Phosphorous dendrimer-mediated biomineralization for synergistic blockade therapy and hypoxia-activated chemotherapy of tumors

Abstract

Blockade therapy involving the artificial induction of biomineralization in tumor tissues has emerged as a promising strategy for treating malignant tumors. However, standalone blockade therapy which merely obstructs tumor growth rather than directly destroying the tumors is quite limited in therapeutic efficacy. Herein, we report the phosphite-terminated phosphorus dendrimers (AK176)/fibronectin (FN) nanocomplexes (NCs) with tumor-targeting and biomineralization-inducing properties to encapsulate a hypoxia-activated tirapazamine (TPZ) to achieve synergistic blockade therapy/chemotherapy of triple-negative breast cancer (TNBC). The constructed AK176@FN/TPZ (AFT) NCs exhibit a spherical shape with a size of 134.1 nm and good colloidal stability, can target tumor cells through specific recognition between the Arg-Gly-Asp sequence of FN and α_vβ₃ integrin receptors, and specifically induce mineral deposition on cancer cytomembranes by means of the inherent calcium ion adsorption property of dendrimers. Notably, the AFT-mediated biomineralization can generate tumor hypoxia and amplify the chemotherapeutic effect of TPZ, thereby effectively inhibiting tumor cell proliferation and lung metastasis through synergistic blockade therapy/chemotherapy in an orthotopic TNBC xenograft model. The developed AFT NCs with a simple composition represent an advanced nanomedicine formulation that can induce synergistic tumor-targeting blockade therapy and chemotherapy, which may be extended to tackle other cancer types.

Statement of Significance

Blockade therapy involving the artificial induction of biomineralization in tumor tissues has emerged as a promising strategy for treating malignant tumors. Herein, phosphite-terminated phosphorus dendrimers (AK176)/fibronectin (FN) nanocomplexes (NCs) with tumor-targeting and biomineralization-inducing properties are developed to encapsulate a hypoxia-activated drug tirapazamine (TPZ), resulting in synergistic blockade therapy/chemotherapy of triple-negative breast cancer in a mouse model. The developed AK176@FN/TPZ (AFT) NCs can target tumor cells through specific recognition between the Arg-Gly-Asp sequence of FN and α_vβ₃ integrin receptors, and specifically induce mineral deposition via the inherent calcium ion adsorption property of bisphosphonate groups of dendrimers, thereby triggering tumor biomineralization for blockade therapy. The AFT-mediated biomineralization on tumor cell membranes generates tumor hypoxia, which further amplifies the chemotherapeutic effect of TPZ.