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Παρασκευή 9 Ιουνίου 2017

Tailored Design of Multifunctional and Programmable pH-responsive Self-assembling Polypeptides as Drug Delivery Nanocarrier for Cancer Therapy

Publication date: Available online 9 June 2017
Source:Acta Biomaterialia
Author(s): Tzu-Wei Wang, Chia-Wei Yeh, Chen-Hsiang Kuan, Li-Wen Wang, Liang-Hsin Chen, Hsi-Chin Wu, Jui-Shen Sun
Breast cancer has become the second leading cause of cancer-related mortality in female wherein more than 90% of breast cancer-related death results from cancer metastasis to distant organs at advanced stage. The purpose of this study is to develop biodegradable nanoparticles composed of natural polypeptides and calcium phosphate (CaP) with sequential pH-responsivity to tumor microenvironments for active targeted drug delivery. Two different amphiphilic copolymers, poly(ethylene glycol)3400-aconityl linkage-poly(L-glutamic acid)15-poly(L-histidine)10-poly(L-leucine)10 and LyP1-poly(ethylene glycol)1100-poly(L-glutamic acid)15-poly(L-histidine)10-poly(L-leucine)10, were exploited to self-assemble into micelles in aqueous phase. The bio-stable nanoparticles provide three distinct functional domains: the anionic PGlu shell for CaP mineralization, the protonation of PHis segment for facilitating anticancer drug release at target site, and the hydrophobic core of PLeu for encapsulation of anticancer drugs. Furthermore, the hydrated PEG outer corona is used for prolonging circulation time, while the active targeting ligand, LyP-1, is served to bind to breast cancer cells and lymphatic endothelial cells in tumor for inhibiting metastasis. Mineralized DOX-loaded nanoparticles (M-DOX NPs) efficiently prevent the drug leakage at physiological pH value and facilitate the encapsulated drug release at acidic condition when compared to DOX-loaded nanoparticles (DOX NPs). M-DOX NPs with LyP-1 targeting ligand effectively accumulated in MDA-MB-231 breast cancer cells. The inhibition effect on cell proliferation also enhances with time, illustrating the prominent anti-tumor efficacy. Moreover, the in vitro metastatic inhibition model shows the profound inhibition effect of inhibitory nanoparticles. In brief, this self-assembling peptide-based drug delivery nanocarrier with multifunctionality and programmable pH-sensitivity is of great promise and potential for anti-cancer therapy.Statement of SignificanceThis tailored-design polypeptide-based nanoparticles with self-assembling and programmable stimulus-responsive properties enable to 1) be stable in physiological pH value with a low level of drug loss and effectively release the encapsulated drug with pH variations according to the tumor microenvironment, 2) enhanced targeting ability to hard-to-treat breast cancer cells and activated endothelial cells (tumor region), 3) significantly inhibit the growth and prevent from malignant metastasis of cancer cells in consonance with promising anti-tumor efficacy, and 4) keep tumors stick to localized position so that these confined solid tumors can be more accessible by different treatment modalities. The contribution of this work is how to design a programmable pH-responsive drug delivery system based on the tailor-designed polypeptides.

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