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.

Hot Topics and Challenges of Regenerative Nanoceria in Application of Antioxidant Therapy

“…The nanocarrier delivery and FA targeting promoted cellular uptake of photosensitizers (PSs), which are selectively accumulated in lysosomes and could be triggered to produce ROS by a 660 nm laser, and then lead to the decreased expression of P-glycoprotein (P-gp) drug-efflux pumps. This phenomenon promoted the chemotherapeutic efficacy of DOX and enhanced phototoxicity in drug-resistant human breast cancer cells [15]. It was found that induction of apoptotic/autophagic or oncosis processes completely depended on the dose of lysosomal-PDT (Figure 8).…”

“…At present, pathogenic mechanism of T2DM and control method became a hot topic in medical research. Different sized nanoceria (15,25,30, and 45 nm) was prepared by Park and coworkers [38] via supercritical synthesis method. Oxidative stress was induced by different concentration nanoceria (5, 10, 20, and 40 g/mL) in cultured human lung epithelial cells (BEAS-2B).…”

“…With the development of targeted drug, photodynamic therapy (PDT) has aroused great concern. Recently, a multifunctional drug delivery system based on chlorin e6 (Ce6)/folic acid-(FA-) loaded branched polyethylenimine-(BPEI-) coated PEGylated ceria nanoparticles (PPCNPs-Ce6/FA) has been reported [15], which was developed for the delivery of Ce6 to cervical cancer cells and imaging-guided synchronous photochemotherapy. The nanocarrier delivery and FA targeting promoted cellular uptake of photosensitizers (PSs), which are selectively accumulated in lysosomes and could be triggered to produce ROS by a 660 nm laser, and then lead to the decreased expression of P-glycoprotein (P-gp) drug-efflux pumps.…”

“…Recently, nanoceria has been paid attention on as a potential therapeutic tool in the treatment of oxidative-stress-related diseases in vivo and animal model. This paper reviews the latest breakthrough of nanoceria as an antioxidant in applications of biosensor, type 2 diabetes mellitus [14], drug delivery [15,16], and tissue engineering on the basis of the author's research work on resistance to oxidation and cytotoxicity.…”

Nanoparticle‐based photothermal and photodynamic immunotherapy for tumor treatment

“…For example, co-loading of hematoporphyrin and doxorubicin in nanoparticles can increase the sensitivity of chemotherapeutic drugs by approximately 12-fold. 102 However, several studies have demonstrated hypoxia is responsible for chemoresistance. 101 Li et al demonstrated that PDT mediated by PSloaded nanocarriers can reverse the drug resistance of breast cancer by decreasing the expression of p-gp and increasing the concentration of DOX in tumor cells.…”