Multimodal folate receptor-targeted liposomes enable photo-chemo-antibiotic synergy for peritoneal cancer therapy

Abstract

The complex and heterogeneous nature of cancer presents significant challenges to effective treatment. Because no single therapy can overcome this complex challenge, rational combination strategies that concurrently target tumor survival pathways and engage non-overlapping mechanisms hold the greatest promise. We previously demonstrated that photodynamic priming and repurposing of the antibiotic minocycline can enhance chemotherapy efficacy in vivo . However, these approaches lack cancer selectivity and require multiple administrations. To address these limitations, we developed a single, stable, folate receptor-targeted liposomal formulation that co-packages irinotecan and minocycline within the aqueous core and incorporates the photosensitizer lipid-anchored benzoporphyrin derivative (BPD) within the lipid bilayer. This unique fol ate receptor-targeted l iposome containing i rinotecan, mi nocycline, and lipid-anchored B PD (FOLIMIB) nanoformulation enhances multidrug delivery to cancer cells, significantly downregulating both topoisomerase 1 (Top1) and tyrosyl-DNA phosphodiesterase 1 (Tdp1), thereby increasing DNA damage in 2D and 3D ovarian cancer models. Furthermore, in a peritoneal metastases mouse model, FOLIMIB achieved higher intratumoral drug accumulation compared with non-targeted l iposome containing i rinotecan, mi nocycline, and lipid-anchored B PD (LIMIB) and demonstrated a light dose-dependent photodynamic enhancement of survival outcomes. This multimodal platform shows promise for enhancing Top1 inhibitor-based chemotherapy by targeting DNA damage and DNA repair pathways, warranting further mechanistic investigation and evaluation under multi-cycle dosing regimens to achieve sustained therapeutic benefit and prolonged animal survival.