Dataset Information

Improved intestinal absorption of paclitaxel by mixed micelles self-assembled from vitamin E succinate-based amphiphilic polymers and their transcellular transport mechanism and intracellular trafficking routes.

ABSTRACT: To ensure that antitumor drugs can be effectively transported across intestinal barrier and then quickly released in tumor cells, mixed polymeric micelles (Mix-PMs) were designed and fabricated by combining poly(2-ethyl-2-oxazoline)-vitamin E succinate (PEOz-VES) with TPGS1000 for enhancing intestinal absorption of paclitaxel. PEOz-VES exhibited an extremely low critical micelle concentration and negligible cytotoxicity. The Mix-PMs were characterized to have about 20?nm in diameter, uniform spherical morphology, high drug-loading content and sustained drug release profile with a retained pH-sensitivity. The results of the transport through Caco-2 cell monolayers and intestinal absorption revealed that Mix-PMs displayed higher transcellular transport efficiency compared with PEOz-VES micelles and Taxol®. The possible mechanism of transcellular transport for Mix-PMs was elucidated to be mainly through clathrin- and caveolae/lipid rafts-mediated transcytosis. Confocal laser scanning micrographs revealed that late endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and mitochondria were all involved in intracellular trafficking of Mix-PMs. The proteins involved in transcytosis of Mix-PMs and finally excreted were unraveled for the first time by the analysis of proteins in the basolateral media according to the proteomics method. Consequently, the fabricated mixed polymeric micelles may have great potential in enhancing intestinal absorption and accelerating drug release in tumor cells.

SUBMITTER: Qu X

PROVIDER: S-EPMC6058530 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Improved intestinal absorption of paclitaxel by mixed micelles self-assembled from vitamin E succinate-based amphiphilic polymers and their transcellular transport mechanism and intracellular trafficking routes.

Qu Xiaoyou X Zou Yang Y He Chuyu C Zhou Yuanhang Y Jin Yao Y Deng Yunqiang Y Wang Ziqi Z Li Xinru X Zhou Yanxia Y Liu Yan Y

Drug delivery 20181101 1

To ensure that antitumor drugs can be effectively transported across intestinal barrier and then quickly released in tumor cells, mixed polymeric micelles (Mix-PMs) were designed and fabricated by combining poly(2-ethyl-2-oxazoline)-vitamin E succinate (PEOz-VES) with TPGS1000 for enhancing intestinal absorption of paclitaxel. PEOz-VES exhibited an extremely low critical micelle concentration and negligible cytotoxicity. The Mix-PMs were characterized to have about 20 nm in diameter, uniform sph ...[more]

PMID: 29313392

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Project description:UNLABELLED:In order to achieve enhanced and synergistic delivery of paclitaxel (PTX), a hydrophobic anticancer agent, two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks, were synthesized. Both POEG-b-PFTS polymers were able to form micelles with intrinsic antitumor activity in vitro and in vivo. Employing these micelles as a carrier to load PTX, their drug loading capacity, stability, in vivo biodistribution and tumor inhibition effect were evaluated. PTX/POEG15-b-PFTS16 mixed micelles exhibited an excellent stability of 9days at 4°C with a PTX loading capacity of 8.2%, which was more effective than PTX/POEG15-b-PFTS6 mixed micelles. In vivo biodistribution data showed that DiR-loaded POEG-b-PFTS micelles were more effectively localized in the tumor than in other organs. Moreover, both PTX/POEG-b-PFTS micelles showed significantly higher antitumor activity than Taxol in a 4T1.2 murine breast tumor model, and the tumor inhibition and animal survival followed the order of PTX/POEG15-b-PFTS16>PTX/POEG15-b-PFTS6>POEG15-b-PFTS16>Taxol?POEG15-b-PFTS6. Our data suggest that POEG-b-PFTS micelles are a promising anticancer drug carrier that warrants more studies in the future. STATEMENT OF SIGNIFICANCE:Polymerization of drug-based monomer represents a facile and precise method to obtain well-defined polymeric prodrug amphiphiles. Currently, most reports largely focus on the synthesis methods and the biophysical properties. There is limited information about their anti-tumor activity and delivery function as prodrug carriers in vitro and in vivo. In this manuscript, we report the development of two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks. Both POEG-b-PFTS polymers were able to self-assemble into nano-sized micelles with intrinsic antitumor activity in vitro and in vivo. More importantly, POEG-b-PFTS polymers were effective in forming stable mixed micelles with various anticancer agents including PTX, DOX, docetaxel, gefitinib, and imatinib. Delivery of PTX via our new carrier led to significantly improved antitumor activity, suggesting effective PTX/FTS combination therapy. We believe that our study shall be of broad interest to the readers in the fields of biomaterials and drug delivery.

Project description:BACKGROUND:Paclitaxel (PTX) is a widely used anti-cancer drug for treating various types of solid malignant tumors including breast, ovarian and lung cancers. However, PTX has a low therapeutic response and is linked with acquired resistance, as well as a high incidence of adverse events, such as allergic reactions, neurotoxicity and myelosuppression. The situation is compounded when its complex chemical structure contributes towards hydrophobicity, shortening its circulation time in blood, causing off-target effects and limiting its therapeutic activity against cancer cells. Formulating a smart nano-carrier may overcome the solubility and toxicity issues of the drug and enable its more selective delivery to the cancerous cells. Among the nano-carriers, natural polymers are of great importance due to their excellent biodegradability, non-toxicity and good accessibility. The aim of the present research is to develop self-assembled sodium caseinate nanomicelles (NaCNs) with PTX loaded into the hydrophobic core of NaCNs for effective uptake of the drug in cancer cells and its subsequent intracellular release. METHODS:The PTX-loaded micelle was characterized with high-performance liquid chromatography (HPLC), Fourier Transform Infrared Spectra (FTIR), High Resolution-Transmission Electron Microscope (HR-TEM), Field Emission Scanning Electron Microscope (FESEM) and Energy Dispersive X-Ray (EDX). Following treatment with PTX-loaded NaCNs, cell viability, cellular uptake and morphological changes were analyzed using MCF-7 and MDA-MB 231 human breast cancer cell lines. RESULTS:We found that PTX-loaded NaCNs efficiently released PTX in an acidic tumor environment, while showing an enhanced cytotoxicity, cellular uptake and in-vivo anti-tumor efficacy in a mouse model of breast cancer when compared to free drug and blank micelles. Additionally, the nanomicelles also presented improved colloidal stability for three months at 4 °C and -20 °C and when placed at a temperature of 37 °C. CONCLUSIONS:We conclude that the newly developed NaCNs is a promising carrier of PTX to enhance tumor accumulation of the drug while addressing its toxicity issues as well.

Dataset Information

Improved intestinal absorption of paclitaxel by mixed micelles self-assembled from vitamin E succinate-based amphiphilic polymers and their transcellular transport mechanism and intracellular trafficking routes.

Publications

Improved intestinal absorption of paclitaxel by mixed micelles self-assembled from vitamin E succinate-based amphiphilic polymers and their transcellular transport mechanism and intracellular trafficking routes.

Similar Datasets

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