Autophagy inhibition alleviates tumor desmoplasia and improves the efficacy of locally and systemically administered liposomal doxorubicin

The abnormal physiology of the tumor microenvironment poses a challenge to the drug delivery in the tumor tissues. The dense tumor stroma hinders the movement of nanomedicine through the interstitium and negatively impacts their efficacy. In this study, hydroxychloroquine (HCQ) was investigated for its impact on alleviating the hindrance offered to the nanomedicine by extracellular matrix (ECM) components such as collagen and hyaluronan. In the current study, the effect of the antifibrotic activity of HCQ on bio-distribution and anticancer efficacy of systemically as well as locally (with the aid of injectable alginate hydrogel) administered liposomal doxorubicin was evaluated. In the in vitro model system, the HCQ treatment showed its antifibrotic potential by reverting the α-SMA⁺ phenotype and reducing the collagen levels in the TGF-β1 stimulated NIH/3T3 cells and also showed parallel reduction in the autophagy. In the 4T1 tumor models, HCQ treatment mediated autophagy inhibition resulted in the ECM synthesis inhibition, represented by reduced levels of TGF-β1, collagen and hyaluronan content in the tumor tissues. The reduction in the ECM components, in-turn, improved the bio-distribution of the intravenously (i.v.) and intratumorally (i.t.) injected liposomal doxorubicin. The anticancer efficacy studies showed consequential improvement in the effectiveness of the i.v. and i.t. injected liposomal doxorubicin. The study unveils the potential of stromal normalization using HCQ in improving the bio-distribution as well as efficacy of the nanotherapeutics.