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

ABSTRACT: 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-? (FR?). 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.

SUBMITTER: Jones SK

PROVIDER: S-EPMC4937801 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Jones Steven K SK Lizzio Vincent V Merkel Olivia M OM

Biomacromolecules 20151216 1

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- ...[more]

PMID: 26636884

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Project description:BACKGROUND: Effective cancer chemotherapy remains an important issue in cancer treatment, and signal transducer and activator of transcription-3 (Stat3) activation leads to cellular resistance of anticancer agents. Polymers are ideal vectors to carry both chemotherapeutics and small interfering ribonucleic acid (siRNA) to enhance antitumor efficacy. In this paper, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and Stat3 siRNA were successfully synthesized, and their applications in cancer cells were investigated. METHODS: Firstly, paclitaxel was enclosed by PLGA nanoparticles through solvent evaporation. They were then coated with cationic polyethylenimine polymer (PLGA-PEI-TAX), enabling it to carry Stat3 siRNA on its surface through electrostatic interactions (PLGA-PEI-TAX-S3SI). The size, zeta potential, deliver efficacy, and release profile of the PLGA nanocomplexes were characterized in vitro. The cellular uptake, intracellular nanoparticle trajectory, and subsequent cellular events were evaluated after treatment with various PLGA nanocomplexes in human lung cancer A549 cells and A549-derived paclitaxel-resistant A549/T12 cell lines with ?-tubulin mutation. RESULTS: A549 and A549/T12 cells contain constitutively activated Stat3, and silencing Stat3 by siRNA made both cancer cells more sensitive to paclitaxel. Therefore, PLGA-PEI-TAX-S3SI was synthesized to test its therapeutic role in A549 and A549/T12 cells. Transmission electron microscopy showed the size of PLGA-PEI-TAX-S3SI to be around 250 nm. PLGA-PEI nanoparticles were nontoxic. PLGA-PEI-TAX was taken up by A549 and A549/T12 cells more than free paclitaxel, and they induced more condensed microtubule bundles and had higher cytotoxicity in these cancer cells. Moreover, the yellowish fluorescence observed in the cytoplasm of the cancer cells indicates that the PLGA-PEI nanoparticles were still simultaneously delivering Oregon Green paclitaxel and cyanine-5-labeled Stat3 siRNA 3 hours after treatment. Furthermore, after the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX. CONCLUSION: The PLGA-PEI-TAX-S3SI complex provides a new therapeutic strategy to control cancer cell growth.

Dataset Information

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

Publications

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

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