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A PEG-Fmoc conjugate as a nanocarrier for paclitaxel.

ABSTRACT: We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(?-Fmoc-?-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25-30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX ?-? stacking interaction, which was demonstrated by fluorescence quenching studies and (13)C NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study.

SUBMITTER: Zhang P

PROVIDER: S-EPMC4102141 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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A PEG-Fmoc conjugate as a nanocarrier for paclitaxel.

Zhang Peng P Huang Yixian Y Liu Hao H Marquez Rebecca T RT Lu Jianqin J Zhao Wenchen W Zhang Xiaolan X Gao Xiang X Li Jiang J Venkataramanan Raman R Xu Liang L Li Song S

Biomaterials 20140522 25

We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synth ...[more]

PMID: 24856103

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Project description:A pH-responsive nanoparticle platform, based on PEG-b-poly (carbonate) block copolymers have been proposed that can respond to low pH as found in many cancer micro- and intracellular environment, including that in pancreatic cancer. The hydrophobic domain, i.e., the poly (carbonate) segment has been substituted with tertiary amine side chains, such as N, N'-dibutylethylenediamine (pKa = 4.0, DB) and 2-pyrrolidin-1-yl-ethyl-amine (pka = 5.4, Py) to generate two different sets of block copolymers namely PEG-DB and PEG-PY systems. These side-chain appended amines promote disassembly of nanoparticles and activation of drug release in response to pH conditions mimicking extra- (pH 6.9-6.5) and intracellular compartments (5.5-4.5, from early endosome to lysosome) of cancer tissues respectively. A frontline chemotherapy used for pancreatic cancer, i.e., gemcitabine (GEM) and a Hedgehog inhibitor (GDC 0449) has been used as the model combination to evaluate the encapsulation and pH-dependent release efficiency of these block copolymers. We found that, depending on the tertiary amine side chains appended to the polycarbonate segment, these block copolymers self-assemble to form nanoparticles with the size range of 100-150?nm (with a critical association concentration value in the order of 10-6 M). We also demonstrated an approach where GEM and GDC 0449-encapsulated PEG-DB and PEG-PY nanoparticles, responsive to two different pH conditions, when mixed at a 1:1?vol ratio, yielded a pH-dependent co-release of the encapsulated contents. We envision that such release behaviour can be exploited to gain spatiotemporal control over drug accumulation in pathological compartments with different pH status. The mixture of pH-responsive nanoparticles was found to suppress pancreatic cancer cell proliferation when loaded with anticancer agents in vitro. Cell-proliferation assay showed that both variants of PEG-b-polycarbonate block copolymers were inherently non-toxic. We have also immobilized iRGD peptide on intracellularly activable PEG-DB systems to augment cellular uptake. These targeted nanoparticles were found to promote selective internalization of particles in pancreatic cancer cells and tumor tissue.

Dataset Information

A PEG-Fmoc conjugate as a nanocarrier for paclitaxel.

Publications

A PEG-Fmoc conjugate as a nanocarrier for paclitaxel.

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