Self-targeted liposomes for enhancing chemotherapeutic efficacy of pancreatic cancer by degrading the extracellular matrix and eradicating intra-tumoral bacteria

Abstract

Pancreatic cancer is one of the lethal malignancies resulting from the dense extracellular matrix (ECM) hindering the diffusion of cancer-chemotherapeutics and the intra-tumoral bacteria promoting tumor growth and inactivating cancer-chemotherapeutics, causing poor treatment prognoses. It is difficult to exert efficacy spatiotemporally by combined administration of chemotherapeutics, ECM degradation agents and antibiotics, and this may disturb the microflora in critically ill patients. To establish intra-tumor co-delivery of cancer-chemotherapeutics, ECM degradation agents and antibiotics, self-targeting DCPA (2-(4-((1,5-bis(octadecyloxy)-1,5-dioxopentan-2-yl)carbamoyl)pyridin-1-ium-1-yl)acetate) liposomes with complexed water as pH responsive functionality were self-assembled and PEGylated ciprofloxacin was used as a lipid-membrane component, together with bromelain and gemcitabine loaded in-core (B/G–C/DCPA-H₂O). These triple-loaded liposomes were stealthily transported in the blood circulation to accumulate in the acidic environment of the tumor site. Upon tumor self-targeting, DCPA-H₂O and PEGylated ciprofloxacin became protonated, disturbing the balance in the lipid membrane to cause liposome burst and simultaneous release of bromelain, PEGylated ciprofloxacin and gemcitabine. Treatment of mice with these self-targeting liposomes yielded significantly higher responses in Escherichia coli infected pancreatic cancer with respect to both infection and tumor volume than the administration of bromelain, gemcitabine and gemcitabine loaded C/DCPA-H₂O liposomes alone.