Spatial specific delivery of combinational chemotherapeutics to combat intratumoral heterogeneity

Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOXDBCO plus iCPPAN3) was developed to spatially deliver two combinational chemotherapeutic drugs (doxorubicin (DOX) and PR104A) to combat hypoxia-induced intratumoral heterogeneity. DOX is highly toxic to tumor cells in normoxia state but less toxic in hypoxia state due to the hypoxia-induced chemoresistance. Meanwhile, PR104A is a hypoxia-activated prodrug has less toxic in normoxia state. Two nanocarriers, NP@DOXDBCO and iCPPAN3, can cross-link near the blood vessel extravasation sites through tumor acidity responsive bioorthogonal click chemistry to enhance the retention of DOX in tumor normoxia. Moreover, PR104A conjugated to the small-sized dendritic polyamidoamine (PAMAM) released under tumor acidity can penetrate deep tumor tissues for hypoxic tumor cell killing. Our study has demonstrated that this site-specific combination chemotherapy is better than the traditional combination chemotherapy. Therefore, spatial specific delivery of combinational therapeutics via in situ size transformable nanocarrier addresses the challenges of hypoxia induced intratumoral heterogeneity and provides insights into the combination therapy.