (Ptx) has previously been improved via its encapsulation in lipid nanocapsules (LNCs). In this work, the interactions between LNCs and intestinal mucus are studied because they are viewed as an important barrier to successful oral delivery. The rheological properties of different batches of pig intestinal mucus were studied under different conditions (the effect of hydration and the presence of LNCs). Fluorescence resonance energy transfer (FRET) was used to study the stability of LNCs in mucus at 37°C for at least 3 hours. Diffusion through 223, 446, and 893 μm mucus layers of 8.4, 16.8, and 42 μg/mL Ptx formulated as Taxol® (Bristol-Myers Squibb, Rueil-Malmaison, France) or encapsulated in LNCs (Ptx-LNCs) were investigated. The effect of the size of the LNCs on their diffusion was also investigated (range, 25-110 nm in diameter). Mucus behaves as a non-Newtonian gel with rheofluidifying properties and a flow threshold. The viscous (G″) and elastic (G') moduli and flow threshold of the two mucus batches varied with water content, but G' remained below G″. LNCs had no effect on mucus viscosity and flow threshold. The FRET efficiency remained at 78% after 3 hours. Because the destruction of the LNCs would lead to a FRET efficiency below 25%, these results suggest only a slight modification of LNCs after their contact with mucus. The diffusion of Taxol® and Ptx-LNCs in mucus decreases if the mucus layer is thicker. Interestingly, the apparent permeability across mucus is higher for Ptx-LNCs than for Taxol® for drug concentrations of 16.8 and 42 μg/mL Ptx (P<0.05). The diffusion of Ptx-LNCs through mucus is not size-dependent. This study shows that LNCs are stable in mucus, do not change mucus rheological properties, and improve Ptx diffusion at low concentrations, thus making these systems good candidates for Ptx oral delivery. The study of the physicochemical interaction between the LNC surface and its diffusion in mucus

  9. Synthesis and evaluation of single-wall carbon nanotube-paclitaxel-folic acid conjugate as an anti-cancer targeting agent.

    PubMed

    Tavakolifard, Sara; Biazar, Esmaeil; Pourshamsian, Khalil; Moslemin, Mohammad H

    2016-08-01

    Single-wall carbon nanotubes (SWCNT) represent a novel nanomaterial applied in various nanotechnology fields because of their surface chemistry properties and high drug cargo capacity. In this study, SWCNT are pre-functionalized covalently with paclitaxel (PTX) - an anticancer drug, and folic acid (FA), as a targeting agent for many tumors. The samples are investigated and evaluated by different analyses such as Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), absorption spectroscopic measurements (UV-Visible), elemental analysis, and cell analyses with cancer cell line cultures. The results show good conjugation of the targeting molecule and the anticancer drug on the surface of the carbon nanotubes (CNT). This work demonstrates that the SWCNT-PTX-FA system is a potentially useful system for the targeted delivery of anticancer drugs. PMID:25783856

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

    NASA Astrophysics Data System (ADS)

    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

    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.

  11. MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer

    NASA Astrophysics Data System (ADS)

    Yang, Xiaoqian; Lyer, Arun K.; Singh, Amit; Choy, Edwin; Hornicek, Francis J.; Amiji, Mansoor M.; Duan, Zhenfeng

    2015-02-01

    Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer.

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

    PubMed

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

    2014-04-01

    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 48 h incubation. MTT assays showed changes in cell viability at different concentrations of PTX formulations, as well as pure PTX (10 μM, 20 μM and 30 μM). 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

  13. Ultrasound-Targeted Retroviral Gene Delivery

    NASA Astrophysics Data System (ADS)

    Taylor, Sarah L.; Rahim, Ahad A.; Bush, Nigel L.; Bamber, Jeffrey C.; Porter, Colin D.

    2007-05-01

    This study demonstrates the ability of focused ultrasound to target retroviral gene delivery. Key to our experiments was the use of non-infectious virus particles lacking the envelope protein required for receptor-mediated entry. The novelty of our approach is that spatial control at a distance is exerted upon viral delivery by subsequent exposure to ultrasound, leading to stable gene delivery. The technology is ideally suited to controlling gene delivery in vivo following systemic vector administration. Our data provide a solution to the critical issue of obtaining tissue specificity with retroviral vectors and impart stability of expression to ultrasound-mediated gene delivery.

  14. A New Carbon Nanotube-Based Breast Cancer Drug Delivery System: Preparation and In Vitro Analysis Using Paclitaxel.

    PubMed

    Shao, Wei; Paul, Arghya; Rodes, Laetitia; Prakash, Satya

    2015-04-01

    Paclitaxel (PTX) is one of the most important drugs for breast cancer; however, the drug effects are limited by its systematic toxicity and poor water solubility. Nanoparticles have been applied for delivery of cancer drugs to overcome their limitations. Toward this goal, a novel single-walled carbon nanotube (SWNT)-based drug delivery system was developed by conjugation of human serum albumin (HSA) nanoparticles for loading of antitumor agent PTX. The nanosized macromolecular SWNT-drug carrier (SWNT-HSA) was characterized by TEM, UV-Vis-NIR spectrometry, and TGA. The SWNT-based drug carrier displayed high intracellular delivery efficiency (cell uptake rate of 80%) in breast cancer MCF-7 cells, as examined by fluorescence-labeled drug carriers, suggesting the needle-shaped SWNT-HSA drug carrier was able to transport drugs across cell membrane despite its macromolecular structure. The drug loading on SWNT-based drug carrier was through high binding affinity of PTX to HSA proteins. The PTX formulated with SWNT-HSA showed greater growth inhibition activity in MCF-7 breast cancer cells than PTX formulated with HSA nanoparticle only (cell viability of 63 vs 70% in 48 h and 53 vs 62% in 72 h). The increased drug efficacy could be driven by SWNT-mediated cell internalization. These data suggest that the developed SWNT-based antitumor agent is functional and effective. However, more studies for in vivo drug delivery efficacy and other properties are needed before this delivery system can be fully realized. PMID:27101155

  15. Targeted Drug Delivery in Pancreatic Cancer

    PubMed Central

    Yu, Xianjun; Zhang, Yuqing; Chen, Changyi; Yao, Qizhi; Li, Min

    2009-01-01

    Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor and antibody has been a success in recent pre-clinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer, and provides important information on potential therapeutic targets for pancreatic cancer treatment. PMID:19853645

  16. The Effect of Short-term Intra-arterial Delivery of Paclitaxel on Neointimal Hyperplasia and the Local Thrombotic Environment after Angioplasty

    SciTech Connect

    Yajun, E; He Nengshu Fan Hailun

    2013-08-01

    PurposeTo evaluate the effects of short-term intra-arterial delivery of paclitaxel on neointimal hyperplasia and the local thrombotic environment after angioplasty.MethodsAn experimental common carotid artery injury model was established in 60 rats, which were divided into experimental groups (40 rats) and controls (20 rats). Local intra-arterial administration of paclitaxel was applied at 2 doses (90 and 180 {mu}g/30 {mu}l), and the effects of short-term delivery of paclitaxel on neointimal hyperplasia and the expression of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated at days 15 and 30 by hematoxylin and eosin staining and immunohistochemistry.ResultsAt 15 and 30 days after injury, neointimal thickness and area, the ratio of intimal area to medial area and the stenotic rate were all significantly decreased in the group provided the high concentrations (180 {mu}g/30 {mu}l) of paclitaxel for 2 min or 10 min and in the group provided the low concentration (90 {mu}g/30 {mu}l) of paclitaxel for 10 min (p < 0.05). At 30 days after injury, there were no significant changes in TF expression among all experimental groups. PAI-1 expression increased in the neointima of the high concentration 10 min group (p < 0.05), while t-PA expression decreased in the neointima of the high concentration 2 min group (p < 0.05).ConclusionIn the rat common carotid artery injury model, the short-term delivery of paclitaxel could effectively inhibit neointimal hyperplasia in the long term, with very little influence on the local expression of TF and PAI-1.

  17. Polymers for Colon Targeted Drug Delivery

    PubMed Central

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

    2010-01-01

    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

  18. MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

    NASA Astrophysics Data System (ADS)

    Ren, Lili; Chen, Shizhen; Li, Haidong; Zhang, Zhiying; Ye, Chaohui; Liu, Maili; Zhou, Xin

    2015-07-01

    Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

  19. Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment.

    PubMed

    Chirio, Daniela; Gallarate, Marina; Peira, Elena; Battaglia, Luigi; Muntoni, Elisabetta; Riganti, Chiara; Biasibetti, Elena; Capucchio, Maria Teresa; Valazza, Alberto; Panciani, Pierpaolo; Lanotte, Michele; Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Filice, Gaetano; Corona, Silvia; Schiffer, Davide

    2014-11-01

    Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300–600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25–90% range.Blood–brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells. PMID:25445304

  20. Targeted delivery of therapeutics to endothelium

    PubMed Central

    Simone, Eric; Ding, Bi-Sen

    2009-01-01

    The endothelium is a target for therapeutic and diagnostic interventions in a plethora of human disease conditions including ischemia, inflammation, edema, oxidative stress, thrombosis and hemorrhage, and metabolic and oncological diseases. Unfortunately, drugs have no affinity to the endothelium, thereby limiting the localization, timing, specificity, safety, and effectiveness of therapeutic interventions. Molecular determinants on the surface of resting and pathologically altered endothelial cells, including cell adhesion molecules, peptidases, and receptors involved in endocytosis, can be used for drug delivery to the endothelial surface and into intracellular compartments. Drug delivery platforms such as protein conjugates, recombinant fusion constructs, targeted liposomes, and stealth polymer carriers have been designed to target drugs and imaging agents to these determinants. We review endothelial target determinants and drug delivery systems, describe parameters that control the binding of drug carriers to the endothelium, and provide examples of the endothelial targeting of therapeutic enzymes designed for the treatment of acute vascular disorders including ischemia, oxidative stress, inflammation, and thrombosis. PMID:18815813

  1. Paclitaxel-conjugated PEG and arginine-grafted bioreducible poly (disulfide amine) micelles for co-delivery of drug and gene

    PubMed Central

    Nam, Kihoon; Nam, Hye Yeong; Kim, Pyung-Hwan; Kim, Sung Wan

    2012-01-01

    We developed a paclitaxel-conjugated polymeric micelle, ABP-PEG3.5k-Paclitaxel (APP) consisting of poly (ethylene glycol) (PEG) and arginine-grafted poly(cystaminebisacrylamide-diaminohexane) (ABP) for the co-delivery of gene and drug. The APP polymer self-assembled into cationic polymeric micelles with a critical micelle concentration (CMC) value of approximately 0.062 mg/mL, which was determined from measurements of the UV absorption of pyrene. The micelles have an average size of about 3 nm and a zeta potential of about +14 mV. Due to the positive surface charge, APP micelles formed polyplexes with plasmid DNA approximately 200 nm in diameter. The luciferase gene and mouse interleukin-12 (IL-12) gene was used to monitor gene delivery potency. APP polyplexes showed increased gene delivery efficiency and cellular uptake with higher anticancer potency than paclitaxel alone. These results demonstrate that an APP micelle-based delivery system is well suitable for the co-delivery of gene and drug. PMID:22871423

  2. Self-assembled nanoparticles from hyaluronic acid-paclitaxel prodrugs for direct cytosolic delivery and enhanced antitumor activity.

    PubMed

    Xu, Chaoran; He, Wei; Lv, Yaqi; Qin, Chao; Shen, Lingjia; Yin, Lifang

    2015-09-30

    A prodrug-based nanosystem obtained by formulating prodrug and nanotechnology into a system is one of the most promising strategies to enhance drug delivery for disease treatment. Herein, we report a new nanosystem based on HA-PTX conjugates (HA-PTX Ns), which penetrated across cell membranes into cytosol, thus enhancing paclitaxel (PTX) delivery. HA-PTX Ns were successfully obtained based on HA-PTX, and their average particle size was approximately 200 nm. Importantly, unlike other prodrug-based nanosystems, HA-PTX Ns obtained cellular entry without entrapment within the lysosomal-endosomal system by using pathways including clathrin-mediated endocytosis, microtubule-associated internalization, macropinocytosis and cholesterol-dependence. Due to significant accumulation in tumors, HA-PTX Ns had more than a 4-fold decrease in tumor volume on day 14 in contrast with PTX alone. In conclusion, HA-PTX Ns could enter cells, bypass the lysosomal-endosomal system and improve PTX delivery. PMID:26232702

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

    PubMed Central

    Xiao, Kai; Luo, Juntao; Fowler, Wiley; Li, Yuanpei; Lee, Joyce; Wang, Li; Lam, Kit S.

    2009-01-01

    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 PEG5k-CA8, a representive telodendrimer, to prepare paclitaxel-loaded nanoparticles (PTX-PEG5k-CA8 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-PEG5k-CA8 NPs after single dose and five consective 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-PEG5k-CA8 NPs achieved superior toxicity profiles and antitumor 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

  4. Matrix metalloproteases: Underutilized targets for drug delivery

    PubMed Central

    Vartak, Deepali G.; Gemeinhart, Richard A.

    2013-01-01

    Pathophysiological molecules in the extracellular environment offer excellent targets that can be exploited for designing drug targeting systems. Matrix metalloproteases (MMPs) are a family of extracellular proteolytic enzymes that are characterized by their overexpression or overactivity in several pathologies. Over the last two decades, the MMP literature reveals heightened interest in the research involving MMP biology, pathology, and targeting. This review describes various strategies that have been designed to utilize MMPs for targeting therapeutic entities. Key factors that need to be considered in the successful design of such systems have been identified based on the analyses of these strategies. Development of targeted drug delivery using MMPs has been steadily pursued; however, drug delivery efforts using these targets need to be intensified and focused to realize the clinical application of the fast developing fundamental MMP research. PMID:17365270

  5. Nanoscale drug delivery for targeted chemotherapy.

    PubMed

    Xin, Yong; Huang, Qian; Tang, Jian-Qin; Hou, Xiao-Yang; Zhang, Pei; Zhang, Long Zhen; Jiang, Guan

    2016-08-28

    Despite significant improvements in diagnostic methods and innovations in therapies for specific cancers, effective treatments for neoplastic diseases still represent major challenges. Nanotechnology as an emerging technology has been widely used in many fields and also provides a new opportunity for the targeted delivery of cancer drugs. Nanoscale delivery of chemotherapy drugs to the tumor site is highly desirable. Recent studies have shown that nanoscale drug delivery systems not only have the ability to destroy cancer cells but may also be carriers for chemotherapy drugs. Some studies have demonstrated that delivery of chemotherapy via nanoscale carriers has greater therapeutic benefit than either treatment modality alone. In this review, novel approaches to nanoscale delivery of chemotherapy are described and recent progress in this field is discussed. PMID:27235607

  6. Nanoparticles for intracellular-targeted drug delivery

    NASA Astrophysics Data System (ADS)

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

    2011-12-01

    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.

  7. Targeted Delivery of Immunomodulators to Lymph Nodes.

    PubMed

    Azzi, Jamil; Yin, Qian; Uehara, Mayuko; Ohori, Shunsuke; Tang, Li; Cai, Kaimin; Ichimura, Takaharu; McGrath, Martina; Maarouf, Omar; Kefaloyianni, Eirini; Loughhead, Scott; Petr, Jarolim; Sun, Qidi; Kwon, Mincheol; Tullius, Stefan; von Andrian, Ulrich H; Cheng, Jianjun; Abdi, Reza

    2016-05-10

    Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo. PMID:27134176

  8. A novel biosensor for quantitative monitoring of on-target activity of paclitaxel

    NASA Astrophysics Data System (ADS)

    Townley, H. E.; Zheng, Y.; Goldsmith, J.; Zheng, Y. Y.; Stratford, M. R. L.; Dobson, P. J.; Ahmed, A. A.

