Tumor Microenvironment‐Responsive Dual Drug Dimer‐Loaded PEGylated Bilirubin Nanoparticles for Improved Drug Delivery and Enhanced Immune‐Chemotherapy of Breast Cancer

Abstract

The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor-specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione-activatable drugs, including dimer-7ethyl-10-hydroxycamptothecin (d-SN38) and dimer-lonidamine (d-LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d-SN38 and d-LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti-PD-L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli-responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.

GSH-responsive SN38 dimer-loaded shape-transformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy

“…Equipped with various responsive bonds to stimuli, including redox, pH, enzyme, light and temperature, dimeric prodrug has emerged as one of the most promising strategies to fulfill the requirement of on-demand drug release 27 , 28 , 29 , 30 . Moreover, it has documented that dimeric prodrugs can also help to address the low drug loading efficiency in amphiphilic copolymers by increasing intermolecular hydrophobic interaction between molecules 31 , 32 . 7-Ethyl-10-hydroxy camptothecin (SN38), the biologically active metabolite of irinotecan (CPT-11), has proven to be approximately 1000-fold more cytotoxic than CPT-11 by inhibiting DNA topoisomerase 33 , 34 .…”

Engineering nanomedicines through boosting immunogenic cell death for improved cancer immunotherapy

“…Cancer monotherapy is limited by tumor heterogenicity and the complex tumor immune microenvironment. Hence, combination therapies may offer some advantages [ 77 , 78 ]. For example, a chemotherapeutic and PS-loaded self-assembling triblock copolymer composed of polyethylene glycol-poly(methyl methacrylate-co-2-amino ethyl methacrylate (thiol/amine))-poly(2-(dimethylamino)ethyl methacrylate) (PEG-P(MMA-co-AEMA (SH/NH 2 )-PDMA)) has been explored for its anticancer activity [ 79 ].…”

Bioresponsive Nanomedicine: The Next Step of Deadliest Cancers' Theranostics

“…As other major factors, the concentrations of reactive oxygen species (ROS) and glutathione (GSH) are extremely higher in TME (Cook et al, 2004), which allow different nano-agents to be applied for treating aggressive cancers including taxane resistant prostate cancer, erlotinib-resistant EGFR-mutated NSCLC cells and TNBC via redox-induced therapeutic functions (He et al, 2018;Dai et al, 2019;Hu et al, 2019;Lin et al, 2019;Liu et al, 2019b;Yang et al, 2019a;Zhang et al, 2019;Gao et al, 2020). In the combination of acidic and GSH sensitive features, a novel P-RUB micelle was designed for co-delivering docetaxel (DTX) and rubone (RUB) in fighting taxane resistant prostate cancer (PC3-TXR) .…”