A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer

Division of Hematology & Oncology, Department of Internal Medicine, UCD Cancer Center, University of California, Davis, Sacramento, CA 95817, USA.
Biomaterials (Impact Factor: 8.31). 09/2009; 30(30):6006-16. DOI: 10.1016/j.biomaterials.2009.07.015
Source: PubMed

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

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Available from: Kai Xiao, Feb 03, 2014
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    • "The nomenclature of the telodendrimers followed the system used in the previous studies: For example, telodendrimer PEG 5K (COOH) 8 -L-CA 8 indicates that the molecular weight of PEG is 5 kDa and there are 8 carboxyl group conjugated on the adjacent layer; eight cholic acid molecules were conjugated at the distal peripheral of telodendrimer and were segregated with a triethylene glycol linker molecule (L). The telodendrimers were synthesized using a solution-phase condensation reaction starting from MeO-PEG 5k -NH 2 (5000 Da) via stepwise peptide chemistry following the previous procedure [22] [23], and briefly described as following: (Fmoc)Lys(Boc)-OH was coupled onto the terminal amino group on PEG by using DIC and HOBt as coupling reagents until a negative Kaiser test result was obtained, which indicated the completion of the coupling reaction. PEGylated molecules were precipitated by pouring reaction solution into excess amounts of cold ether, followed by centrifugation and then washed with cold ether one or two times. "
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    ABSTRACT: 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. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Biomaterials 10/2014; 37C:456-468. DOI:10.1016/j.biomaterials.2014.10.044 · 8.31 Impact Factor
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    • "The loading amount of PTX in c-HANP was calculated using the HPLC system (Agilent 1200 series, Agilent Technologies, USA) [20]. PTX-c-HANP was dissolved in acetonitrile/distilled water (45:55 v/v, 1 mg/1 ml), and HPLC analysis was performed with the symmetry column (Waters) at 25 C. "
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    ABSTRACT: One of the major hurdles of the nanoparticles as drug carriers is the unintended burst release of loaded drugs during blood circulation. To surmount this issue, we developed photo-crosslinked hyaluronic acid nanoparticles (c-HANPs) with improved stability for tumor-targeted drug delivery. They were readily prepared via UV-triggered chemical crosslinking with the acrylate groups in the polymer backbone. The size of c-HANPs was not much different from that of uncrosslinked HANPs. However, c-HANPs exhibited significantly high stability in a physiological buffer and released the loaded drug, paclitaxel (PTX), in a sustained manner. It is noteworthy that the drug release rate from c-HANPs remarkably increased in the presence of hyaluronidase, an enzyme abundant at the intracellular compartments of the tumor cells. It was found from in vitro cellular uptake tests that c-HANPs were rapidly taken up by the tumor cells via the receptor (CD44)-mediated endocytosis, which was not inhibited by photo-crosslinking. In non-invasive animal imaging results, they showed higher tumor-targeting ability than uncrosslinked HANPs because high stability of c-HANPs enabled their long circulation in the body. Owing to the sustained release of the drug and enhanced tumor-targeting ability, c-HANPs showed higher therapeutic efficacy compared to free PTX and uncrosslinked HANPs. These data implied the promising potential of c-HANP as tumor-targeting drug carriers and demonstrated the remarkable effect of the improved stability upon the biodistribution and therapeutic efficacy of drug-loaded nanoparticles.
    Biomaterials 04/2013; 34(21). DOI:10.1016/j.biomaterials.2013.03.050 · 8.31 Impact Factor
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    • "To overcome these problems, great efforts have been made to develop new delivery systems for PTX, e.g. liposomes (Klibanov et al., 1991), nanoparticles (Danhier et al., 2009a; Xiao et al., 2009; Yu et al., 2010) and polymeric micelles (Huh et al., 2005; Zhang et al., 2009). Among them, biodegradable block copolymeric micelles (BCMs) are expected to be one of the effective vectors to improve the bioavailability of PTX with specific delivery and minimal side-effects (Maeda et al., 2001, 2000). "
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    ABSTRACT: A series of biodegradable polydepsipeptides based new triblock copolymers, poly (ethylene glycol)-poly(L-lactide)-poly(3(S)-methyl-morpholine-2,5-dione) (mPEG-PLLA-PMMD) have been synthesized and characterized as self-assembly micelle delivery system for paclitaxel (PTX). Compared to the mPEG(2000)-PLLA(2000) diblock copolymers, the triblock copolymers present more benefits such as lower CMC value, positive-shifted zeta potential, better drug loading efficiency and stability. Among the triblock polymers, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles present low cytotoxicity and promote the anti-cancer activity of PTX on A-549 and HCT-116cells. In addition, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles prolongs the circulation time of PTX in rat after i.v. injection (5 mg/kg) than that of mPEG(2000)-PLLA(2000) micelles and Taxol. The half life (t(1/2β)), mean residence time (MRT), AUC(0-∞) and clearance (CL) for PTX-loaded mPEG(2000)-PLLA(2000)-PMMD(1400) micelles are determined to be 1.941 h, 2.683 h, 5.220 μg/m Lh (1.8-fold to mPEG(2000)-PLLA(2000) group), 0.967 L/h kg(-1), respectively. In conclusion, mPEG(2000)-PLLA(2000)-PMMD(1400) copolymer could be developed as one of the promising vectors to anti-cancer agents for chemotherapeutics.
    International Journal of Pharmaceutics 04/2012; 430(1-2):282-91. DOI:10.1016/j.ijpharm.2012.03.043 · 3.65 Impact Factor
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