    2014-12-01

    This study describes a system for quantifying paclitaxel activity using the C-terminus of α-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of α-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of α-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle.This study describes a system for quantifying paclitaxel activity using the C-terminus of α-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of α-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of α-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the

  9. Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment.

    PubMed

    Assanhou, Assogba G; Li, Wenyuan; Zhang, Lei; Xue, Lingjing; Kong, Lingyi; Sun, Hongbin; Mo, Ran; Zhang, Can

    2015-12-01

    Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual-functionalized cationic liposome containing a synthetic cationic lipid, 1,5-dioctadecyl-N-histidyl-L-glutamate (HG2C18) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C18 lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment. PMID:26426537

  10. Targeting the brain: advances in drug delivery.

    PubMed

    Blumling Iii, James P; Silva, Gabriel A

    2012-09-01

    The blood-brain barrier (BBB) represents a significant obstacle for drug delivery to the brain. Many therapeutics with potential for treating neurological conditions prove incompatible with intravenous delivery simply because of this barrier. Rather than modifying drugs to penetrate the BBB directly, it has proven more efficacious to either physically bypass the barrier or to use specialized delivery vehicles that circumvent BBB regulatory mechanisms. Controlled-release intracranial polymer implants and particle injections are the clinical state of the art with regard to localized delivery, although these approaches can impose significant surgical risks. Focused ultrasound provides a non-invasive alternative that may prove more desirable for acute treatment of brain tumors and other conditions requiring local tissue necrosis. For targeting the brain as a whole, cell-penetrating peptides (CPPs) and molecular trojan horses (MTHs) have demonstrated particular ability as delivery molecules and will likely see increased application. CPPs are not brain specific but offer the potential for efficient traversal of the BBB, and tandem systems with targeting molecules may produce extremely effective brain drug delivery tools. Molecular trojan horses utilize receptor-mediated transcytosis to transport cargo and are thus limited by the quantity of relevant receptors; however, they can be very selective for the BBB endothelium and have shown promise in gene therapy. PMID:23016646

  11. Polymeric nanoparticles based on chitooligosaccharide as drug carriers for co-delivery of all-trans-retinoic acid and paclitaxel.

    PubMed

    Zhang, Jing; Han, Jian; Zhang, Xiuli; Jiang, Jing; Xu, Maolei; Zhang, Daolai; Han, Jingtian

    2015-09-20

    An amphiphilic all-trans-retinoic acid (ATRA)-chitooligosaccharide (RCOS) conjugate was synthesized to form self-assembled polymeric nanoparticles to facilitate the co-delivery of ATRA and paclitaxel (PTX). The blank RCOS nanoparticles possessed low hemolytic activity and cytotoxicity, and could efficiently load PTX with a drug loading of 22.2% and a high encapsulation efficiency of 71.3%. PTX-loaded RCOS nanoparticles displayed a higher cytotoxicity to HepG2 cells compared to PTX plus ATRA solution when corrected by the accumulated drug release. Cellular uptake profiles of RCOS nanoparticles were evaluated via confocal laser scanning microscope and flow cytometry with FITC as a fluorescent mark. The RCOS nanoparticles could be rapidly and continuously taken up by HepG2 cells via endocytosis and transported into the nucleus, and the uptake rates increased with particle concentration. These results revealed the promising potential of RCOS nanoparticles as drug carriers for co-delivery of ATRA and PTX or other hydrophobic therapeutic agents. PMID:26050884

  12. Delivery of paclitaxel from cobalt–chromium alloy surfaces without polymeric carriers

    PubMed Central

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

    2014-01-01

    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. PMID:20398928

  13. Synergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibition with paclitaxel -polymer micelles to overcome multi-drug resistance.

    PubMed

    Wang, Feihu; Zhang, Dianrui; Zhang, Qiang; Chen, Yuxuan; Zheng, Dandan; Hao, Leilei; Duan, Cunxian; Jia, Lejiao; Liu, Guangpu; Liu, Yue

    2011-12-01

    Multidrug resistance (MDR) in tumor cells is a significant obstacle for successful cancer chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is a key factor contributing to the development of tumor drug resistance. Verapamil (VRP), a P-gp inhibitor, has been reported to be able to reverse completely the resistance caused by P-gp. For optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. Herein, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel (PTX), along with VRP, using DOMC-FA micelles to overcome tumor drug resistance. The floate-functionalized dual agent loaded micelles resulted in the similar cytotoxicity to PTX-loaded micelles/free VRP combination and co-administration of two single-agent loaded micelles, which was higher than that of PTX-loaded micelles. Enhanced therapeutic efficacy of dual agent micelles could be ascribe to increased accumulation of PTX in drug-resistant tumor cells. We suggest that the synergistic effect of folate receptor-mediated internalization and VRP-mediated overcoming MDR could be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into tumor cells. As a result, the difunctional micelle systems is a very promising approach to overcome tumor drug resistance. PMID:21903258

  14. D-α-tocopherol polyethylene glycol succinate-based derivative nanoparticles as a novel carrier for paclitaxel delivery

    PubMed Central

    Wu, Yupei; Chu, Qian; Tan, Songwei; Zhuang, Xiangting; Bao, Yuling; Wu, Tingting; Zhang, Zhiping

    2015-01-01

    Paclitaxel (PTX) is one of the most effective antineoplastic drugs. Its current clinical administration Taxol® is formulated in Cremophor EL, which causes serious side effects. Nanoparticles (NP) with lower systemic toxicity and enhanced therapeutic efficiency may be an alternative formulation of the Cremophor EL-based vehicle for PTX delivery. In this study, novel amphipathic 4-arm-PEG-TPGS derivatives, the conjugation of D-α-tocopherol polyethylene glycol succinate (TPGS) and 4-arm-polyethylene glycol (4-arm-PEG) with different molecular weights, have been successfully synthesized and used as carriers for the delivery of PTX. These 4-arm-PEG-TPGS derivatives were able to self-assemble to form uniform NP with PTX encapsulation. Among them, 4-arm-PEG5K-TPGS NP exhibited the smallest particle size, highest drug-loading efficiency, negligible hemolysis rate, and high physiologic stability. Therefore, it was chosen for further in vitro and in vivo investigations. Facilitated by the effective uptake of the NP, the PTX-loaded 4-arm-PEG5K-TPGS NP showed greater cytotoxicity compared with free PTX against human ovarian cancer (A2780), non-small cell lung cancer (A549), and breast adenocarcinoma cancer (MCF-7) cells, as well as a higher apoptotic rate and a more significant cell cycle arrest effect at the G2/M phase in A2780 cells. More importantly, PTX-loaded 4-arm-PEG5K-TPGS NP resulted in a significantly improved tumor growth inhibitory effect in comparison to Taxol® in S180 sarcoma-bearing mice models. This study suggested that 4-arm-PEG5K-TPGS NP may have the potential as an anticancer drug delivery system. PMID:26316751

  15. Self-assembled silk sericin/poloxamer nanoparticles as nanocarriers of hydrophobic and hydrophilic drugs for targeted delivery

    NASA Astrophysics Data System (ADS)

    Mandal, Biman B.; Kundu, S. C.

    2009-09-01

    In recent times self-assembled micellar nanoparticles have been successfully employed in tissue engineering for targeted drug delivery applications. In this review, silk sericin protein from non-mulberry Antheraea mylitta tropical tasar silk cocoons was blended with pluronic F-127 and F-87 in the presence of solvents to achieve self-assembled micellar nanostructures capable of carrying both hydrophilic (FITC-inulin) and hydrophobic (anticancer drug paclitaxel) drugs. The fabricated nanoparticles were subsequently characterized for their size distribution, drug loading capability, cellular uptake and cytotoxicity. Nanoparticle sizes ranged between 100 and 110 nm in diameter as confirmed by dynamic light scattering. Rapid uptake of these particles into cells was observed in in vitro cellular uptake studies using breast cancer MCF-7 cells. In vitro cytotoxicity assay using paclitaxel-loaded nanoparticles against breast cancer cells showed promising results comparable to free paclitaxel drugs. Drug-encapsulated nanoparticle-induced apoptosis in MCF-7 cells was confirmed by FACS and confocal microscopic studies using Annexin V staining. Up-regulation of pro-apoptotic protein Bax, down-regulation of anti-apoptotic protein Bcl-2 and cleavage of regulatory protein PARP through Western blot analysis suggested further drug-induced apoptosis in cells. This study projects silk sericin protein as an alternative natural biomaterial for fabrication of self-assembled nanoparticles in the presence of poloxamer for successful delivery of both hydrophobic and hydrophilic drugs to target sites.

  16. Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers.

    PubMed

    Zhu, Caihong; Jung, Sooyeon; Luo, Sibin; Meng, Fenghua; Zhu, Xiulin; Park, Tae Gwan; Zhong, Zhiyuan

    2010-03-01

    Biodegradable cationic micelles were prepared from PDMAEMA-PCL-PDMAEMA triblock copolymers and applied for the delivery of siRNA and paclitaxel into cancer cells. PDMAEMA-PCL-PDMAEMA copolymers were readily obtained by reversible addition-fragmentation chain transfer (RAFT) polymerization of dimethylaminoethyl methacrylate (DMAEMA) using CPADN-PCL-CPADN (CPADN: 4-cyanopentanoic acid dithionaphthalenoate; PCL: 3600 Da) as a macro-RAFT agent. The molecular weights of PDMAEMA blocks, controlled by monomer/CPADN-PCL-CPADN mole ratios, varied from 2700, 4800 to 9100 (denoted as polymer 1, 2 and 3, respectively). These triblock copolymers formed nano-sized micelles in water with positive surface charges ranging from +29.3 to +35.5 mV. Both micelles 1 and 2 revealed a low cytotoxicity. Gel retardation assay showed that micelles 1 and 2 could effectively complex with siRNA at and above N/P ratios of 4/1 and 2/1, respectively. Notably, GFP siRNA complexed with micelle 1 exhibited significantly enhanced gene silencing efficiency as compared to that formulated with 20 kDa PDMAEMA or 25kDa branched PEI in GFP-expressed MDA-MB-435-GFP cells. Moreover, micelle 1 loaded with paclitaxel displayed higher drug efficacy than free paclitaxel in PC3 cells, due to most likely improved cellular uptake. The combinatorial delivery of VEGF siRNA and paclitaxel showed an efficient knockdown of VEGF expression. Confocal laser scanning microscope studies on GFP siRNA complexed with nile red-loaded micelle revealed that nile red was delivered into GFP-expressed MDA-MB-435-GFP cells and that GFP expression was significantly inhibited. These results demonstrated that cationic biodegradable micelles are highly promising for the combinatorial delivery of siRNA and lipophilic anti-cancer drugs. PMID:19963269

  17. Paclitaxel Injection

    MedlinePlus

    ... with other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to treat ovarian cancer (cancer that ... cancer, and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also used to treat Kaposi's sarcoma (a ...

  18. Paclitaxel Injection

    MedlinePlus

    ... other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to treat ovarian cancer (cancer that ... and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also used to treat Kaposi's sarcoma (a ...

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

    PubMed Central

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

    2012-01-01

    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 μm) 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. PMID:22178261

  20. Solid-Nanoemulsion Preconcentrate for Oral Delivery of Paclitaxel: Formulation Design, Biodistribution, and γ Scintigraphy Imaging

    PubMed Central

    Ahmad, Javed; Mir, Showkat R.; Kohli, Kanchan; Chuttani, Krishna; Mishra, Anil K.; Panda, A. K.

    2014-01-01

    Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC) using oil [propylene glycol monocaprylate/glycerol monooleate, 4 : 1 w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1 : 1 w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1 : 1 w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel), respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in γ scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC. PMID:25114933

  1. Prodrug Strategies for Paclitaxel.

    PubMed

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

    2016-01-01

    Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID:27223283

  2. Prodrug Strategies for Paclitaxel

    PubMed Central

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

    2016-01-01

    Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID:27223283

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

    NASA Astrophysics Data System (ADS)

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

    2010-02-01

    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.

  4. Poly-α,β-Polyasparthydrazide-Based Nanogels for Potential Oral Delivery of Paclitaxel: In Vitro and In Vivo Properties.

    PubMed

    Guo, Jingwen; Ma, Mingxin; Chang, Di; Zhang, Qiang; Zhang, Chen; Yue, Yang; Liu, Jia; Wang, Siling; Jiang, Tongying

    2015-12-01

    A family of nanogel drug carriers has been designed to enhance the oral absorption of paclitaxel (PTX). The PAHy-based nanogels were prepared by the interpenetration of poly-α,β-polyasparthydrazide (PAHy) chains and dicarboxyl-poly (ethylene glycol) (CPEG), forming a smart chain network. The PAHy-based nanogels were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), dynamic light scattering (DLS), X-ray diffraction (XRD) and high performance liquid chromatography (HPLC). The adhesion and retention properties of fluorescein isothiocyanate (FITC)-nanogels in vivo were investigated using an in vivo imaging system and confocal laser scanning microscopy (CLSM). The smart nanogels had a particle size of -200 nm, increased the degree and rate of release, and spent over 12 h in the gastrointestinal tract. They also produced excellent adhesion, permeability and retention (APR) effects and increased oral absorption, confirming their use as potential sustained-release carriers for the oral delivery of the hydrophobic anticancer agent PTX. PMID:26510316

  5. Low molecular weight chitosan-coated polymeric nanoparticles for sustained and pH-sensitive delivery of paclitaxel

    PubMed Central

    Abouelmagd, Sara A.; Ku, Youn Jin; Yeo, Yoon

    2015-01-01

    Low molecular weight chitosan (LMWC) is a promising polymer for surface modification of nanoparticles (NPs), which can impart both stealth effect and electrostatic interaction with cells at mildly acidic pH of tumors. We previously produced LMWC-coated NPs via covalent conjugation to poly(lactic-co-glycolic) acid (PLGA-LMWC NPs). However, this method had several weaknesses including inefficiency and complexity of the production as well as increased hydrophilicity of the polymer matrix, which led to poor drug release control. Here, we used the dopamine polymerization method to produce LMWC-coated NPs (PLGA-pD-LMWC NPs), where the core NPs were prepared with PLGA that served best to load and retain drugs and then functionalized with LMWC via polydopamine layer. The PLGA-pD-LMWC NPs overcame the limitations of PLGA-LMWC NPs while maintaining their advantages. First of all, PLGA-pD-LMWC NPs attenuated the release of paclitaxel to a greater extent than PLGA-LMWC NPs. Moreover, PLGA-pD-LMWC NPs had a pH-dependent surface charge profile and cellular interactions similar to PLGA-LMWC NPs, enabling acid-specific NP-cell interaction and enhanced drug delivery to cells in weakly acidic environment. Although the LMWC layer did not completely prevent protein binding in serum solution, PLGA-pD-LMWC NPs showed less phagocytic uptake than bare PLGA NPs. PMID:26453168

  6. In vivo pharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle.

    PubMed

    Rezazadeh, Mahboubeh; Emami, Jaber; Hasanzadeh, Farshid; Sadeghi, Hojjat; Minaiyan, Mohsen; Mostafavi, Abolfazl; Rostami, Mahboubeh; Lavasanifar, Afsaneh

    2016-06-01

    A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the Vd, T1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX. PMID:25188785

  7. 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

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

    2012-05-01

    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 PEG₂₀₀₀-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

  8. A novel localized co-delivery system with lapatinib microparticles and paclitaxel nanoparticles in a peritumorally injectable in situ hydrogel.

