ABSTRACT
Photodynamic therapy (PDT) and ferroptosis show significant potential in tumor treatment. However, their therapeutic efficacy is often hindered by the oxygen-deficient tumor microenvironment and the challenges associated with efficient intracellular drug delivery into tumor cells. Toward this end, this work synthesized perfluorocarbon (PFC)-modified Pluronic F127 (PFC-F127), and then exploits it as a carrier for codelivery of photosensitizer Chlorin e6 (Ce6) and the ferroptosis promoter sorafenib (Sor), yielding an oxygen self-supplying nanoplatform denoted as Ce6-Sor@PFC-F127. The PFCs on the surface of the micelle play a crucial role in efficiently solubilizing and delivering oxygen as well as increasing the hydrophobicity of the micelle surface, giving rise to enhanced endocytosis by cancer cells. The incorporation of an oxygen-carrying moiety into the micelles enhances the therapeutic impact of PDT and ferroptosis, leading to amplified endocytosis and cytotoxicity of tumor cells. Hypotonic saline technology was developed to enhance the cargo encapsulation efficiency. Notably, in a murine tumor model, Ce6-Sor@PFC-F127 effectively inhibited tumor growth through the combined use of oxygen-enhanced PDT and ferroptosis. Taken together, this work underscores the promising potential of Ce6-Sor@PFC-F127 as a multifunctional therapeutic nanoplatform for the codelivery of multiple cargos such as oxygen, photosensitizers, and ferroptosis inducers.
Subject(s)
Antineoplastic Agents , Chlorophyllides , Drug Screening Assays, Antitumor , Ferroptosis , Fluorocarbons , Micelles , Oxygen , Photochemotherapy , Photosensitizing Agents , Ferroptosis/drug effects , Fluorocarbons/chemistry , Fluorocarbons/pharmacology , Animals , Mice , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemical synthesis , Humans , Oxygen/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Materials Testing , Particle Size , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Biocompatible Materials/chemical synthesis , Porphyrins/chemistry , Porphyrins/pharmacology , Cell Survival/drug effects , Cell Proliferation/drug effects , Mice, Inbred BALB C , Sorafenib/chemistry , Sorafenib/pharmacology , Sorafenib/administration & dosage , Poloxamer/chemistry , Cell Line, Tumor , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Molecular StructureABSTRACT
Colistin is a potent antibiotic but its severe side effects including nephrotoxicity and neurotoxicity are the roadblock for their wide use in clinics. To solve this problem, we synthesized a new prodrug, mannose-maltose-colistin conjugate, termed MMCC that can reversibly mask the five amines of colistin that are primarily responsible for the toxicity. The deliberated design of disulfide-based self-immolative linker warranted the reversibly release of the pristine amines of colistin on demand without sacrificing antimicrobial efficacy. Once MMCC was delivered in cells, reducing agents cleaves the disulfide bond and release the pristine amines. The targeting ligands of maltose and mannose were grafted on colistin conjugate for targeting delivery of colistin to bacteria and macrophages, respectively. Taken together, MMCC as a new class of antimicrobial biomaterials, demonstrates its great potential for the treatment of intracellular bacterial infections.