Cascade targeting codelivery of ingenol-3-angelate and doxorubicin for enhancing cancer chemoimmunotherapy through synergistic effects in prostate cancer

Abstract

Immunotherapy has led to an expansion of the treatment of malignancies, but its effect in prostate cancer (PCa) patients is modest. Chemoimmunotherapy is a promising approach that has attracted substantial attention. Although the widely used clinical chemotherapeutic drug doxorubicin (DOX) elicits immunogenic cell death (ICD), its weak ICD effect and the abnormal vasculature of tumors severely limit its efficacy in chemoimmunotherapy. Ingenol-3-angelate (I3A), an emerging antitumor drug with dual chemotherapeutic and immune response-eliciting effects, is expected to exert synergistic effects when administered in combination with DOX. I3A induces the ICD of PCa cells by triggering mitophagy and apoptosis and promotes the normalization of tumor vessels, resulting in sufficient infiltration of immune cells into tumors. A synergistic effect of I3A and DOX was observed in vitro at a molar ratio of 1:4. To codeliver this ratio of I3A and DOX to tumor and ensure their uptake, we designed a dual-targeting delivery system, polylactide-poly(ethylene) glycol-2-(3-((S)-5-amino-1-carboxypentyl)-ureido) pentanedioate/triphenylphosphonium (PLA-PEG-ACUPA/TPP), which targets prostate-specific membrane antigen (PSMA) and mitochondria. Delivery of these nanomedicines led to inhibited tumor growth and a strong antitumor immune response. This study sheds light on the mitophagic and antiangiogenic mechanisms underlying I3A treatment of PCa and provides a strategy for combining vascular normalization and chemoimmunotherapy for PCa treatment.

SLC1A5 is a novel biomarker associated with ferroptosis and the tumor microenvironment: a pancancer analysis

“…Through the analysis of drugs whose sensitivity may be related to SLC1A5 expression, we found that ingenol, prostratin, and parthenolide can be used as potential small molecule drugs for cancer treatment. A previous study showed that ingenol induces immunogenic cell death of prostate cancer cells by triggering mitophagy and apoptosis, promotes the normalization of tumor blood vessels, and allows immune cells to fully infiltrate the tumor, thereby exerting antitumor effects [ 58 ]. Therefore, it can be determined that ingenol, as an emerging antitumor drug, can affect the tumor microenvironment.…”

Effective therapy of advanced breast cancer through synergistic anticancer by paclitaxel and P-glycoprotein inhibitor

“…Furthermore, we also detected the stability of the HT@PTX and HT@ER/PTX in different conditions in vitro according to the protocol described in Ref. [ 40 ].…”

Emerging Trends of Nanomedicines in the Management of Prostate Cancer: Perspectives and Potential Applications

“…The delivery of these nanomedicines resulted in a potent antitumor immune response as well as reduced tumor development. It demonstrated that I3A blocked VEGF expression in tumor cells to restore normal tumor vasculature and induced mitophagy and death in human and mouse prostate cancer cells [ 91 ].…”