    PubMed

    Hu, Hongxiang; Lin, Zhiqiang; He, Bing; Dai, Wenbing; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Hua; Zhang, Qiang

    2015-12-28

    The combination of high dose of oral lapatinib (LAPA), a HER2 tyrosine kinase inhibitor, with intravenous paclitaxel (PTX) exhibited a clinical survival advantage compared with PTX alone against HER2 positive breast cancer. However, localized delivery system with high regional drug level may greatly decrease the dose of drug, leading to higher safety and lower cost. In an attempt to imitate the fast and slow exposure of these two drugs in clinic use, we incorporated PTX nanoparticles and LAPA microparticles into a thermosensitive hydrogel (PL-gel) for peritumoral injection, using PTX-gel plus LAPA-oral (P-gel+L-oral) and so on as controls. To visually study in vitro or in vivo, PTX/DID and LAPA/DIR hybrid crystals were prepared. In vitro and in vivo studies demonstrated the fast and short-term release of PTX, as well as the slow and long-term release of LAPA from the PL-gel. The most synergistic effect was found between LAPA and PTX on the cell line overexpressing both HER2 and P-gp, and the mechanisms related to LAPA-induced inhibition on P-gp expression, more G2/M phase arrest of PTX and more uptake of PTX in tumor cells. With a dose of LAPA in PL-gel group only less than 5% of that in P-gel+L-oral group, PL-gel demonstrated significant tumor suppression similar to P-gel+L-oral group, and showed longer mice survival time. Besides, PL-gel achieved more steady LAPA accumulation in tumors and revealed significantly less toxicity compared with P-gel+L-oral group. To summarize, this localized co-delivery system with good synergistic effects between LAPA and PTX might offer a potential strategy for HER2 and P-gp positive breast cancer. PMID:26474677

  9. Targeted TFO delivery to hepatic stellate cells.

    PubMed

    Yang, Ningning; Singh, Saurabh; Mahato, Ram I

    2011-10-30

    Triplex-forming oligonucleotides (TFOs) represent an antigene approach for gene regulation through direct interaction with genomic DNA. While this strategy holds great promise owing to the fact that only two alleles need silencing to impact gene regulation, delivering TFOs to target cells in vivo is still a challenge. Our recent efforts have focused on conjugating TFOs to carrier molecules like cholesterol to enhance their cellular uptake and mannose-6-phosphate-bovine serum albumin (M6P-BSA) to target TFO delivery to hepatic stellate cells (HSCs) for treating liver fibrosis. These approaches however are rendered less effective owing to a lack of targeted delivery, as seen with lipid-conjugates, and the potential immune reactions due to repeated dosing with high molecular weight BSA conjugated TFO. In this review, we discuss our latest efforts to enhance the effectiveness of TFO for treating liver fibrosis. We have shown that conjugation of TFOs to M6P-HPMA can enhance TFO delivery to HSCs and has the potential to treat liver fibrosis by inhibiting collagen synthesis. This TFO conjugate shows negligible immunogenicity owing to the use of HPMA, one of the least immunogenic copolymers, thereby making it a suitable and more effective candidate for antifibrotic therapy. PMID:21763370

  10. Targeted TFO Delivery to Hepatic Stellate Cells

    PubMed Central

    Yang, Ningning; Singh, Saurabh; Mahato, Ram I

    2011-01-01

    Triplex-forming oligonucleotides (TFOs) represent an antigene approach for gene regulation through direct interaction with genomic DNA. While this strategy holds great promise owing to the fact that only two alleles need silencing to impact gene regulation, delivering TFOs to target cells in vivo is still a challenge. Our recent efforts have focused on conjugating TFOs to carrier molecules like cholesterol to enhance their cellular uptake and mannose-6-phosphate-bovine serum albumin (M6P-BSA) to target TFO delivery to hepatic stellate cells (HSCs) for treating liver fibrosis. These approaches however are rendered less effective owing to a lack of targeted delivery, as seen with lipid-conjugates, and the potential immune reactions due to repeated dosing with high molecular weight BSA conjugated TFO. In this review, we discuss our latest efforts to enhance the effectiveness of TFO for treating liver fibrosis. We have shown that conjugation of TFOs to M6P-HPMA can enhance TFO delivery to HSCs and has the potential to treat liver fibrosis by inhibiting collagen synthesis. This TFO conjugate shows negligible immunogenicity owing to the use of HPMA, one of the least immunogenic copolymers, thereby making it a suitable and more effective candidate for antifibrotic therapy. PMID:21763370

  11. Combined Delivery and Anti-Cancer Activity of Paclitaxel and Curcumin Using Polymeric Micelles.

    PubMed

    Gao, Xiang; Wang, Bilan; Wu, Qinjie; Wei, Xiawei; Zheng, Fengjin; Men, Ke; Shi, Huashan; Huang, Ning; Wei, Yuquan; Gong, Changyang

    2015-04-01

    Paclitaxel (PTX) is efficacious in treating various solid tumors. However, the severe adverse effects of its present formulation (Cremophor EL and ethanol) and the development of drug resistance by the activation of nuclear factor-κB (NF-κB) reduce the anti-tumor activities of PTX. Curcumin (Cur) demonstrates anti-tumor activity by means of antiangiogenesis and induction of apoptosis as well as suppression of the activity of NF-κB. Therefore, to improve its antitumor activity and eliminate the toxicity of the commercial formulation of PTX, we prepared biodegradable monomethoxy poly(ethyleneglycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to co-deliver PTX and Cur using a solid dispersion method. The mixed PTX and Cur polymeric micelles (PTX-Cur-M) produced were monomorphous micelles of 38 nm in diameter that released PTX and Cur for an extended period of time and induced cell apoptosis in vitro. In addition, the PTX-Cur-M exhibited anti-angiogenic activity in vitro and in vivo. Furthermore, the therapeutic efficacy of PTX-Cur-M in a mouse model of colon cancer was evaluated. PTX-Cur-M micelles produced significantly more inhibition of tumor growth than Cur micelles (Cur-M) and PTX micelles (PTX-M) alone at the same dose (P < 0.05 and P < 0.05, respectively). Immunohistochemical and immunofluorescent analyses demonstrated that PTX-Cur-M enhanced tumor cell apoptosis and inhibited angiogenesis to a greater extent than control treatment. Our data suggested that PTX-Cur-M may have potential clinical applications in cancer therapy. PMID:26310065

  12. Controlled delivery of paclitaxel from stent coatings using novel styrene maleic anhydride copolymer formulations.

    PubMed

    Richard, Robert; Schwarz, Marlene; Chan, Ken; Teigen, Nikolai; Boden, Mark

    2009-08-01

    The controlled release of paclitaxel (PTx) from stent coatings comprising an elastomeric polymer blended with a styrene maleic anhydride (SMA) copolymer is described. The coated stents were characterized for morphology by scanning electron microscopy (SEM) and atomic force microscopy (AFM), and for drug release using high-performance liquid chromatography (HPLC). Differential scanning calorimetry (DSC) was used to measure the extent of interaction between the PTx and polymers in the formulation. Coronary stents were coated with blends of poly(b-styrene-b-isobutylene-b-styrene) (SIBS) and SMA containing 7% or 14% maleic anhydride (MA) by weight. SEM examination of the stents showed that the coating did not crack or delaminate either before or after stent expansion. Examination of the coating surface via AFM after elution of the drug indicated that PTx resides primarily in the SMA phase and provided information about the mechanism of PTx release. The addition of SMA altered the release profile of PTx from the base elastomer coatings. In addition, the presence of the SMA enabled tunable release of PTx from the elastomeric stent coatings, while preserving mechanical properties. Thermal analysis reveled no shift in the glass transition temperatures for any of the polymers at all drug loadings studied, indicating that the PTx is not miscible with any component of the polymer blend. An in vivo evaluation indicated that biocompatibility and vascular response results for SMA/SIBS-coated stents (without PTx) are similar to results for SIBS-only-coated and bare stainless steel control stents when implanted in the non-injured coronary arteries of common swine for 30 and 90 days. PMID:18563805

  13. Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

    PubMed Central

    2011-01-01

    Background Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m2 with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation. PMID:21745358

  14. Simultaneous delivery of therapeutic antagomirs with paclitaxel for the management of metastatic tumors by a pH-responsive anti-microbial peptide-mediated liposomal delivery system.

    PubMed

    Zhang, Qianyu; Ran, Rui; Zhang, Li; Liu, Yayuan; Mei, Ling; Zhang, Zhirong; Gao, Huile; He, Qin

    2015-01-10

    The roles of microRNAs (miRNAs) in the regulation of metastasis have been widely recognized in the recent years. Mir-10b antagomir (antagomir-10b) was shown to impede metastasis through the down-regulation of mir-10b; however, it could not stunt the growth of primary tumors. In this study we showed that the co-delivery of antagomir-10b with paclitaxel (PTX) by a novel liposomal delivery system modified with an anti-microbial peptide [D]-H6L9 (D-Lip) could significantly both hinder the migration of 4T1 cells and induce evident cellular apoptosis and cell death in the meantime. The histidines in the sequence of [D]-H6L9 allowed the peptide to get protonated under pH5.0 (mimicking the lysosome/endosome environment), and strong membrane lytic effect could thus be activated, leading to the escape of liposomes from the lysosomes and the decrease of of mir-10b expression. The in vivo and ex vivo fluorescence imaging showed that D-Lip could reach 4T1 tumors efficaciously. Incorporation of PTX did not influence the antagomir-10b delivery effect of D-Lip; for the in vivo tumor inhibition assay, compared with all the other groups, the combination of antagomir-10b and PTX delivered by D-Lip could prominently delay the growth of 4T1 tumors and reduce the lung metastases at the same time, and the expression of Hoxd10 in tumors was also significantly up-regulated. Taken together, these results demonstrated that D-Lip could act as a sufficient tool in co-delivering antagomir-10b and PTX. PMID:25445692

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

    PubMed Central

    2013-01-01

    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

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

    PubMed Central

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

    2011-01-01

    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

  17. Nanogel Carrier Design for Targeted Drug Delivery

    PubMed Central

    Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

  18. Biodistribution and Bioimaging Studies of Hybrid Paclitaxel Nanocrystals: Lessons Learned of the EPR Effect and Image-Guided Drug Delivery

    PubMed Central

    Hollis, Christin P.; Weiss, Heidi L.; Leggas, Markos; Evers, B. Mark; Gemeinhart, Richard A.; Li, Tonglei

    2013-01-01

    Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 hours by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20 mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for hybrid nanocrystals, in tracking drug distribution and pharmacokinetics. PMID:23920039

  19. Cooperative assembly in targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Auguste, Debra

    2012-02-01

    Described as cell analogues, liposomes are self-assembled lipid bilayer spheres that encapsulate aqueous volumes. Liposomes offer several drug delivery advantages due to their structural versatility related to size, composition, bilayer fluidity, and ability to encapsulate a large variety of compounds non-covalently. However, liposomes lack the structural information embedded within cell membranes. Partitioning of unsaturated and saturated lipids into liquid crystalline (Lα) and gel phase (Lβ) domains, respectively, affects local molecular diffusion and elasticity. Liposome microdomains may be used to pattern molecules, such as antibodies, on the liposome surface to create concentrated, segregated binding regions. We have synthesized, characterized, and evaluated a series of homogeneous and heterogeneous liposomal vehicles that target inflamed endothelium. These drug delivery vehicles are designed to complement the heterogeneous presentation of lipids and receptors on endothelial cells (ECs). EC surfaces are dynamic; they segregate receptors within saturated lipid microdomains on the cell surface to regulate binding and signaling events. We have demonstrated that cooperative binding of two antibodies enhances targeting by multiple fold. Further, we have shown that organization of these antibodies on the surface can further enhance cell uptake. The data suggest that EC targeting may be enhanced by designing liposomes that mirror the segregated structure of lipid and receptor molecules involved in neutrophil-EC adhesion. This strategy is employed in an atherosclerotic mouse model in vivo.

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

    PubMed Central

    2014-01-01

    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

  1. β-Cyclodextrin-Based Inclusion Complexation Bridged Biodegradable Self-Assembly Macromolecular Micelle for the Delivery of Paclitaxel.

    PubMed

    Chen, Yanzuo; Huang, Yukun; Qin, Dongdong; Liu, Wenchao; Song, Chao; Lou, Kaiyan; Wang, Wei; Gao, Feng

    2016-01-01

    In this study, a novel adamantanamine-paclitaxel (AD-PTX) incorporated oligochitosan- carboxymethyl-β-cyclodextrin (CSO-g-CM-β-CD) self-assembly macromolecular (CSO-g-CM-β-CD@AD-PTX) micelle was successfully prepared in water through sonication. The formed molecules were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance (NMR) spectroscopy, two-dimensional NMR, elemental analysis, and liquid chromatography-mass spectrometry, while the correspondent micelles were characterized by dynamic light scattering and transmission electron microscopy. We showed that the macromolecular micelle contained a spherical core-shell structure with a diameter of 197.1 ± 3.3 nm and zeta potential of -19.1 ± 4.3 mV. The CSO-g-CM-β-CD@AD-PTX micelle exhibited a high drug-loading efficacy up to 31.3%, as well as a critical micelle concentration of 3.4 × 10-7 M, which indicated good stability. Additionally, the in vitro release profile of the CSO-g-CM-β-CD@AD-PTX micelle demonstrated a long-term release pattern, 63.1% of AD-PTX was released from the micelle during a 30-day period. Moreover, the CSO-g-CM-β-CD@AD-PTX micelle displayed cytotoxicity at a sub-μM scale similar to PTX in U87 MG cells, and CSO-g-CM-β-CD exhibited a good safety profile by not manifesting significant toxicity at concentrations up to 100 μM. These results indicated that β-CD-based inclusion complexation resulting in biodegradable self-assembled macromolecular micelles can be utilized as nanocarrier, and may provide a promising platform for drug delivery in the future medical applications. PMID:26964047

  2. β-Cyclodextrin-Based Inclusion Complexation Bridged Biodegradable Self-Assembly Macromolecular Micelle for the Delivery of Paclitaxel

    PubMed Central

    Chen, Yanzuo; Huang, Yukun; Qin, Dongdong; Liu, Wenchao; Song, Chao; Lou, Kaiyan; Wang, Wei; Gao, Feng

    2016-01-01

    In this study, a novel adamantanamine-paclitaxel (AD-PTX) incorporated oligochitosan- carboxymethyl-β-cyclodextrin (CSO-g-CM-β-CD) self-assembly macromolecular (CSO-g-CM-β-CD@AD-PTX) micelle was successfully prepared in water through sonication. The formed molecules were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance (NMR) spectroscopy, two-dimensional NMR, elemental analysis, and liquid chromatography-mass spectrometry, while the correspondent micelles were characterized by dynamic light scattering and transmission electron microscopy. We showed that the macromolecular micelle contained a spherical core-shell structure with a diameter of 197.1 ± 3.3 nm and zeta potential of −19.1 ± 4.3 mV. The CSO-g-CM-β-CD@AD-PTX micelle exhibited a high drug-loading efficacy up to 31.3%, as well as a critical micelle concentration of 3.4 × 10-7 M, which indicated good stability. Additionally, the in vitro release profile of the CSO-g-CM-β-CD@AD-PTX micelle demonstrated a long-term release pattern, 63.1% of AD-PTX was released from the micelle during a 30-day period. Moreover, the CSO-g-CM-β-CD@AD-PTX micelle displayed cytotoxicity at a sub-μM scale similar to PTX in U87 MG cells, and CSO-g-CM-β-CD exhibited a good safety profile by not manifesting significant toxicity at concentrations up to 100 μM. These results indicated that β-CD-based inclusion complexation resulting in biodegradable self-assembled macromolecular micelles can be utilized as nanocarrier, and may provide a promising platform for drug delivery in the future medical applications. PMID:26964047

  3. Targeted polysaccharide nanoparticle for adamplatin prodrug delivery.

    PubMed

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

    2013-12-12

    A series of conjugated hyaluronic acid particles (HAP), composed of a hydrophobic anticancer drug core and hydrophilic cyclodextrin/hyaluronic acid shell, were prepared through self-assembling and characterized by (1)H NMR titration, electron microscopy, zeta potential, and dynamic light-scattering experiments. The nanometer-sized HAP thus prepared was biocompatible and biodegradable and was well-recognized by the hyaluronic acid receptors overexpressed on the surface of cancer cells, which enabled us to exploit HAP as an efficient targeted delivery system for anticancer drugs. Indeed, HAP exhibited anticancer activities comparable to the commercial anticancer drug cisplatin but with lower side effects both in vitro and in vivo. PMID:24252070

  4. Hyaluronic acid-shelled acid-activatable paclitaxel prodrug micelles effectively target and treat CD44-overexpressing human breast tumor xenografts in vivo.

