Antifibrotic Agent Mediated Tumor Microenvironment Modulation and Improved Nanomedicine Delivery in Solid Tumor

The unique physiology of tumors limits the efficacy ofchemotherapeutics.In efforts to improve the effectiveness of the existing chemotherapydrugs, nanomedicine emerged as a new hope but proved inadequate dueto the transport barriers present within the tumor tissues, whichlimits the potential of nanomedicine. Dense collagen networks in fibrotictissues contribute to hindering the penetration of molecular- or nano-scalemedicine through tumor interstitium. In the present study, human serumalbumin (HSA)-based nanoparticles (NPs) were developed for gemcitabine(GEM) and losartan (LST), which could offer secreted protein acidsrich in cysteine (SPARC) and enhanced permeability and retention effect(EPR)-mediated drug accumulation in tumors. Also, the tumor microenvironment(TME) modulation approach using LST was coupled to investigate theimpact on antitumor efficacy. GEM-HSA NPs and LST-HSA NPs were preparedby the desolvation-cross-linking method and characterized for size,potential, morphology, drug loading, drug-polymer interactions,and hemocompatibility. For investigating the efficacy of preparedNPs, cytotoxicity and mechanisms of cell death were elucidated invitro by using various assays. Intracellular uptake studies of preparedHSA NPs indicated their uptake and cytoplasmic localization. Furthermore,in vivo studies demonstrated significantly improved anticancer efficacyof GEM-HSA NPs in combination with LST pretreatment. Extended LSTtreatment further improved the anticancer potential. It was shownthat the improved efficacy of the nanomedicine was correlated withthe reduced thrombospondin-1 (TSP-1) and collagen level in tumor tissueupon LST pretreatment. Moreover, this approach exhibited augmentednanomedicine accumulation in the tumor, and hematological, biochemical,and tissue histology indicated the safety profile of this combinationregimen. Concisely, the undertaken study demonstrated the potentialof the triple targeting (SPARC, EPR, TME modulation) approach foraugmented efficacy of chemotherapeutics.