Tumor Microenvironment-Response Controllable Nanopharmaceutics For Cancer Theranostics

Nanomedicines(NMs)have become a promising tool for improving the conventional anticancer drug therapeutic index.This is mainly due to the preferable accumulation of NMs in tumors site via enhanced permeability and retention(EPR)effects.However,the main obstacles to the clinical transformation of NMs are the low accumulation in the deep region of the tumor and the suboptimal penetration.In addition,areas of hypoxic tumour tissue are known to be resistant to treatment.Based on the EPR effect and hypoxic microenvironment in tumor,a series of cascaded response nanomedicines were designed for tumor diagnosis and therapy.The details are as follows:Firstly,suboptimal intratumor accumulation and poorly controllable release of encapsulated drugs remain unresolved challenges.We conceived near-infrared lasertriggered transformable Bi S@HSA/DTX multiple nanorods(m NRs),which were made of small bundles of bismuth sulfide nanorods(Bi S NRs)coated with docetaxel(DTX)-inlaid human serum albumin(HSA).NIR laser irradiation of the tumor area caused rapid disassembly of the Bi S@HSA/DTX m NRs into individual HSA-coated Bi S nanorods and triggered the release of DTX from the HSA corona,due to the local temperature increase generated by Bi S NRs via the photothermal effect.The laserinduced transformation into Bi S@HSA i NRs facilitated their penetration and increased the retention time in tumor.Therefore,efficient tumor combinatorial therapy was achieved via concurrent hyperthermia and chemotherapy in mice treated with Bi S@HSA/DTX m NRs upon NIR laser irradiation.Secondly,based on tumor adaptive treatment tolerance associated with chemotherapy originates from low tumor accumulation and hypoxic microenvironment,human serum albumin-based nanomedicines modified with diazirine and loaded with indocyanine green(ICG)and tirapazamine(TPZ),denoted as ICG/TPZ@HSA d NMs are developed.Thus,upon the laser irradiations,a cascade of aggregation,phototherapy,and bioactivated chemotherapy is successfully triggered,which achieves efficient precise eradication of tumors in vivo.Finally,in order to clarify the relationship between hypoxia levels of tumor cells and cisplatin resistance,the oxygen levels between cisplatin-resistant tumor cells and sensitive tumor cells were compared in various ways by three pairs of cells.The experimental results demonstrate that drug-resistant cells were more hypoxic than sensitive cells at the single-cell level.Thus,it is favorable to design liposome with cisplatin,TPZ and glucose oxidase(GOx)loaded to overcome drug-resistant tumor cells.With the combined application of GOx to exhaust intratumoral oxygen and then to activate the bioreductive prodrug TPZ for effective cancer treatment.In addition,the DNA self-repairing protein XPF,which is highly expressed in cisplatin-resistant cells,could be inhibited by TPZ in hypoxic conditions and improve the effect of cisplatin.Therefore,the cisplatin-resistant tumor cells could be reversed by Pt/TPZ/GOx@Lipo through intracellular hypoxic characteristics.In summary,we have successfully developed a serious of cascaded response nanomedicines,which may be further promising the application and development of nanotechnology in the field of cancer diagnosis and treatment.