    PubMed

    Zhong, Yinan; Goltsche, Katharina; Cheng, Liang; Xie, Fang; Meng, Fenghua; Deng, Chao; Zhong, Zhiyuan; Haag, Rainer

    2016-04-01

    The therapeutic efficacy of nanoscale anticancer drug delivery systems is severely truncated by their low tumor-targetability and inefficient drug release at the target site. Here, we report the design and development of novel endosomal pH-activatable paclitaxel prodrug micelles based on hyaluronic acid-b-dendritic oligoglycerol (HA-dOG-PTX-PM) for active targeting and effective treatment of CD44-overexpressing human breast cancer xenografts in nude mice. HA-dOG-PTX-PM had a high drug content of 20.6 wt.% and an average diameter of 155 nm. The release of PTX was slow at pH 7.4 but greatly accelerated at endosomal pH. MTT assays, flow cytometry and confocal experiments showed that HA-dOG-PTX-PM possessed a high targetability and antitumor activity toward CD44 receptor overexpressing MCF-7 human breast cancer cells. The in vivo pharmacokinetics and biodistribution studies showed that HA-dOG-PTX-PM had a prolonged circulation time in the nude mice and a remarkably high accumulation in the MCF-7 tumor (6.19%ID/g at 12 h post injection). Interestingly, HA-dOG-PTX-PM could effectively treat mice bearing MCF-7 human breast tumor xenografts with little side effects, resulting in complete inhibition of tumor growth and a 100% survival rate over an experimental period of 55 days. These results indicate that hyaluronic acid-shelled acid-activatable PTX prodrug micelles have a great potential for targeted chemotherapy of CD44-positive cancers. PMID:26851390

  5. Targeted delivery of colloids by swimming bacteria

    PubMed Central

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

    2013-01-01

    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. PMID:24100868

  6. Injected nanocrystals for targeted drug delivery

    PubMed Central

    Lu, Yi; Li, Ye; Wu, Wei

    2016-01-01

    Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies. PMID:27006893

  7. Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol®-resistant ovarian cancer

    PubMed Central

    Shen, Yao-An; Li, Wai-Hou; Chen, Po-Hung; He, Chun-Lin; Chang, Yen-Hou; Chuang, Chi-Mu

    2015-01-01

    Taxol® remained as the mainstay therapeutic agent in the treatment of ovarian cancer, however recurrence rate is still high. Cancer stem cells (CSCs) represent a subset of cells in the bulk of tumors and play a central role in inducing drug resistance and recurrence. Furthermore, cancer metabolism has been an area under intensive investigation, since accumulating evidence has shown that CSCs and cancer metabolism are closely linked, an effect named as metabolic reprogramming. In this work, we aimed to investigate the impacts of a novel liposome-encapsulated paclitaxel (Nano-Taxol) on the stemness phenotype and metabolic reprogramming. A paclitaxel-resistant cell line (TR) was established at first. Tumor growth was induced in the mice peritoneal cavity by inoculation of TR cells. A 2x2 factorial experiment was designed to test the therapeutic efficacy in which factor 1 represented the comparison of drugs (Taxol® versus Nano-Taxol), while factor 2 represented the delivery route (intravenous versus intraperitoneal delivery). In this work, we found that intraperitoneal delivery of Nano-Taxol redirects metabolic reprogramming, from glycolysis to oxidative phosphorylation, and effectively suppresses cancer stem cells. Also, intraperitoneal delivery of Nano-Taxol led to a significantly better control of tumor growth compared with intravenous delivery of Taxol® (current standard treatment). This translational research may serve as a novel pathway for the drug development of nanomedicine. In the future, this treatment modality may be extended to treat several relevant cancers that have been proved to be suitable for the loco-regional delivery of therapeutic agents, including colon cancer, gastric cancer, and pancreatic cancer. PMID:26175846

  8. Targeted Lung Delivery of Nasally Administered Aerosols

    PubMed Central

    Tian, Geng; Hindle, Michael; Longest, P. Worth

    2014-01-01

    Using the nasal route to deliver pharmaceutical aerosols to the lungs has a number of advantages including co-administration during non-invasive ventilation. The objective of this study was to evaluate the growth and deposition characteristics of nasally administered aerosol throughout the conducting airways based on delivery with streamlined interfaces implementing two forms of controlled condensational growth technology. Characteristic conducting airways were considered including a nose-mouth-throat (NMT) geometry, complete upper tracheobronchial (TB) model through the third bifurcation (B3), and stochastic individual path (SIP) model to the terminal bronchioles (B15). Previously developed streamlined nasal cannula interfaces were used for the delivery of submicrometer particles using either enhanced condensational growth (ECG) or excipient enhanced growth (EEG) techniques. Computational fluid dynamics (CFD) simulations predicted aerosol transport, growth and deposition for a control (4.7 μm) and three submicrometer condensational aerosols with budesonide as a model insoluble drug. Depositional losses with condensational aerosols in the cannula and NMT were less than 5% of the initial dose, which represents an order-of-magnitude reduction compared to the control. The condensational growth techniques increased the TB dose by a factor of 1.1–2.6x, delivered at least 70% of the dose to the alveolar region, and produced final aerosol sizes ≥2.5 μm. Compared to multiple commercial orally inhaled products, the nose-to-lung delivery approach increased dose to the biologically important lower TB region by factors as large as 35x. In conclusion, nose-to-lung delivery with streamlined nasal cannulas and condensational aerosols was highly efficient and targeted deposition to the lower TB and alveolar regions. PMID:24932058

  9. Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy.

    PubMed

    Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo D; Gaitzsch, Jens; Braun, Gary B; Willmore, Anne-Mari A; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet

    2016-04-01

    Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer-related mortality, with a median survival of 1 to 3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here, we used flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with paclitaxel and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to 4 months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound paclitaxel (Abraxane). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed an intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation-independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of paclitaxel-polymersomes in the treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with paclitaxel-polymersomes improved the therapeutic index of drug over free paclitaxel and Abraxane, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions. Mol Cancer Ther; 15(4); 670-9. ©2016 AACR. PMID:26880267

  10. Tumor-targeted paclitaxel-loaded folate conjugated poly(ethylene glycol)-poly(L-lactide) microparticles produced by supercritical fluid technology.

    PubMed

    Huang, Xiaobei; Zhang, Yanzhi; Yin, Guangfu; Pu, Ximing; Liao, Xiaoming; Huang, Zhongbing; Chen, Xianchun; Yao, Yadong

    2015-02-01

    The new biodegradable diblock copolymers poly(ethylene glycol)-poly(L-lactide) (PEG-PLLA) were synthesized and were chemically conjugated with folate (FA) in the PEG terminal ends to form FA-PEG-PLLA. Then the hydrophobic drug paclitaxel (PTX) loaded microparticles (PTX/FA-PEG-PLLA) were produced via solution enhanced dispersion by supercritical fluids (SEDS). These microparticles exhibited sphere-like shape by scanning electron microscopy observation and showed narrow hydrodynamic size distributions by dynamic light scattering measurement. Drug loading of PTX loaded microparticles was about 7-9% and the encapsulation efficiency of PTX loaded microparticles was about 18-23%. Flow cytometry and confocal laser scanning microscope analyses revealed that fluorescein isothiocyanate labeled FA conjugated microparticles presented significantly higher cellular uptake than FA-free group due to the FA-receptor-mediated endocytosis. In vitro cytotoxicity evaluation indicated that FA-PEG-PLLA expressed negligible cytotoxicity to mouse fibroblasts L929 cells. Moreover, PTX/FA-PEG-PLLA microparticles exhibited much higher anti-cancer efficacy than PTX/PEG-PLLA microparticles against human ovarian cancer SKOV3 cells. Nude mice xenografted with SKOV3 cells were used in biodistribution studies, the results indicated that an increased amount of PTX was accumulated in the tumor tissue deal with PTX/FA-PEG-PLLA microparticles. These results collectively suggested that PTX/FA-PEG-PLLA microparticles prepared by SEDS would have potential in anti-tumor applications as a tumor-targeted drug delivery formulation. PMID:25649516

  11. Targeted estrogen delivery reverses the metabolic syndrome

    PubMed Central

    Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

    2013-01-01

    We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

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

    PubMed

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

    2016-08-10

    In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. PMID:27238442

  13. Tumor hypoxia, the Warburg effect, and multidrug resistance: Modulation of hypoxia induced MDR using EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine therapy

    NASA Astrophysics Data System (ADS)

    Jabr-Milane, Lara Scheherazade

    Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, non-responsive disease. The biological focus of this work is to explore the relationship between the hypoxic microenvironment of a tumor, the development of MDR, and the energetic profile characteristic of the Warburg effect (aerobic glycolysis). The therapeutic aim of this research is to develop an EGFR-targeted nanocarrier system for combination (paclitaxel/lonidamine) therapy for the treatment of MDR cancer. The stability of the nanocarrier formulation was validated in vitro and the system was characterized for drug release kinetics, size, surface modification, and EGFR-targeting ability. An orthotopic animal model of hypoxic, MDR breast cancer was developed for the pre-clinical evaluation of this system. The EGFR-targeted nanoparticles loaded with lonidamine and paclitaxel demonstrated superior pharmacokinetic parameters relative to non-targeted nanoparticles and drug solution. Combination therapy with lonidamine and paclitaxel, in solution and EGFR-targeted nanoparticle form, was more effective at suppressing tumor growth than single agent treatment. However, combination therapy with EGFR-targeted nanoparticles was less toxic than treatment with drug solution. Combination therapy did change the MDR and hypoxic character of the tumors as demonstrated by a decrease in marker proteins. This EGFR-targeted combination nanocarrier therapy has the potential to make the successful treatment of MDR a clinical reality.

  14. Targeted medication delivery using magnetic nanostructures

    SciTech Connect

    Yoon, Mina

    2007-01-01

    We use quaternion molecular dynamics simulations to describe field-induced structural transitions in systems of few magnetic dipoles and their use for targeted medication delivery. Compact ring isomers of magnetic particles are contained, together with molecules of an active medication, inside inert microcapsules. The filled microcapsules may be transported within the body using a weak,inhomogeneous magnetic field. Medication release is triggered by puncturing the container during a structural transition within the magnetic subsystem, induced by an externally applied strong magnetic field. Our simulations describe not only the time evolution of the magnetic subsystem during a successful medication release, but also address ways to suppress an accidental release induced by thermal and magnetic fluctuations.

  15. The Na+ /H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells

    PubMed Central

    Amith, Schammim Ray; Wilkinson, Jodi Marie; Baksh, Shairaz; Fliegel, Larry

    2015-01-01

    Dysregulation of Na+ /H+ exchanger isoform one (NHE1) activity is a hallmark of cells undergoing tumorigenesis and metastasis, the leading cause of patient mortality. The acidic tumor microenvironment is thought to facilitate the development of resistance to chemotherapy drugs and to promote extracellular matrix remodeling leading to metastasis. Here, we investigated NHE1 as a co-adjuvant target in paclitaxel chemotherapy of metastatic breast cancer. We generated a stable NHE1-knockout of the highly invasive, triple-negative, MDA-MB-231 breast cancer cells. The NHE1-knockout cells proliferated comparably to parental cells, but had markedly lower rates of migration and invasion in vitro. In vivo xenograft tumor growth in athymic nude mice was also dramatically decreased compared to parental MDA-MB-231 cells. Loss of NHE1 expression also increased the susceptibility of knockout cells to paclitaxel-mediated cell death. NHE1 inhibition, in combination with paclitaxel, resulted in a dramatic decrease in viability, and migratory and invasive potential of triple-negative breast cancer cells, but not in hormone receptor-positive, luminal MCF7 cells. Our data suggest that NHE1 is critical in triple-negative breast cancer metastasis, and its chemical inhibition boosts the efficacy of paclitaxel in vitro, highlighting NHE1 as a novel, potential co-adjuvant target in breast cancer chemotherapy. PMID:25514463

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

    PubMed Central

    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

    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 μg/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

  17. Heating drug delivery to vascular wall with Rhodamine B and fluorescence labeled Paclitaxel ranging 50 to 70°C: ex vivo study

    NASA Astrophysics Data System (ADS)

    Homma, R.; Shinozuka, M.; Shimazaki, N.; Arai, T.

    2016-03-01

    We studied heating drug delivery to vascular wall with Rhodamine B ranging 50 to 70°C ex vivo study. Porcine carotid artery was dipped in the heated Rhodamine B solution in 15 s and then cooled by 37°C saline. Rhodamine B concentration distribution in the vascular wall cross-section was measured by a fluorescence microscope using 550 nm for excitation and 620 nm emission for fluorescence detection. The total amount of measured fluorescence in the vascular wall was calculated as a indication of delivered Rhodamine B quantity. The delivered Rhodamine B quantity was increased with increasing heating temperature with 50 to 70°C. In the cases of 60 to 70°C heating, the delivered Rhodamine B quantity was 3.1 to 23.3 fold by that of 37°C. Defined penetration depth of the delivered Rhodamine B in the vascular wall was also significantly increased with 65°C and 70°C heating. We also studied heating drug delivery to the vascular wall with fluorescence labeled Paclitaxel with 70°C in 15 s and 60 s heating ex vivo. In both contact duration, the delivered Paclitaxel quantity was increased. To understand these drug delivery enhancement effects, we investigated the vascular cross-sectional structure change by the heating. Some holes over 50 nm in diameter appeared on the internal elastic lamina with 70°C heating. We prospected that vascular surface structure change by the heating might enhance drug delivery to the vascular wall.

