Multifunctional hybrid nanoconstructs facilitates intracellular localization of Doxorubicin and Genistein to enhance apoptotic and anti-angiogenic efficacy in breast adenocarcinoma
The progressive development of tumor leading to angiogenesis marks the advancement of cancer which requires specific targeted treatment preferably with combination chemotherapy. However, there is still a long way to go to have efficient delivery system that could overcome the tumor microenvironment to achieve efficient delivery. Herein, we have developed spermine (SPM) tethered lipo-polymeric hybrid nanoconstructs with two tier strategiescell surface heparan sulfate proteoglycans (HSPG) specificity for higher intracellular localization and pH dependent charge reversal in tumor microenvironment (below pH 5.8) to facilitate Doxorubicin (Dox) and Genistein (Gen) release in synergistic combination. We have observed specific uptake of SPM anchored hybrid nano-constructs by receptor-mediated endocytosis in human breast cancer cells (MDA-MB-231) through HSPG receptor. The SPM-D+G/NPs induced higher rate of apoptosis in MDA-MB-231 cells via disruption of mitochondrial membrane potential and also exhibited stronger anti-angiogenic effect governing inhibition of VEGF pathway modulation, proliferation, invasion and migration of HUVEC in vitro and in vivo Balb/c mice model. Involvement of Akt/, Hif1α/VEGF dependent signal cascading and its down- regulation with a pro-apoptotic drug, Dox and anti-angiogenic agent Gen was evident as demonstrated by both in silico docking and subsequently proven by RT-PCR and western blotting. Altogether this study highlights the potential role of SPM for targeting HSPG receptor and synergistic delivery of Dox and Gen as a promising strategy to effectively inhibit BAC progression and these findings could open a new window to deliver combination of chemotherapeutic agents along with anti-angiogenic ligands using hybrid nanoparticles.