Polyaminoacid–doxorubicin prodrug micelles as highly selective therapeutics for targeted cancer therapy

Abstract

An amphiphilic copolymer carrying high-dose doxorubicin (21% on a weight basis), PHEA-EDA-P,C-Doxo, was prepared by coupling doxorubicin with a biocompatible polyaminoacid through a pH-sensitive spacer.Additional derivatization with 4-pentynoic acid endows it with self-assembling properties by means of p-p stacking. These micelles can be triggered to promptly release drug in lysosomes ($40% in 12 h) through pHdependent micelle hydrolysis after uptake. In vitro tests on co-cultures of cancer (MDA-MB 231) and normal (HB-2) breast cells proved that the conjugate was selectively internalized into the former rather than normal cells, exploiting the caveolae-dependent endocytosis pathway, explaining the selective cytotoxic effect toward cancer cells. Intracellular trafficking study of MDA-MB 231 showed that the delivery of the endocytosed drug occurs through the direct fusion of caveosomes with late lysosomes, triggering a massive release in the cytoplasm, bringing about cell death. Dose-effectiveness and mechanistic data indicate that PHEA-EDA-P,C-Doxo is endowed with a distinctive combination of selectivity and pharmacological potency (EC50 13 mM, E max ¼ 77% and EC50 > 25 mM, E max ¼ 21% for cancer and healthy cells respectively) that makes it an excellent candidate for future preclinical studies.

A Tumor-Activatable Theranostic Nanomedicine Platform for NIR Fluorescence-Guided Surgery and Combinatorial Phototherapy

“…In addition, fluorescence microscopy analysis of the selected kidney cells that were transfected with FITC-labeled SiNc-PNP revealed that only negligible SiNc fluorescence signal appeared after 24 h of incubation (Figure S6 ). Similar behaviors of nanoparticles, including micelles, has been previously reported 47 , 48 . For example, by performing in vitro tests on co-cultures of cancer and normal breast cells, Mauro et al demonstrated that self-assembled micelles were selectively internalized into the cancer rather than normal cells 48 .…”

Engineered Doxorubicin Delivery System Using Proteinoid-Poly (L-Lactic Acid) Polymeric Nanoparticles of Narrow Size Distribution and High Molecular Weight for Cancer Treatment

“…Although it is wildly used, its use in chemotherapy has been limited, mainly due to severe side effects, including cardiotoxicity and nephrotoxicity [1][2][3][4][5]. Many research labs have been struggling with the need to avoid and overcome the Dox side effects, without reducing the drug potency, usually by developing nanosized biospecific drug carriers [1,3,6,7]. The most important requirement for potential drug carriers is a combination of a high drug loading capacity and a long bloodstream circulation time [8].…”

Smart Nanoparticles in Biomedicine: An Overview of Recent Developments and Applications

“…Furthermore, cellular uptake is also depending on size [24]. NPs are internalized faster and 15-250 times more than microparticles of 1-10 µm rage [25] through many mechanisms: large NPs are generally involved in micropinocytosis; 100 nm NPs in clathrin-mediated endocytosis, while 15-80 nm NPs in caveolae-mediated endocytosis [26], [27].…”