  18. Bioinspired Nanonetworks for Targeted Cancer Drug Delivery.

    PubMed

    Raz, Nasibeh Rady; Akbarzadeh-T, Mohammad-R; Tafaghodi, Mohsen

    2015-12-01

    A biomimicry approach to nanonetworks is proposed here for targeted cancer drug delivery (TDD). The swarm of bioinspired nanomachines utilizes the blood distribution network and chemotaxis to carry drug through the vascular system to the cancer site, recognized by a high concentration of vascular endothelial growth factor (VEGF). Our approach is multi-scale and includes processes that occur both within cells and with their neighbors. The proposed bionanonetwork takes advantage of several organic processes, some of which already occur within the human body, such as a plate-like structure similar to those of red blood cells for more environmental contact; a berry fruit architecture for its internal multi-foams architecture; the penetrable structure of cancer cells, tissue, as well as the porous structure of the capillaries for drug penetration; state of glycocalyx for ligand-receptor adhesion; as well as changes in pH state of blood and O 2 release for nanomachine communication. For a more appropriate evaluation, we compare our work with a conventional chemotherapy approach using a mathematical model of cancer under actual experimental parameter settings. Simulation results show the merits of the proposed method in targeted cancer therapy by improving the densities of the relevant cancer cell types and VEGF concentration, while following more organic and natural processes. PMID:26529771

  19. Mitochondrial biology, targets, and drug delivery.

    PubMed

    Milane, Lara; Trivedi, Malav; Singh, Amit; Talekar, Meghna; Amiji, Mansoor

    2015-06-10

    In recent years, mitochondrial medicine has emerged as a new discipline resting at the intersection of mitochondrial biology, pathology, and pharmaceutics. The central role of mitochondria in critical cellular processes such as metabolism and apoptosis has placed mitochondria at the forefront of cell science. Advances in mitochondrial biology have revealed that these organelles continually undergo fusion and fission while functioning independently and in complex cellular networks, establishing direct membrane contacts with each other and with other organelles. Understanding the diverse cellular functions of mitochondria has contributed to understanding mitochondrial dysfunction in disease states. Polyplasmy and heteroplasmy contribute to mitochondrial phenotypes and associated dysfunction. Residing at the center of cell biology, cellular functions, and disease pathology and being laden with receptors and targets, mitochondria are beacons for pharmaceutical modification. This review presents the current state of mitochondrial medicine with a focus on mitochondrial function, dysfunction, and common disease; mitochondrial receptors, targets, and substrates; and mitochondrial drug design and drug delivery with a focus on the application of nanotechnology to mitochondrial medicine. Mitochondrial medicine is at the precipice of clinical translation; the objective of this review is to aid in the advancement of mitochondrial medicine from infancy to application. PMID:25841699

  20. In vitro and in vivo anticancer activity of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles.

    PubMed

    Venkatasubbu, G Devanand; Ramasamy, S; Reddy, G Pramod; Kumar, J

    2013-08-01

    Targeted drug delivery using nanocrystalline materials delivers the drug at the diseased site. This increases the efficacy of the drug in killing the cancer cells. Surface modifications were done to target the drug to a particular receptor on the cell surface. This paper reports synthesis of hydroxyapatite and titanium dioxide nanoparticles and modification of their surface with polyethylene glycol (PEG) followed by folic acid (FA). Paclitaxel, an anticancer drug, is attached to functionalized hydroxyapatite and titanium dioxide nanoparticles. The pure and functionalised nanoparticles are characterised with XRD, TEM and UV spectroscopy. Anticancer analysis was carried out in DEN induced hepatocarcinoma animals. Biochemical, hematological and histopathological analysis show that the surface modified paclitaxel attached nanoparticles have an higher anticancer activity than the pure paclitaxel and surface modified nanoparticles without paclitaxel. This is due to the targeting of the drug to the folate receptor in the cancer cells. PMID:23615724

  1. Toward Intracellular Targeted Delivery of Cancer Therapeutics

    PubMed Central

    Pandya, Hetal; Debinski, Waldemar

    2013-01-01

    A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells. PMID:22671766

  2. Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression

    PubMed Central

    Puvvada, Nagaprasad; Rajput, Shashi; Kumar, B.N. Prashanth; Sarkar, Siddik; Konar, Suraj; Brunt, Keith R.; Rao, Raj R.; Mazumdar, Abhijit; Das, Swadesh K.; Basu, Ranadhir; Fisher, Paul B.; Mandal, Mahitosh; Pathak, Amita

    2015-01-01

    Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues. PMID:26145450

  3. Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression.

    PubMed

    Puvvada, Nagaprasad; Rajput, Shashi; Kumar, B N Prashanth; Sarkar, Siddik; Konar, Suraj; Brunt, Keith R; Rao, Raj R; Mazumdar, Abhijit; Das, Swadesh K; Basu, Ranadhir; Fisher, Paul B; Mandal, Mahitosh; Pathak, Amita

    2015-01-01

    Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues. PMID:26145450

  4. Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression

    NASA Astrophysics Data System (ADS)

    Puvvada, Nagaprasad; Rajput, Shashi; Kumar, B. N. Prashanth; Sarkar, Siddik; Konar, Suraj; Brunt, Keith R.; Rao, Raj R.; Mazumdar, Abhijit; Das, Swadesh K.; Basu, Ranadhir; Fisher, Paul B.; Mandal, Mahitosh; Pathak, Amita

    2015-07-01

    Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues.

  5. Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles for the treatment of non-small lung cancer

    PubMed Central

    He, Zelai; Huang, Jingwen; Xu, Yuanyuan; Zhang, Xiangyu; Teng, Yanwei; Huang, Can; Wu, Yufeng; Zhang, Xi; Zhang, Huijun; Sun, Wenjie

    2015-01-01

    An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and

  6. Polymer-Lipid Hybrid Theranostic Nanoparticles Co-Delivering Ultrasmall Superparamagnetic Iron Oxide and Paclitaxel for Targeted Magnetic Resonance Imaging and Therapy in Atherosclerotic Plaque.

    PubMed

    Dong, Yinmei; Chen, Huaiwen; Chen, Chao; Zhang, Xuefeng; Tian, Xia; Zhang, Yingying; Shi, Zhang; Liu, Qi

    2016-06-01

    Magnetic resonance imaging (MRI) combined with ultrasmall superparamagnetic iron oxide (USPIO) is effective for the detection of atherosclerotic (AS) plaque, and paclitaxel is effective for the treatment of AS. C11 is a polypeptide with high affinity and specificity for collagen IV. It is abundantly expressed in the outer layer of AS plaque. This study aimed to develop USPIO + paclitaxel-loaded polymer-lipid hybrid theranostic nanoparticles conjugated with C11 (UP-NP-C11) for simultaneous imaging and treatment AS plaque. UP-NP-C11 was developed by the nanoprecipitation method, and the theranostics of AS plaque by UP-NP-C11 were evaluated both in vitro and in the rabbit AS model. UP-NP-C11 was of desired particle size (140.2 nm), showed encapsulation efficiency of 35.5% and 55.2% for USPIO and paclitaxel, respectively, and had drug release profile. The accumulation of USPIO in Matrigel (containing abundant collagen IV) and macrophages coated on the Matrigel was significantly higher in the UP-NP-C11-treated group than in the group treated by UP-NP (USPIO + paclitaxel-loaded nanoparticles). Thus, UP-NP-C11 exerted better growth inhibitory effect and MRI ability in macrophages than UP-NP. Significantly, UP-NP-C11 showed better in vivo MRI ability and therapeutic effect in rabbit AS plaque than UP-NP and commercial USPIO + paclitaxel, and Prussian blue staining revealed significantly greater accumulation of USPIOs in the UP-NP-C11-treated group than in the control group. Furthermore, UP-NP-C11 did not cause severe toxicity to the rabbits. UP-NP-C11 represents a potential approach for targeted MRI and therapy in AS plaque. PMID:27319218

  7. Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer.

    PubMed

    Milane, Lara; Duan, Zhenfeng; Amiji, Mansoor

    2011-01-01

    The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this system for EGFR-targeted

  8. Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer

    PubMed Central

    Yang, Xiaoqian; Iyer, Arun K.; Singh, Amit; Milane, Lara; Choy, Edwin; Hornicek, Francis J.; Amiji, Mansoor M.; Duan, Zhenfeng

    2014-01-01

    Purpose Approaches for the synthesis of biomaterials to facilitate the delivery of “biologics” is a major area of research in cancer therapy. Here we designed and characterized a hyaluronic acid (HA) based self-assembling nanoparticles that can target CD44 receptors overexpressed on multidrug resistance (MDR) ovarian cancer. The nanoparticle system is composed of HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) designed to deliver MDR1 siRNA for the treatment of MDR in an ovarian cancer model. Methods HA-PEI/HA-PEG nanoparticles were synthesized and characterized, then the cellular uptake and knockdown efficiency of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles was further determined. A human xenograft MDR ovarian cancer model was established to evaluate the effects of the combination of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles and paclitaxel on MDR tumor growth. Results Our results demonstrated that HA-PEI/HA-PEG nanoparticles successfully targeted CD44 and delivered MDR1 siRNA into OVCAR8TR (established paclitaxel resistant) tumors. Additionally, HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and P-glycoprotein (Pgp), inhibited the functional activity of Pgp, and subsequently increased cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment inhibited tumor growth in MDR ovarian cancer mouse models. Conclusions These findings suggest that this CD44 targeted HA-PEI/HA-PEG nanoparticle platform may be a clinicaly relevant gene delivery system for systemic siRNA-based anticancer therapeutics for the treatment of MDR cancers. PMID:25515492

  9. Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel

    PubMed Central

    Tyler, Betty M.; Hdeib, Alia; Caplan, Justin; Legnani, Federico G.; Fowers, Kirk D.; Brem, Henry; Jallo, George; Pradilla, Gustavo

    2014-01-01

    Object Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. Methods Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 μl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 μl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. Results OncoGel was safe for intramedullary injection in rats in doses up to 5 μl of 3.0 mg/ml of paclitaxel; a dose of 5 μl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0

  10. pH-Sensitive Biocompatible Nanoparticles of Paclitaxel-Conjugated Poly(styrene-co-maleic acid) for Anticancer Drug Delivery in Solid Tumors of Syngeneic Mice.

    PubMed

    Dalela, Manu; Shrivastav, T G; Kharbanda, Surender; Singh, Harpal

    2015-12-01

    In the present study, we have synthesized poly(styrene-co-maleic anhydride), a biocompatible copolymer that was further conjugated with paclitaxel (PTX) via ester linkage and self-assembled to form poly(styrene-co-maleic acid)-paclitaxel (PSMAC-PTX) nanoparticles (NPs). The in vitro release of PTX from PSMAC-PTX NPs showed a higher release at lower pH than at the physiological pH of 7.4, confirming its pH-dependent release. The cell viability of PSMAC-PTX nanoparticles was evaluated using MTT assay. IC50 values of 9.05-18.43 ng/mL of PTX equivalent were observed in various cancer cell lines after 72 h of incubation. Confocal microscopy, Western blotting, and Flow cytometry results further supported that the cellular uptake and apoptosis of cancer cells with PSMAC-PTX NPs. Pharmacokinetic studies revealed that the conjugation of PTX to the PSMAC co-polymer not only increased the plasma and tumor C(max) of PTX but also prolonged its plasma half-life and retention in tumor via enhanced permeability and retention (EPR) effect. Administration of PSMAC-PTX NPs showed significant tumor growth inhibition with improved apoptosis effects in vivo on Ehrlich Ascites Tumor (EAT)-bearing BALB/c syngeneic mice in comparison with Taxol, without showing any cytotoxicity. On the basis of preliminary results, no subacute toxicity was observed in major organs, tissues and hematological system up to a dosage of 60 mg/kg body weight in mice. Therefore, PSMAC-PTX NPs may be considered as an alternative nanodrug delivery system for the delivery of PTX in solid tumors. PMID:26528585

  11. Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells' sensitivity to paclitaxel.

    PubMed

    Tambe, Mahesh; Pruikkonen, Sofia; Mäki-Jouppila, Jenni; Chen, Ping; Elgaaen, Bente Vilming; Straume, Anne Hege; Huhtinen, Kaisa; Cárpen, Olli; Lønning, Per Eystein; Davidson, Ben; Hautaniemi, Sampsa; Kallio, Marko J

    2016-03-15

    The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3' UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy. PMID:26943585

  12. Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells’ sensitivity to paclitaxel

    PubMed Central

    Mäki-Jouppila, Jenni; Chen, Ping; Elgaaen, Bente Vilming; Straume, Anne Hege; Huhtinen, Kaisa; Cárpen, Olli; Lønning, Per Eystein; Davidson, Ben; Hautaniemi, Sampsa; Kallio, Marko J.

    2016-01-01

    The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3′ UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy. PMID:26943585

  13. Targeted Delivery Systems for Molecular Therapy in Skeletal Disorders

    PubMed Central

    Dang, Lei; Liu, Jin; Li, Fangfei; Wang, Luyao; Li, Defang; Guo, Baosheng; He, Xiaojuan; Jiang, Feng; Liang, Chao; Liu, Biao; Badshah, Shaikh Atik; He, Bing; Lu, Jun; Lu, Cheng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk of toxic effects in non-skeletal tissues, which remain clinical challenges in the treatment of skeletal disorders. Thus, targeted delivery systems are urgently needed to achieve higher drug delivery efficiency, improve therapeutic efficacy in the targeted cells/tissues, and minimize toxicities in non-targeted cells/tissues. In this review, we summarize recent progress in the application of different targeting moieties and nanoparticles for targeted drug delivery in skeletal disorders, and also discuss the advantages, challenges and perspectives in their clinical translation. PMID:27011176

  14. Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer

    PubMed Central

    Lemort, Marc; Wilke, Celine; Vanderbeeken, Marie-Catherine; D’Hondt, Veronique; De Azambuja, Evandro; Gombos, Andrea; Lebrun, Fabienne; Dal Lago, Lissandra; Bustin, Fanny; Maetens, Marion; Ameye, Lieveke; Veys, Isabelle; Michiels, Stefan; Paesmans, Marianne; Larsimont, Denis; Sotiriou, Christos; Nogaret, Jean-Marie; Piccart, Martine; Awada, Ahmad

    2016-01-01

    Background EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel. Methods HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. Results Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04). Conclusions The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment

  15. pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel.

    PubMed

    Ma, Yakun; Fan, Xiaohui; Li, Lingbing

    2016-02-10

    A doxorubicin conjugated prodrug incorporated acid-sensitive linkage between drug and Pluronic F127-chitosan (F127-CS) polymer was successfully synthesized. Subsequently a pH-sensitive polymeric micelle system was designed based on the conjugated prodrugs (F127-CS-DOX) to co-deliver doxorubicin and paclitaxel. Paclitaxel (PTX) was physically entrapped in the hydrophobic inner core of the micelles simultaneously. The structures of conjugates were analyzed by means of (1)H NMR and UV-vis spectrum. Size distribution and morphology of the micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results indicated that obtained micelles had good dispersity and the diameter was between 56.3 and 403.4 nm. The loading of PTX into the micelle increased with higher DOX content. DOX and PTX release from polymeric micelles followed an acid-triggered manner. Furthermore, in vivo pharmacokinetic study also showed that the area under the plasma concentration time curve (AUC0-∞) values of PTX and DOX for PTX-loaded F127-CS-DOX micelles in rats were 3.97 and 4.38-fold higher than those for PTX plus DOX solution. These results suggested the PTX-loaded F127-CS-DOX micelles would be a promising carrier for co-delivering DOX and PTX. PMID:26686101

  16. Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model

    PubMed Central

    Yang, Ming; Yu, Tao; Wood, Joseph; Wang, Ying-Ying; Tang, Benjamin C.; Zeng, Qi; Simons, Brian W.; Fu, Jie; Chuang, Chi-Mu; Lai, Samuel K.; Wu, T.-C.; Hung, Chien-Fu; Hanes, Justin

    2014-01-01

    Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (~ 13% w/w) and prolonged release (~ 13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol® (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated, with only minimal to mild inflammation. Our findings support PTX/PEG–PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer, and potentially other metastatic peritoneal cancers. PMID:24816829

  17. Magnetic nanoscale metal organic frameworks for potential targeted anticancer drug delivery, imaging and as an MRI contrast agent.

