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: 8.56). 09/2009; 30(30):6006-16. DOI: 10.1016/j.biomaterials.2009.07.015
Source: PubMed


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

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Available from: Kai Xiao, Feb 03, 2014
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    • "The telodendrimers containing the coumarin derivative (namely as P-I: PEG 5K Co 8 , P-II: PEG 5K -CA 4 -LO-Co 4 , P-III: PEG 5K -CA 4 -LO-LO 4 Co 4 and P-IV: PEG 5K -CA 4 -LO-LS 4 Co 4 respectively ; nomenclature: name the abbreviations: PEG (poly(ethylene glycol), CA (cholic acid), LO, LS, Co(coumarin)) were synthesized using a solution-phase condensation reaction starting from MeO-PEG-NH 2 (5000 Da) via stepwise Fmoc peptide chemistry following the previous procedure [29] [31]. The typical synthesis of PEG 5K -CA 4 -LO-Co 4 was as follows: (Fmoc)Lys(Boc)-OH was coupled onto the terminal amino group on PEG using DIC (3 equivalent) and HOBt (3 equivalent) as coupling reagents at room temperature until a negative Kaiser test result (yellow) was obtained indicating the completion of the coupling reaction. "
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    ABSTRACT: Four coumarin-containing telodendrimers (denoted as P-I, P-II, P-III and P-IV) were designed and synthesized to self-assemble into the corresponding nanoparticles. Of those, two nanoparticles (P-II and P-IV micelles) were screened and selected for targeted drug delivery of 7-ethyl-10-hydroxy camptothecin (SN-38), a prominent and efficacious anticancer agent, for the treatment of colon cancers. The nanoparticle encapsulation significantly increased the solubility of SN-38 in aqueous solution. Dynamic light scattering (DLS) showed the size of these SN-38 nanoparticles to be around 50 nm, and rod-shaped micelles were observed using transmission electron microscopy (TEM). These two novel nanoformulations of SN-38/P-II and SN-38/P-IV were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug (SN-38 in DMSO) and were 500-fold more potent than Irinotecan (a prodrug of SN-38). In addition, near infrared fluorescent (NIRF) optical imaging was utilized to monitor the tumor targeted delivery of SN-38/NPs via co-loading a NIRF dye. It was demonstrated that these NPs preferentially accumulated in tumors when compared to healthy tissue. A pharmacokinetics study showed that SN-38 micelle formulations had a longer circulating time in blood than Irinotecan. Furthermore, SN-38 loaded nanoformulations exhibit superior anti-tumor efficacy when compared with Irinotecan at equivalent SN-38 dose in HT-29 human colon cancer xenograft models. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Apr 2015 · Acta biomaterialia
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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.
    Full-text · Article · Oct 2014 · Biomaterials
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    • "Boc-NH-PEG2k-CA4 telodendrimer (Fig. 1) was first synthesized using Boc-NH-PEG-NH2 (MW, 2000 Da), lysine and cholic acid as building blocks via solution phase condensation reactions as described previously [6]. Briefly, Fmoc peptide chemistry was used to couple Fmoc-Lys(Fmoc)-OH onto the unprotected amino group of PEG for three rounds to generate a third generation of dendritic polylysine. "
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    ABSTRACT: Nanocarriers can deliver a wide variety of drugs, target them to sites of interest, and protect them from degradation and inactivation by the body. They have the capacity to improve drug action and decrease undesirable systemic effects. We have previously developed a well-defined non-toxic PEG-dendritic block telodendrimer for successful delivery of chemotherapeutics agents and, in these studies, we apply this technology for therapeutic development in asthma. In these proof-of-concept experiments, we hypothesized that dexamethasone contained in self-assembling nanoparticles (Dex-NP) and delivered systemically would target the lung and decrease allergic lung inflammation and airways hyper-responsiveness to a greater degree than equivalent doses of dexamethasone (Dex) alone. We found that ovalbumin (Ova)-exposed mice treated with Dex-NP had significantly fewer total cells (2.78±0.44×10(5) (n = 18) vs. 5.98±1.3×10(5) (n = 13), P<0.05) and eosinophils (1.09±0.28×10(5) (n = 18) vs. 2.94±0.6×10(5) (n = 12), p<0.05) in the lung lavage than Ova-exposed mice alone. Also, lower levels of the inflammatory cytokines IL-4 (3.43±1.2 (n = 11) vs. 8.56±2.1 (n = 8) pg/ml, p<0.05) and MCP-1 (13.1±3.6 (n = 8) vs. 28.8±8.7 (n = 10) pg/ml, p<0.05) were found in lungs of the Dex-NP compared to control, and they were not lower in the Dex alone group. In addition, respiratory system resistance was lower in the Dex-NP compared to the other Ova-exposed groups suggesting a better therapeutic effect on airways hyperresponsiveness. Taken together, these findings from early-stage drug development studies suggest that the encapsulation and protection of anti-inflammatory agents such as corticosteroids in nanoparticle formulations can improve efficacy. Further development of novel drugs in nanoparticles is warranted to explore potential treatments for chronic inflammatory diseases such as asthma.
    Full-text · Article · Oct 2013 · PLoS ONE
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