Amphiphilic poly(gamma-glutamic acid) derivatives for delivering doxorubicin in cancer cells

Abstract

One of the most limiting factors in cancer treatment is the difficulty of delivering anticancer agents effectively to tumor sites. Toovercome this challenge, this research focuses on developing a carrier that has been modified to possess amphiphilic propertieswhile remaining biodegradable and biocompatible. Amphiphilic esters derived from poly(¿-glutamic acid) by modifying thecarboxylate side groups with 4-phenyl-butyl bromide were prepared. These copolymers self-assembled into nanoparticles viananoprecipitation. The cytocompatibility of the nanoparticles was assessed through lactate dehydrogenase release and metabolicactivity of U-87 glioma cells. Fluorescein isothiocyanate labeling demonstrated effective cellular uptake of nanoparticles. Thesenanoparticles were further decorated with polyethylene glycol (PEG) and a PEG-folic acid conjugate (FA-PEG-NH 2 ), their sizesbeing 174 and 156 nm, respectively. Successful grafting was confirmed through 1 H-NMR and FTIR spectroscopy. The nanoparticleswere loaded with doxorubicin, and release studies showed their sensitivity to the pH of the environment, the encapsulateddrug being released faster at pH 4.2 compared to pH 7.4. Encapsulated doxorubicin’s effect on U-87 cells was tested at variousconcentrations and time points, showing significantly better performance compared to free doxorubicin. These results suggestthat those poly(¿-glutamic acid) derivatives hold great promise for improving the delivery of hydrophobic drugs and enhancingcancer treatment.

The authors would like to acknowledge the Ministerio de Ciencia, Inno- vación y Universidades of Spain (MCIU/AEI/FEDER, UE) (Project No. RTI2018-095041-B-C33). M.R.G.M. and S.C.G. acknowledge the support of FCT – Portuguese Foundation for Science and Technology for their fellowship (2022.13353. BD) and contract (PTDC/BTM-MAT/4156/2021), respectively. A.P.P. acknowledges the MOBILIsE Project, which has received funding from the European Union’s Horizon 2020 Research and Innovation program (under grant agreement no. 951723). The authors also acknowledge the support of the Bioimaging and Advanced Light Microscopy i3S Scientific Platforms (both part of the PPBI—Portuguese Platform of Bioimaging; PPBI-POCI-01-0145-FEDER-022122).

Peer Reviewed

Postprint (published version)