    PubMed

    Ray Chowdhuri, Angshuman; Bhattacharya, Dipsikha; Sahu, Sumanta Kumar

    2016-02-21

    The development of a novel multifunctional porous nanoplatform for targeted anticancer drug delivery with cell imaging and magnetic resonance imaging has been realised in the current work. Here we have developed a magnetic nanoscale metal organic frameworks (NMOF) for potential targeted drug delivery. These magnetic NMOFs were fabricated by incorporation of Fe3O4 nanoparticles into porous isoreticular metal organic frameworks (IRMOF-3). To achieve targeted drug delivery towards cancer cells specifically, folic acid was conjugated to the NMOF surface. Then, the fluorescent molecule rhodamine B isothiocyanate (RITC) was conjugated to the NMOFs for biological imaging applications. The synthesized magnetic NMOFs were fully characterised by FTIR, powder XRD, XPS, SQUID, TGA, TEM, FESEM, and DLS. The synthesized magnetic NMOFs were observed to be smaller than 100 nm and were found to be nontoxic towards human cervix adenocarcinoma (HeLa) and murine fibroblast (NIH3T3) cells according to cell viability assays. The cancer chemotherapy drug paclitaxel was conjugated to the magnetic NMOFs through hydrophobic interactions with a relatively high loading capacity. Moreover, these folic acid-conjugated magnetic NMOFs showed stronger T2-weighted MRI contrast towards the cancer cells, justifying their possible significance in imaging. PMID:26754449

  18. Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts.

    PubMed

    Moschetta, Michele; Pretto, Francesca; Berndt, Alexander; Galler, Kerstin; Richter, Petra; Bassi, Andrea; Oliva, Paolo; Micotti, Edoardo; Valbusa, Giovanni; Schwager, Kathrin; Kaspar, Manuela; Trachsel, Eveline; Kosmehl, Hartwig; Bani, Maria Rosa; Neri, Dario; Giavazzi, Raffaella

    2012-04-01

    The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine. Coadministration of paclitaxel increased the uptake of F8 in xenografted melanomas, enhancing tumor perfusion and permeability. Paclitaxel also boosted the recruitment of F8-IL2-induced natural killer (NK) cells to the tumor, suggesting a host response as part of the observed therapeutic benefit. In support of this likelihood, NK cell depletion impaired the antitumor effect of paclitaxel plus F8-IL2. Importantly, this combination reduced both the tumor burden and the number of pulmonary metastatic nodules. The combination did not cause cumulative toxicity. Together, our findings offer a preclinical proof that by acting on the tumor stroma paclitaxel potentiates the antitumor activity elicited by a targeted delivery of IL2, thereby supporting the use of immunochemotherapy in the treatment of metastatic melanoma. PMID:22392081

  19. Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

    PubMed Central

    Ren, Muqing; Duval, Kayla; Guo, Xing; Chen, Zi

    2016-01-01

    Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this article, we provide an overview of three different targeted drug delivery methods (passive targeting, active targeting and physical targeting), compare methods of action, advantages, limitations, and the current stage of research. For the most commonly used nanoparticle carriers, fabrication methods are also reviewed. This is followed by a review of computational simulations and models on nanoparticle-based drug delivery. PMID:27398083

  20. Effective method of chitosan-coated alginate nanoparticles for target drug delivery applications.

    PubMed

    Wang, Fang; Yang, Siqian; Yuan, Jian; Gao, Qinwei; Huang, Chaobo

    2016-07-01

    In the present study, alginate nanoparticles were firstly prepared for paclitaxel (PTX) delivery with an average size of 200 ± 21 nm. To improve the stability and targeting effect, the chitosan (CS) and folate-chitosan (FA-CS) were introduced to form PTX-loaded CS/ALG NPs and FA-CS/ALG NPs by a new double emulsion cross-linking electrostatic attraction method. The optimization chitosan concentration was 0.5% obtained from the experiment results. The CS/ALG-PTX NPs and FA-CS/ALG-PTX NPs had the average particle size of 306.9 ± 12.9 nm and 283.6 ± 19.2 nm with the zeta potential of 31.1 ± 1.3 mV and -2.98 ± 0.7 mV, and had higher drug loading and entrapment efficiencies than ALG-PTX NPs. The in vitro drug release profile along with release kinetics and mechanism from PTX-loaded NPs were studied under two simulated physiological conditions. Further, the in vitro anti-cancer activity of nanoparticles and the cellular uptake of nanoparticles on HepG2 cells were investigated. The results demonstrated that alginate, CS/ALG and FA-CS/ALG can be used as nanoformulation drug carriers by our new method, and FA-CS/ALG was a promising vehicle for anticancer drug targeted delivery system. PMID:27164869

  1. β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    PubMed

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-01

    β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency

  2. Functionalized Nanosystems for Targeted Mitochondrial Delivery

    PubMed Central

    Durazo, Shelley A.; Kompella, Uday B.

    2011-01-01

    Mitochondrial dysfunction including oxidative stress and DNA mutations underlies the pathology of various diseases including Alzheimer’s disease and diabetes, necessitating the development of mitochondria targeted therapeutic agents. Nanotechnology offers unique tools and materials to target therapeutic agents to mitochondria. As discussed in this paper, a variety of functionalized nanosystems including polymeric and metallic nanoparticles as well as liposomes are more effective than plain drug and non-functionalized nanosystems in delivering therapeutic agents to mitochondria. Although the field is in its infancy, studies to date suggest the superior therapeutic activity of functionalized nanosystems for treating mitochondrial defects. PMID:22138492

  3. Surface modulatable nanocapsids for targeting and tracking toward nanotheranostic delivery.

    PubMed

    Stark, Marie; Cheng, R Holland

    2016-09-01

    Nanoparticle diagnostics and therapeutics (nanotheranostics) have significantly advanced cancer detection and treatment. However, many nanotheranostics are ineffective due to defects in tumor localization and bioavailability. An engineered Hepatitis E Virus (HEV) nanocapsid is a proposed platform for targeted cancer-cell delivery. Self-assembling from HEV capsid subunits, nanocapsids retain the capacity to enter cells and resist proteolytic/acidic conditions, but lack infectious viral elements. The nanocapsid surface was modified for chemical activation to confer tumor-specific targeting and detection, immune-response manipulation and controlled theranostic delivery. Nanotheranostic molecules can be packaged in the hollow nanocapsid shell during in vitro assembly. Complementing the adapted stability and cell-entry characteristics of the HEV capsid, a modified nanocapsid serves as a tunable tumor-targeting platform for nanotheronostic delivery. PMID:27610752

  4. Use of a Lipid-Coated Mesoporous Silica Nanoparticle Platform for Synergistic Gemcitabine and Paclitaxel Delivery to Human Pancreatic Cancer in Mice

    PubMed Central

    2015-01-01

    Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved

  5. Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice.

    PubMed

    Meng, Huan; Wang, Meiying; Liu, Huiyu; Liu, Xiangsheng; Situ, Allen; Wu, Bobby; Ji, Zhaoxia; Chang, Chong Hyun; Nel, Andre E

    2015-01-01

    Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved

  6. Synthetic LDL as targeted drug delivery vehicle

    SciTech Connect

    Forte, Trudy M.; Nikanjam, Mina

    2012-08-28

    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  7. Convection-Enhanced Delivery for Targeted Delivery of Antiglioma Agents: The Translational Experience

    PubMed Central

    Yun, Jonathan; Rothrock, Robert J.; Canoll, Peter; Bruce, Jeffrey N.

    2013-01-01

    Recent improvements in the understanding of glioblastoma (GBM) have allowed for increased ability to develop specific, targeted therapies. In parallel, however, there is a need for effective methods of delivery to circumvent the therapeutic obstacles presented by the blood-brain barrier and systemic side effects. The ideal delivery system should allow for adequate targeting of the tumor while minimizing systemic exposure, applicability across a wide range of potential therapies, and have existing safe and efficacious systems that allow for widespread application. Though many alternatives to systemic delivery have been developed, this paper will focus on our experience with convection-enhanced delivery (CED) and our focus on translating this technology from pre-clinical studies to the treatment of human GBM. PMID:23476784

  8. Targeted delivery to bone and mineral deposits using bisphosphonate ligands.

    PubMed

    Cole, Lisa E; Vargo-Gogola, Tracy; Roeder, Ryan K

    2016-04-01

    The high concentration of mineral present in bone and pathological calcifications is unique compared with all other tissues and thus provides opportunity for targeted delivery of pharmaceutical drugs, including radiosensitizers and imaging probes. Targeted delivery enables accumulation of a high local dose of a therapeutic or imaging contrast agent to diseased bone or pathological calcifications. Bisphosphonates (BPs) are the most widely utilized bone-targeting ligand due to exhibiting high binding affinity to hydroxyapatite mineral. BPs can be conjugated to an agent that would otherwise have little or no affinity for the sites of interest. This article summarizes the current state of knowledge and practice for the use of BPs as ligands for targeted delivery to bone and mineral deposits. The clinical history of BPs is briefly summarized to emphasize the success of these molecules as therapeutics for metabolic bone diseases. Mechanisms of binding and the relative binding affinity of various BPs to bone mineral are introduced, including common methods for measuring binding affinity in vitro and in vivo. Current research is highlighted for the use of BP ligands for targeted delivery of BP conjugates in various applications, including (1) therapeutic drug delivery for metabolic bone diseases, bone cancer, other bone diseases, and engineered drug delivery platforms; (2) imaging probes for scintigraphy, fluorescence, positron emission tomography, magnetic resonance imaging, and computed tomography; and (3) radiotherapy. Last, and perhaps most importantly, key structure-function relationships are considered for the design of drugs with BP ligands, including the tether length between the BP and drug, the size of the drug, the number of BP ligands per drug, cleavable tethers between the BP and drug, and conjugation schemes. PMID:26482186

  9. Galactose engineered solid lipid nanoparticles for targeted delivery of doxorubicin.

    PubMed

    Jain, Ashay; Kesharwani, Prashant; Garg, Neeraj K; Jain, Atul; Jain, Som Akshay; Jain, Amit Kumar; Nirbhavane, Pradip; Ghanghoria, Raksha; Tyagi, Rajeev Kumar; Katare, Om Prakash

    2015-10-01

    The present investigation reports the preparation, optimization, and characterization of surface engineered solid lipid nanoparticles (SLNs) encapsulated with doxorubicin (DOX). Salient features such as biocompatibility, controlled release, target competency, potential of penetration, improved physical stability, low cost and ease of scaling-up make SLNs viable alternative to liposomes for effective drug delivery. Galactosylation of SLNs instructs some gratifying characteristic, which leads to the evolution of promising delivery vehicles. The impendence of lectin receptors on different cell surfaces makes the galactosylated carriers admirable for targeted delivery of drugs to ameliorate their therapeutic index. Active participation of some lectin receptors in immune responses to antigen overlaid the application of galactosylated carriers in delivery of antigen and immunotherapy for treatment of maladies like cancer. These advantages revealed the promising potential of galactosylated carriers in each perspective of drug delivery. The developed DOX loaded galactosylated SLNs formulation was found to have particle size 239 ± 2.40 nm, PDI 0.307 ± 0.004, entrapment efficiency 72.3 ± 0.9%. Higher cellular uptake, cytotoxicity, and nuclear localization of galactosylated SLNs against A549 cells revealed higher efficiency of the formulation. In a nutshell, the galactosylation strategy with SLNs could be a promising approach in improving the delivery of DOX for cancer therapy. PMID:26142628

  10. Development of a thermally responsive nanogel based on chitosan-poly(N-isopropylacrylamide-co-acrylamide) for paclitaxel delivery.

    PubMed

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

    2014-07-01

    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 μg/mL, much smaller than CTS-poly(NIPAAm) nanogels (5.00 μg/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. PMID:24823900

  11. PEG-Derivatized Embelin as a Nanomicellar Carrier For Delivery of Paclitaxel to Breast and Prostate Cancers

    PubMed Central

    Lu, Jianqin; Huang, Yixian; Zhao, Wenchen; Marquez, Rebecca T.; Meng, Xiaojie; Li, Jiang; Gao, Xiang; Venkataramanan, Raman; Wang, Zhou; Li, Song

    2012-01-01

    Paclitaxel (PTX) is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its therapeutic benefit is often limited by severe side effects. We have developed a micelle-based PTX formulation based on a simple conjugate derived from polyethylene glycol 5000 (PEG5K) and embelin (EB). Embelin is a natural product and exhibits antitumor activity through blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). PEG5K-EB2 conjugate self-assembles to form stable micelles in aqueous solution and efficiently encapsulates hydrophobic drugs such as PTX. PEG5K-EB2 micelles have a relatively low CMC of 0.002mg/mL (0.35μM) with sizes in the range of 20 ~ 30 nm with or without loaded PTX. In vitro cell uptake study showed that the PEG5K-EB2 micelles were efficiently taken up by tumor cells. In vitro release study showed that PTX formulated in PEG5K-EB2 micelles was slowly released over 5 days with much slower release kinetics than that of Taxol formulation. PTX formulated in PEG5K-EB2 micelles exhibited more potent cytotoxicity than Taxol in several cultured tumor cell lines. Total body near infrared fluorescence (NIRF) imaging showed that PEG5K-EB2 micelles were selectively accumulated at tumor site with minimal uptake in major organs including liver and spleen. PTX-loaded PEG5K-EB2 micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of 100–120 mg PTX/kg in mice, which was significantly higher than that for Taxol (15–20 mg PTX/kg). Finally, PTX formulated in PEG5K-EB2 micelles showed superior anti-tumor activity compared to Taxol in murine models of breast and prostate cancers. PMID:23182923

  12. A smart multifunctional drug delivery nanoplatform for targeting cancer cells.

    PubMed

    Hoop, M; Mushtaq, F; Hurter, C; Chen, X-Z; Nelson, B J; Pané, S

    2016-07-01

    Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies. PMID:27297037

  13. Strategies on the nuclear-targeted delivery of genes

    PubMed Central

    Yao, Jing; Fan, Ying; Li, Yuanke; Huang, Leaf

    2016-01-01

    To improve the nuclear-targeted delivery of non-viral vectors, extensive effort has been carried out on the development of smart vectors which could overcome multiple barriers. The nuclear envelope presents a major barrier to transgene delivery. Viruses are capable of crossing the nuclear envelope to efficiently deliver their genome into the nucleus through the specialized protein components. However, non-viral vectors are preferred over viral ones because of the safety concerns associated with the latter. Non-viral delivery systems have been designed to include various types of components to enable nuclear translocation at the periphery of the nucleus. This review summarizes the progress of research regarding nuclear transport mechanisms. “Smart” non-viral vectors that have been modified by peptides and other small molecules are able to facilitate the nuclear translocation and enhance the efficacy of gene expression. The resulting technology may also enhance delivery of other macromolecules to the nucleus. PMID:23964565

  14. Membrane-targeting liquid crystal nanoparticles (LCNPs) for drug delivery

    NASA Astrophysics Data System (ADS)

    Nag, Okhil K.; Naciri, Jawad; Spillmann, Christopher M.; Delehanty, James B.

