Antitumour and anti-angiogenesis efficacy of a multifunctional self-oxygenated active-targeting drug delivery system by encapsulating biological and chemotherapeutic drugs

The hypoxic tumour microenvironment (TME), resulting from abnormal tumour angiogenesis, is a major factor contributing to treatment failure in breast cancer patients. In this study, we present a ZnO₂-based oestrone-conjugated PEGylated liposome (ZnO₂@EPL-CDDP/EGCG) that incorporates cisplatin (CDDP) and epigallocatechin-3-gallate (EGCG). ZnO₂ remains stable in neutral environments but decomposes under mildly acidic conditions, releasing Zn²⁺ and H₂O₂. These byproducts inhibit the electron transport chain, stimulate the endogenous reactive oxygen species production for chemodynamic therapy (CDT), and generate oxygen at tumour sites to alleviate hypoxia and enhance anti-angiogenic efficacy. EGCG inhibits tumour angiogenesis by down-regulating hypoxia-inducible factor-1α (HIF-1α) and its downstream pathways, while also exhibiting synergistic anti-tumour effects with CDDP. Oestrone-conjugated and polyethylene glycol (PEG) modifications facilitate targeted accumulation at tumour sites. Our findings indicate that ZnO₂@EPL-CDDP/EGCG significantly improves the therapeutic efficacy of both EGCG and CDDP, remodels tumour vasculature, and alleviates hypoxia within the TME. This self-oxygenated, actively targeted drug delivery system notably extends the survival of healthy ICR mice without observed toxicity. This novel approach, which co-encapsulates ZnO₂, EGCG, and CDDP in an active-targeting liposomal formulation for the first time, represents a promising strategy for effective cancer treatment.