Tailored design of multifunctional and programmable pH-responsive self-assembling polypeptides as drug delivery nanocarrier for cancer therapy
Journal
Acta Biomaterialia
Journal Volume
58
Pages
54-66
Date Issued
2017
Author(s)
Abstract
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 Significance This tailored-design polypeptide-based nanoparticles with self-assembling and programmable stimulus-responsive properties enable to 1) have stable pH in physiological value with a low level of drug loss and effectively release the encapsulated drug with pH variations according to the tumor microenvironment, 2) enhance targeting ability to hard-to-treat breast cancer cells and activate 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) make tumors stick to localized position so that these confined solid tumors can be more accessible by different treatment modalities. This work contributes to designing a programmable pH-responsive drug delivery system based on the tailor-designed polypeptides. ? 2017 Acta Materialia Inc.
SDGs
Other Subjects
Amino acids; Calcium phosphate; Cell proliferation; Controlled drug delivery; Diseases; Endothelial cells; Ethylene glycol; Ligands; Nanoparticles; Oncology; Pathology; Polyethylene glycols; Polyols; Targeted drug delivery; Tumors; Breast Cancer; Breast cancer cells; Nanocarriers; PH-responsive; Poly(L-histidine); Poly-(L-glutamic acid); Poly-L-glutamic acids; Programmable ph responsive; Self-assembling; Tumor microenvironments; Peptides; aconitic acid; amphophile; calcium phosphate; copolymer; doxorubicin; leucine; ligand; macrogol; nanocarrier; nanoparticle; polyglutamic acid; polyhistidine; polypeptide; doxorubicin; drug carrier; nanoparticle; peptide; acidity; antineoplastic activity; aqueous solution; Article; biodegradability; breast cancer; cancer therapy; cell proliferation; circulation time; controlled study; drug delivery system; drug efficacy; drug release; human; human cell; hydrophobicity; in vitro study; lymph vessel endothelium; MDA-MB-231 cell line; metastasis inhibition; micelle; mineralization; nanoencapsulation; particle size; pH; priority journal; proton transport; tumor microenvironment; breast tumor; chemistry; delayed release formulation; drug design; metabolism; pathology; pharmacology; tumor cell line; umbilical vein endothelial cell; Breast Neoplasms; Cell Line, Tumor; Delayed-Action Preparations; Doxorubicin; Drug Carriers; Drug Design; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Nanoparticles; Peptides
Publisher
Acta Materialia Inc
Type
journal article