    2016-03-01

    In addition to maintaining the structural integrity of the cell, the plasma membrane regulates multiple important cellular processes, such as endocytosis and trafficking, apoptotic pathways and drug transport. The modulation or tracking of such cellular processes by means of controlled delivery of drugs or imaging agents via nanoscale delivery systems is very attractive. Nanoparticle-mediated delivery systems that mediate long-term residence (e.g., days) and controlled release of the cargoes in the plasma membrane while simultaneously not interfering with regular cellular physiology would be ideal for this purpose. Our laboratory has developed a plasma membrane-targeted liquid crystal nanoparticle (LCNP) formulation that can be loaded with dyes or drugs which can be slowly released from the particle over time. Here we highlight the utility of these nanopreparations for membrane delivery and imaging.

  15. Targeted Delivery of Bleomycin: A Comprehensive Anticancer Review.

    PubMed

    Yu, Zhiqiang; Yan, Bo; Gao, Liqian; Dong, Chenbo; Zhong, Jian; D Ortenzio, Mathew; Nguyen, Brandon; Seong Lee, Su; Hu, Xianglong; Liang, Feng

    2016-01-01

    Despite being one of the most effective broad-spectrum chemotherapeutic agents in the treatment of cancers, the clinical applications of bleomycins (BLMs) have been limited due to their poor drug delivery abilities, and the side effect of causing lung fibrosis. With the increased therapeutics and the reduction of side effects, research and development of targeted drug delivery systems (TDDS) with BLMs have become essential for the expansive clinical usage of BLM-based therapeutics. This review summarizes the recent developments of various TDDS for BLMs, including techniques such as photochemical internalization, ultrasound, and micelle, liposome, and nanoparticle formation. The advantages and disadvantages for each delivery approach are outlined, along with the specific challenges associated with each delivery system. PMID:26632436

  16. Delivery of Therapeutic RNAs Into Target Cells IN VIVO

    NASA Astrophysics Data System (ADS)

    Ng, Mei Ying; Hagen, Thilo

    2014-02-01

    RNA-based therapy is one of the most promising approaches to treat human diseases. Specifically, the use of short interfering RNA (siRNA) siRNA and microRNA (miRNA) mimics for in vivo RNA interference has immense potential as it directly lowers the expression of the therapeutic target protein. However, there are a number of major roadblocks to the successful implementation of siRNA and other RNA based therapies in the clinic. These include the instability of RNAs in vivo and the difficulty to efficiently deliver the RNA into the target cells. Hence, various innovative approaches have been taken over the years to develop effective RNA delivery methods. These methods include liposome-, polymeric nanoparticle- and peptide-mediated cellular delivery. In a recent innovative study, bioengineered bacterial outer membrane vesicles were used as vehicles for effective delivery of siRNA into cells in vivo.

  17. Chondroitin sulfate derived theranostic nanoparticles for targeted drug delivery.

    PubMed

    Varghese, Oommen P; Liu, Jianping; Sundaram, Karthi; Hilborn, Jöns; Oommen, Oommen P

    2016-08-16

    Glycosaminoglycan derived nanoparticles are a promising delivery system owing to their unique tumour targeting ability. Exploiting fluorescein for inducing amphiphilicity in these biopolymers provides inherent imaging and drug stabilization capabilities by π-π stacking interactions with aromatic antineoplastic agents. This offers a versatile and highly customizable nanocarrier with narrow size distribution and high drug loading efficiency (80%) with sustained drug release. PMID:27431007

  18. The Targeted-liposome Delivery System of Antitumor Drugs.

    PubMed

    Wu, Wei-dang; Yi, Xiu-lin; Jiang, Li-xin; Li, Ya-zhuo; Gao, Jing; Zeng, Yong; Yi, Rong-da; Dai, Li-peng; Li, Wei; Ci, Xiao-yan; Si, Duan-yun; Liu, Chang-xiao

    2015-01-01

    The liposome delivery system has been intensively explored as novel drug delivery system (DDS) for antitumor drugs, due to its safety, selective cytotoxicity, long circulation and slow elimination in blood, which is favorable for cancer therapy. The liposome-based chemotherapeutics are used to treat a variety of cancers to enhance the therapeutic index of antitumor drugs. Here, the author reviewed the important targets for cancer therapy and the pharmacokinetic behavior of liposomal drugs in vivo, as well as the application of the targeting liposomal system in cancer therapy. Considering further application for clinical use, the great challenges of the liposome-based delivery system were also proposed as follows: 1) prepare stealth liposome with steric stabilization and further enhance the therapeutic effects and safety; 2) explore more safe clinical targets and complementary or different types of targeting liposome; 3) thirdly, more investment is needed on the research of pharmacokinetics of the elements such as the ligands (antibody), PEG and lipids of liposome delivery system as well as safety evaluation. Considering the complex process of the liposomal encapsulation drugs in vivo, the author inferred that there are maybe different forms of the encapsulation drug to be internalized by the tumor tissues at the same time and space, although there are little reports on it. PMID:26652257

  19. Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery

    NASA Astrophysics Data System (ADS)

    Moyer, Tyson

    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

  20. Clinical implementation of target tracking by breathing synchronized delivery

    SciTech Connect

    Tewatia, Dinesh; Zhang Tiezhi; Tome, Wolfgang; Paliwal, Bhudatt; Metha, Minesh

    2006-11-15

    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

  1. Effect of lipid bilayer alteration on transdermal delivery of a high-molecular-weight and lipophilic drug: studies with paclitaxel.

    PubMed

    Panchagnula, Ramesh; Desu, Hariraghuram; Jain, Amit; Khandavilli, Sateesh

    2004-09-01

    Skin forms an excellent barrier against drug permeation, due to the rigid lamellar structure of the stratum corneum (SC) lipids. Poor permeability of drugs can be enhanced through alteration in partition and diffusion coefficients, or concentration gradient of drug with an appropriate choice of solvent system, along with penetration enhancers. The aim of the current investigation was to assess applicability of lipid bilayer alteration by fatty acids and terpenes toward the permeation enhancement of a high-molecular-weight, lipophilic drug, paclitaxel (PCL) through rat skin. From among the fatty acids studied using ethanol/isopropyl myristate (1:1) vehicle, no significant enhancement in flux of PCL was observed (p > 0.05). In the case of cis mono and polyunsaturated fatty acids lag time was found to be similar to control (p > 0.05). This suggests that the permeation of a high-molecular-weight, lipophilic drug may not be enhanced by the alteration of the lipid bilayer, or the main barrier to permeation could lie in lower hydrophilic layers of skin. A significant increase in lag time was observed with trans unsaturated fatty acids unlike the cis isomers, and this was explained on the basis of conformation and preferential partitioning of fatty acids into skin. From among the terpenes, flux of PCL with cineole was significantly different from other studied terpenes and controls, and after treatment with menthol and menthone permeability was found to be reduced. Menthol and menthone cause loosening of the SC lipid bilayer due to breaking of hydrogen bonding between ceramides, resulting in penetration of water into the lipids of the SC lipid bilayer that leads to creation of new aqueous channels and is responsible for increased hydrophilicity of SC. This increased hydrophilicity of the SC bilayer might have resulted in unfavorable conditions for ethanol/isopropyl myristate (1:1) along with PCL to penetrate into skin, therefore permeability was reduced. The findings of

  2. Microrough cobalt-chromium alloy surfaces for paclitaxel delivery: preparation, characterization, and in vitro drug release studies.

    PubMed

    Lancaster, Susan; Kakade, Sandeep; Mani, Gopinath

    2012-08-01

    Cobalt-chromium (Co-Cr) alloys have extensive biomedical applications including drug-eluting stents (DES). This study investigates the use of eight different microrough Co-Cr alloy surfaces for delivering paclitaxel (PAT) for potential use in DES. The eight different surfaces include four bare microrough and four self-assembled monolayer (SAM) coated microrough surfaces. The bare microrough surfaces were prepared by grit blasting Co-Cr with glass beads (50 and 100 μm in size) and Al(2)O(3) (50 and 110 μm). The SAM coated surfaces were prepared by depositing a -COOH terminated phosphonic acid monolayer on the different microrough surfaces. PAT was then deposited on all the bare and SAM coated microrough surfaces. The surfaces were characterized using scanning electron microscopy (SEM), 3D optical profilometry, and Fourier transform infrared spectroscopy (FTIR). SEM showed the different morphologies of microrough surfaces without and with PAT coating. An optical profiler showed the 3D topography of the different surfaces and the changes in surface roughness and surface area after SAM and PAT deposition. FTIR showed ordered SAMs were formed on glass bead grit blasted surfaces, while the molecules were disordered on Al(2)O(3) grit blasted surfaces. Also, FTIR showed the successful deposition of PAT on these surfaces. The PAT release was investigated for up to two weeks using high performance liquid chromatography. Al(2)O(3) grit blasted bare microrough surfaces showed sustained release profiles, while the glass bead grit blasted surfaces showed burst release profiles. All SAM coated surfaces showed biphasic drug release profiles, which is an initial burst release followed by a slow and sustained release. SAM coated Al(2)O(3) grit blasted surfaces prolonged the sustained release of PAT in a significant amount during the second week of drug elution studies, while this behavior was not observed for any other surfaces used in this study. Thus, this study demonstrates the

  3. Tetraspecific ligand for tumor-targeted delivery of nanomaterials.

    PubMed

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

    2014-07-01

    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, αvβ3 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

  4. Tetraspecific Ligand for Tumor-Targeted Delivery of Nanomaterials

    PubMed Central

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

    2014-01-01

    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, αvβ3 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 E. 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

  5. Delivery of Polymeric Nanoparticles to Target Vascular Diseases

    PubMed Central

    Agyare, Edward; Kandimalla, Karunyna

    2015-01-01

    Current advances in nanotechnology have paved the way for the early detection, prevention and treatment of various diseases such as vascular disorders and cancer. These advances have provided novel approaches or modalities of incorporating or adsorbing therapeutic, biosensor and targeting agents into/on nanoparticles. With significant progress, nanomedicine for vascular therapy has shown significant advantages over traditional medicine because of its ability to selectively target the disease site and reduce adverse side effects. Targeted delivery of nanoparticles to vascular endothelial cells or the vascular wall provides an effective and more efficient way for early detection and/or treatment of vascular diseases such as atherosclerosis, thrombosis and Cerebrovascular Amyloid Angiopathy (CAA). Clinical applications of biocompatible and biodegradable polymers in areas such as vascular graft, implantable drug delivery, stent devices and tissue engineering scaffolds have advanced the candidature of polymers as potential nano-carriers for vascular-targeted delivery of diagnostic agents and drugs. This review focuses on the basic aspects of the vasculature and its associated diseases and relates them to polymeric nanoparticle-based strategies for targeting therapeutic agents to diseased vascular site. PMID:26069867

  6. Targeted gene delivery via N-acetylglucosamine receptor mediated endocytosis.

    PubMed

    Singh, Bijay; Maharjan, Sushila; Kim, You-Kyoung; Jiang, Tai; Islam, Mohammad Ariful; Kang, Sang-Kee; Cho, Myung-Haing; Choi, Yun-Jaie; Cho, Chong-Su

    2014-11-01

    Receptor-mediated endocytosis is a promising approach of gene delivery into the target cells via receptor-ligand interaction. Vimentins at the cell surface are recently known to bind N-acetylglucosamine (GlcNAc) residue, therefore, the cell surfaces of vimentin-expressing cells could be targeted by using the GlcNAc residue as a specific ligand for receptor-mediated gene delivery. Here, we have developed polymeric gene delivery vectors, based on poly(ethylene oxide)(PEO) and poly(aspartamide), namely poly[(aspartamide)(diethylenetriamine)]-b-[PEO-(GlcNAc)] (PADPG) and poly[(aspartamide)(diethylenetriamine)]-b-[PEO] (PADP) to elucidate the efficiency of GlcNAc ligand for gene delivery through receptor mediated endocytosis. To determine the efficiency of these polymeric vectors for specific gene delivery, the DNA condensation ability of PADPG and PADP and the subsequent formation of polymeric nanoparticles were confirmed by gel retardation assay and transmission electron microscopy respectively. Both PADPG and PADP had lower cytotoxicity than polyethylenimine 25 K (PEI 25 K). However, their transfection efficiency was comparatively lower than PEI 25 K due to hydrophilic property of PEO in the vectors. To observe the stability of polymeric nanoparticles, the transfection of PADPG and PADP was carried out in the presence of serum. Favorably, the interfering effect of serum on the transfection efficiency of PADPG and PADP was also very low. Finally, when the cell specificity of these polymeric vectors was investigated, PADPG had high gene transfection in vimentin-expressing cells than vimentin-deficiency cells. The high transfection efficiency of PADPG was attributed to the GlcNAc in the polymeric vector which interact specifically with vimentin in the cells for the receptor-mediated endocytosis. The competitive inhibition assay further proved the receptor-mediated endocytosis of PADPG. Thus, this study demonstrates that conjugation of GlcNAc is an effective and rational

  7. Pericyte-targeting drug delivery and tissue engineering

    PubMed Central

    Kang, Eunah; Shin, Jong Wook

    2016-01-01

    Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes. PMID:27313454

  8. Active Targeted Drug Delivery for Microbes Using Nano-Carriers

    PubMed Central

    Lin, Yung-Sheng; Lee, Ming-Yuan; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Although vaccines and antibiotics could kill or inhibit microbes, many infectious diseases remain difficult to treat because of acquired resistance and adverse side effects. Nano-carriers-based technology has made significant progress for a long time and is introducing a new paradigm in drug delivery. However, it still has some challenges like lack of specificity toward targeting the infectious site. Nano-carriers utilized targeting ligands on their surface called ‘active target’ provide the promising way to solve the problems like accelerating drug delivery to infectious areas and preventing toxicity or side-effects. In this mini review, we demonstrate the recent studies using the active targeted strategy to kill or inhibit microbes. The four common nano-carriers (e.g. liposomes, nanoparticles, dendrimers and carbon nanotubes) delivering encapsulated drugs are introduced. PMID:25877093

  9. Non-Spherical Particles for Targeted Drug Delivery

    PubMed Central

    Chen, Jinrong; Clay, Nicholas; Kong, Hyunjoon

    2015-01-01

    Nano- and microparticles loaded with various bioimaging contrast agents or therapeutic molecules have been increasingly used for the diagnosis and treatment of diseases and tissue defects. These particles, often a filled or hollow sphere, can extend the lifetime of encapsulated biomedical modalities in circulation and in target tissue. However, there is a great need to improve the drug loading and targeting efficiency of these particles. Recently, several simulation and in vitro experimental studies reported that particle shape plays a pivotal role in the targeted delivery of molecules. To better understand these findings and subsequently expedite the use of particles in biomedical applications, this review paper summarizes the methods to prepare non-spherical nano- and micro-scaled particles. In addition, this review covers studies reporting the effects of particle shape on the loading, delivery and release of encapsulated bioactive cargos. Finally, it discusses future directions to further improve the properties of non-spherical particles. PMID:25838583

  10. Pericyte-targeting drug delivery and tissue engineering.

    PubMed

    Kang, Eunah; Shin, Jong Wook

    2016-01-01

    Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes. PMID:27313454

  11. The role of acoustofluidics in targeted drug delivery

    PubMed Central

    Bose, Nilanjana; Zhang, Xunli; Maiti, Tapas K.; Chakraborty, Suman

    2015-01-01

    With the fast development of acoustic systems in clinical and therapeutic applications, acoustically driven microbubbles have gained a prominent role as powerful tools to carry, transfer, direct, and target drug molecules in cells, tissues, and tumors in the expanding fields of targeted drug delivery and gene therapy. The aim of the present study is to establish a biocompatible acoustic microfluidic system and to demonstrate the generation of an acoustic field and its effects on microbubbles and biological cells in the microfluidic system. The acoustic field creates non-linear oscillations of the microbubble-clusters, which results in generation of shear stress on cells in such microsystems. This effectively helps in delivering extracellular probes in living cells by sonoporation. The sonoporation is investigated under the combined effects of acoustic stress and hydrodynamic stress during targeted drug and gene delivery. PMID:26339329

  12. Targeted drug delivery using genetically engineered diatom biosilica.

    PubMed

    Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

    2015-01-01

    The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites. PMID:26556723

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

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

  14. Hydrotropic polymeric mixed micelles based on functional hyperbranched polyglycerol copolymers as hepatoma-targeting drug delivery system.

