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Paclitaxel‐loaded polypeptide‐polyacrylamide nanomicelles overcome drug‐resistance by enhancing lysosomal membrane permeability and inducing apoptosis
Author(s) -
Abbasi Sahar,
Yousefi Gholamhossein,
Tamaddon Alimohammad,
Firuzi Omidreza
Publication year - 2021
Publication title -
journal of biomedical materials research part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.849
H-Index - 150
eISSN - 1552-4965
pISSN - 1549-3296
DOI - 10.1002/jbm.a.37003
Subject(s) - rhodamine 123 , cytotoxicity , apoptosis , flow cytometry , acridine orange , paclitaxel , multiple drug resistance , biophysics , materials science , in vitro , in vivo , cell culture , pharmacology , microbiology and biotechnology , biology , biochemistry , chemotherapy , genetics , antibiotics
The aim of the current project was to investigate the in vitro properties of Paclitaxel (PTX)‐loaded pHPMA 5kD ‐pHis 5kD ‐pLeu 3kD nanomicelles (NMs) on multidrug resistance cell line. Circular dichroism analysis was done to investigate the effect of pH on the secondary structure of the copolymer. Cytotoxicity assay together with fluorescence imaging and flow cytometry were performed to get an insight about toxicity and cellular uptake mechanism of NMs. Acridine orange assay, rhodamine 123 (Rh123) accumulation assay, and apoptosis analysis were conducted for further investigation. It was found that the secondary structure of the copolymer changed in response to pH, PTX‐loaded NMs had higher cytotoxicity on both drug‐sensitive (MES‐SA and MCF‐7) and multidrug resistant cells (MES‐SA/DX5) compared to free PTX, and interestinly free copolymer inhibited the growth of MES‐SA/DX5 cells while it was nontoxic on drug‐sensitive cells. Moreover, the copolymer was able to induce lysosome membrane permeation and increase Rh123 accumulation inside cells indicating inhibition of the P‐gp efflux pumps. Finally, apoptosis was strongly induced in MES‐SA/DX5 cells upon treatment with PTX‐loaded NMs. It can be concluded that the designed hybrid copolymer is a good candidate for in vivo assay and developing a powerful system against multidrug resistance tumors.