title: Nanoceria-Mediated Drug Delivery for Targeted Photodynamic Therapy on Drug-Resistant Breast Cancer.
abstract: Photodynamic therapy (PDT) has shown great potential for overcoming drug-resistant cancers. Here, we report a multifunctional drug delivery system based on chlorin e6 (Ce6)/folic acid (FA)-loaded branched polyethylenimine-PEGylation ceria nanoparticles (PPCNPs-Ce6/FA), which was developed for targeted PDT to overcome drug-resistant breast cancers. Nanocarrier delivery and FA targeting significantly promoted the cellular uptake of photosensitizers (PSs), followed by their accumulation in lysosomes. PPCNPs-Ce6/FA generated reactive oxygen species (ROS) after near-infrared irradiation (NIR, 660 nm), leading to reduced P-glycoprotein (P-gp) expression, lysosomal membrane permeabilization (LMP), and excellent phototoxicity toward resistant MCF-7/ADR cells, even at ultralow doses. Moreover, we identified NIR-triggered lysosomal-PDT using the higher dose of PPCNPs-Ce6/FA, which stimulated cell death by plasma membrane blebbing, cell swelling, and energy depletion, indicating an oncosis-like cell death pathway, despite the occurrence of apoptotic or autophagic mechanisms at lower drug doses. In vivo studies showed prolonged blood circulation times, low toxicity in mice, and high tumor accumulation of PPCNPs-Ce6/FA. In addition, using NIR-triggered PDT, PPCNPs-Ce6/FA displayed excellent potency for tumor regression in the MCF-7/ADR xenograft murine model. This study suggested that multifunctional PPCNPs-Ce6/FA nanocomposites are a versatile and effective drug delivery system that may potentially be exploited for phototherapy to overcome drug-resistant cancers, and the mechanisms of cell death induced by PDT should be considered in the design of clinical protocols.
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Zeng
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Hao
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Zhang-You
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University , Chongqing 400038, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002563:Cerium / Q000737:chemistry*; D006801:Humans; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D011166:Porphyrins
chemical_list: D017319:Photosensitizing Agents; D011166:Porphyrins; D002563:Cerium; C030583:ceric oxide
keywords: breast cancers; ceria nanoparticles; drug resistance; oncosis; targeted photodynamic therapy