    PubMed

    Zhang, Xuejiao; Zhang, Xinge; Yu, Peien; Han, Yucai; Li, Yangguang; Li, Chaoxing

    2013-01-01

    Mixed copolymer nanoparticles (NPs) self-assembled from β-cyclodextrin-grafted hyperbranched polyglycerol (HPG-g-CD) and lactobionic acid (LA)-grafted hyperbranched polyglycerol (HPG-g-LA) were applied as carriers for a hydrophobic antitumor drug, paclitaxel (PTX), achieving hepatocellular carcinoma-targeted delivery. The resulting NPs exhibited high drug loading capacity and substantial stability in aqueous solution. In vitro drug release studies demonstrated a controlled drug release profile with increased release at acidic pH. Remarkably, tumor proliferation assays showed that PTX-loaded mixed copolymer NPs inhibited asialoglycoprotein (ASGP) receptor positive HepG2 cell proliferation in a concentration-dependent manner in comparison with ASGP receptor negative BGC-823 cells. Moreover, the competition assay demonstrated that the small molecular LA inhibited the cellular uptake of the PTX-loaded mixed copolymer NPs, indicating the ASGP receptor-mediated endocytosis in HepG2 cells. In addition, the intracellular uptake tests by confocal laser scanning microscopy showed that the mixed copolymer NPs were more efficiently taken up by HepG2 cells compared with HPG-g-CD NPs. These results suggest a feasible application of the mixed copolymer NPs as nanocarriers for hepatoma-targeted delivery of potent antitumor drugs. PMID:23132353

  15. Targeted Liposomal Drug Delivery to Monocytes and Macrophages

    PubMed Central

    Kelly, Ciara; Jefferies, Caroline; Cryan, Sally-Ann

    2011-01-01

    As the role of monocytes and macrophages in a range of diseases is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS), particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge and lipid composition can have a very significant effect on the efficiency with which liposomes target MPS cells. MPS cells express a range of receptors including scavenger receptors, integrins, mannose receptors and Fc-receptors that can be targeted by the addition of ligands to liposome surfaces. These ligands include peptides, antibodies and lectins and have the advantages of increasing target specificity and avoiding the need for cationic lipids to trigger intracellular delivery. The goal for targeting monocytes/macrophages using liposomes includes not only drug delivery but also potentially a role in cell ablation and cell activation for the treatment of conditions including cancer, atherosclerosis, HIV, and chronic inflammation. PMID:21512579

  16. Targeted Cellular Drug Delivery using Tailored Dendritic Nanostructures

    NASA Astrophysics Data System (ADS)

    Kannan, Rangaramanujam; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

    2002-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorble, ‘peripheral’ functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug and gene delivery. The large number of end groups can also be tailored to create special affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, in-vitro drug loading, in-vitro drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Polyamidoamine and Polyol dendrimers, with different generations and end-groups are studied, with drugs such as Ibuprofen and Methotrexate. Our results indicate that a large number of drug molecules can be encapsulated/attached to the dendrimers, depending on the end groups. The drug-encapsulated dendrimer is able to enter the cells rapidly and deliver the drug. Targeting strategies being explored

  17. Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

    PubMed Central

    Davis, Thomas P.

    2013-01-01

    Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion–transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia. PMID:23343976

  18. A smart multifunctional drug delivery nanoplatform for targeting cancer cells

    NASA Astrophysics Data System (ADS)

    Hoop, M.; Mushtaq, F.; Hurter, C.; Chen, X.-Z.; Nelson, B. J.; Pané, S.

    2016-06-01

    Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies.Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of

  19. Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.

    PubMed

    Wu, Bainan; Wang, Si; De, Surya K; Barile, Elisa; Quinn, Bridget A; Zharkikh, Irina; Purves, Angela; Stebbins, John L; Oshima, Robert G; Fisher, Paul B; Pellecchia, Maurizio

    2015-07-23

    The development of novel, targeted delivery agents for anti-cancer therapies requires the design and optimization of potent and selective tumor-targeting agents that are stable and amenable to conjugation with chemotherapeutic drugs. While short peptides represent potentially an excellent platform for these purposes, they often get degraded and are eliminated too rapidly in vivo. In this study, we used a combination of nuclear magnetic resonance-guided structure-activity relationships along with biochemical and cellular studies to derive a novel tumor-homing agent, named 123B9, targeting the EphA2 tyrosine kinase receptor ligand-binding domain. Conjugating 123B9 to the chemotherapeutic drug paclitaxel (PTX) via a stable linker results in an agent that is significantly more effective than the unconjugated drug in both a pancreatic cancer xenograft model and a melanoma lung colonization and metastases model. Hence, 123B9 could represent a promising strategy for the development of novel targeted therapies for cancer. PMID:26165155

  20. Immunoliposomes for Targeted Delivery of an Antifibrotic Drug.

    PubMed

    Schuster, Liane; Seifert, Oliver; Vollmer, Stefanie; Kontermann, Roland E; Schlosshauer, Burkhard; Hartmann, Hanna

    2015-09-01

    Excessive extracellular matrix formation in organs and tissues arises from an imbalance between the synthesis and degradation of matrix proteins, especially collagen. This condition interferes with proper wound healing and regeneration, and to date, no specific treatment is available. In the present study, we propose a targeted drug delivery system consisting of cell-specific immunoliposomes (ILs) loaded with deferoxamine (DFO) as an antifibrotic drug. ILs were functionalized with polyethylene glycol (PEG) to improve the steric stability and prolong their half-life. In addition, a single-chain Fv (scFv) antibody fragment that specifically targets fibroblast activation protein (FAP) was incorporated. An in vitro fibrosis model was employed to test this construct. This model consisted of highly activated pro-fibrotic fibroblasts with 2- to 6-fold induction of selected fibrosis markers: cell/matrix deposited collagen I, total soluble collagen, and α smooth muscle actin. The activation was accompanied by a significant and cell-specific elevation of FAP expression and activity, thereby confirming that FAP is an adequate target for antifibrotic drug delivery. Purified anti-FAP scFv was shown to bind specifically to these cells without influencing the FAP enzymatic activity. DFO was demonstrated to have a dose-dependent antifibrotic activity as quantified by collagen deposition. Specific binding and intracellular uptake of DiI-labeled ILs into the activated fibroblasts were shown by flow cytometry and microscopy. Finally, DFO-loaded ILs targeted to FAP caused a significant reduction in the collagen deposition, whereas no effect was observed using liposomes that lacked the targeting antibody fragment. These results suggest that the FAP-specific scFv-conjugated liposomes have considerable potential for cell-specific targeting applicable as a therapy for excessive collagen deposition during fibrosis. In general, through liposome encapsulation, bioactive molecules, such as

  1. The Platin-X series: activation, targeting, and delivery.

    PubMed

    Basu, Uttara; Banik, Bhabatosh; Wen, Ru; Pathak, Rakesh K; Dhar, Shanta

    2016-08-16

    Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains the hunt for the "magic bullet" which can satisfy the requirements of an effective chemotherapeutic drug formulation. Pt(iv) complexes are kinetically more inert than the Pt(ii) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting, or drug delivery. The ultimate aim of functionalization is to enhance the tumor selective action and attenuate systemic toxicity of the drugs. Moreover, an increase in cellular accumulation to surmount the resistance of the tumor against the drugs is also of paramount importance in drug development and discovery. In this review, we will address the attempts made in our lab to develop Pt(iv) prodrugs that can be activated and delivered using targeted nanotechnology-based delivery platforms. PMID:27493131

  2. Breakable mesoporous silica nanoparticles for targeted drug delivery.

    PubMed

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A; Robinet, Eric; De Cola, Luisa

    2016-04-01

    "Pop goes the particle". Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. PMID:26974603

  3. Recent Advances in Targeted Drug Delivery Approaches Using Dendritic Polymers

    PubMed Central

    Bugno, Jason; Hsu, Hao-Jui; Hong, Seungpyo

    2014-01-01

    Since they were first synthesized over 30 years ago, dendrimers have seen rapid translation into various biomedical applications. A number of reports have not only demonstrated their clinical utility, but also revealed novel design approaches and strategies based on the elucidation of underlying mechanisms governing their biological interactions. This review focuses on presenting the latest advances in dendrimer design, discussing the current mechanistic understandings, and highlighting recent developments and targeted approaches using dendrimers in drug/gene delivery. PMID:26221937

  4. Breakable mesoporous silica nanoparticles for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A.; Robinet, Eric; de Cola, Luisa

    2016-03-01

    ``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. Electronic supplementary information (ESI) available: Full experimental procedures, additional SEM and TEM images of particles, complete UV-Vis and PL-monitored characterization of the breakdown of

  5. Targeted gene knockout by direct delivery of ZFN proteins

    PubMed Central

    Gaj, Thomas; Guo, Jing; Kato, Yoshio; Sirk, Shannon J.; Barbas, Carlos F.

    2012-01-01

    Zinc-finger nucleases (ZFNs) are versatile reagents that have redefined genome engineering. Realizing the full potential of this technology requires the development of safe and effective methods for delivering ZFNs into cells. We demonstrate the intrinsic cell-penetrating capabilities of the standard ZFN architecture and show that direct delivery of ZFNs as proteins leads to efficient endogenous gene disruption in a variety of mammalian cell types with minimal off-target effects. PMID:22751204

  6. Magnetically Targeted Stem Cell Delivery for Regenerative Medicine

    PubMed Central

    Cores, Jhon; Caranasos, Thomas G.; Cheng, Ke

    2015-01-01

    Stem cells play a special role in the body as agents of self-renewal and auto-reparation for tissues and organs. Stem cell therapies represent a promising alternative strategy to regenerate damaged tissue when natural repairing and conventional pharmacological intervention fail to do so. A fundamental impediment for the evolution of stem cell therapies has been the difficulty of effectively targeting administered stem cells to the disease foci. Biocompatible magnetically responsive nanoparticles are being utilized for the targeted delivery of stem cells in order to enhance their retention in the desired treatment site. This noninvasive treatment-localization strategy has shown promising results and has the potential to mitigate the problem of poor long-term stem cell engraftment in a number of organ systems post-delivery. In addition, these same nanoparticles can be used to track and monitor the cells in vivo, using magnetic resonance imaging. In the present review we underline the principles of magnetic targeting for stem cell delivery, with a look at the logic behind magnetic nanoparticle systems, their manufacturing and design variants, and their applications in various pathological models. PMID:26133387

  7. Self-Assembled Smart Nanocarriers for Targeted Drug Delivery.

    PubMed

    Cui, Wei; Li, Junbai; Decher, Gero

    2016-02-01

    Nanostructured drug-carrier systems promise numerous benefits for drug delivery. They can be engineered to precisely control drug-release rates or to target specific sites within the body with a specific amount of therapeutic agent. However, to achieve the best therapeutic effects, the systems should be designed for carrying the optimum amount of a drug to the desired target where it should be released at the optimum rate for a specified time. Despite numerous attempts, fulfilling all of these requirements in a synergistic way remains a huge challenge. The trend in drug delivery is consequently directed toward integrated multifunctional carrier systems, providing selective recognition in combination with sustained or triggered release. Capsules as vesicular systems enable drugs to be confined for controlled release. Furthermore, carriers modified with recognition groups can enhance the capability of encapsulated drug efficacy. Here, recent advances are reviewed regarding designing and preparing assembled capsules with targeting ligands or size controllable for selective recognition in drug delivery. PMID:26436442

  8. Magnetically Targeted Stem Cell Delivery for Regenerative Medicine.

    PubMed

    Cores, Jhon; Caranasos, Thomas G; Cheng, Ke

    2015-01-01

    Stem cells play a special role in the body as agents of self-renewal and auto-reparation for tissues and organs. Stem cell therapies represent a promising alternative strategy to regenerate damaged tissue when natural repairing and conventional pharmacological intervention fail to do so. A fundamental impediment for the evolution of stem cell therapies has been the difficulty of effectively targeting administered stem cells to the disease foci. Biocompatible magnetically responsive nanoparticles are being utilized for the targeted delivery of stem cells in order to enhance their retention in the desired treatment site. This noninvasive treatment-localization strategy has shown promising results and has the potential to mitigate the problem of poor long-term stem cell engraftment in a number of organ systems post-delivery. In addition, these same nanoparticles can be used to track and monitor the cells in vivo, using magnetic resonance imaging. In the present review we underline the principles of magnetic targeting for stem cell delivery, with a look at the logic behind magnetic nanoparticle systems, their manufacturing and design variants, and their applications in various pathological models. PMID:26133387

  9. Peptide Anchor for Folate-Targeted Liposomal Delivery.

    PubMed

    Nogueira, Eugénia; Mangialavori, Irene C; Loureiro, Ana; Azoia, Nuno G; Sárria, Marisa P; Nogueira, Patrícia; Freitas, Jaime; Härmark, Johan; Shimanovich, Ulyana; Rollett, Alexandra; Lacroix, Ghislaine; Bernardes, Gonçalo J L; Guebitz, Georg; Hebert, Hans; Moreira, Alexandra; Carmo, Alexandre M; Rossi, Juan Pablo F C; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

    2015-09-14

    Specific folate receptors are abundantly overexpressed in chronically activated macrophages and in most cancer cells. Directed folate receptor targeting using liposomes is usually achieved using folate linked to a phospholipid or cholesterol anchor. This link is formed using a large spacer like polyethylene glycol. Here, we report an innovative strategy for targeted liposome delivery that uses a hydrophobic fragment of surfactant protein D linked to folate. Our proposed spacer is a small 4 amino acid residue linker. The peptide conjugate inserts deeply into the lipid bilayer without affecting liposomal integrity, with high stability and specificity. To compare the drug delivery potential of both liposomal targeting systems, we encapsulated the nuclear dye Hoechst 34580. The eventual increase in blue fluorescence would only be detectable upon liposome disruption, leading to specific binding of this dye to DNA. Our delivery system was proven to be more efficient (2-fold) in Caco-2 cells than classic systems where the folate moiety is linked to liposomes by polyethylene glycol. PMID:26241560

  10. Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery

    PubMed Central

    Liong, Monty; Lu, Jie; Kovochich, Michael; Xia, Tian; Ruehm, Stefan G.; Nel, Andre E.; Tamanoi, Fuyuhiko; Zink, Jeffrey I.

    2009-01-01

    Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle. Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye molecules and coated with hydrophilic groups to prevent aggregation. Water-insoluble anticancer drugs were delivered into human cancer cells; surface conjugation with cancer-specific targeting agents increased the uptake into cancer cells relative to that in non-cancerous fibroblasts. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications. PMID:19206485