Reduction Sensitive Polymers Delivering Cationic Platinum Drugs as STING Agonists for Enhanced Chemo‐Immunotherapy

Abstract

STING agonists have made great progress in tumor immunotherapy. However, the inherent instability and low bioavailability have limited their wide applications. Herein, a reduction sensitive polymer with pair-wised carboxyl groups that further encapsulate a cationic phenanthriplatin drug (PhenPt) as STING agonists into nanoparticles (PhenPt NPs) via electrostatic interactions is designed. PhenPt NP can release PhenPt in cancer cells, which then induce DNA damage, activate the STING signaling pathway, stimulate innate and adaptive immune responses, and improve the chemo-immunotherapy efficacy. In vitro, for the first time it is found that PhenPt NP can activate cGAS-STING pathway. Further genome-wide RNA-sequencing reveals that DNA replication, mismatch repair, homologous recombination, and other gene repair-related pathways are involved. In vivo, PhenPt NP are found to completely inhibit the tumor growth, thereby shifting the tumor microenvironment from immunosuppressive to immunostimulatory phenotype, and boosting antitumor immune responses for long-term immunity. In addition, PhenPt NP combined with checkpoint blockade therapy (a-PD-L1) can elicit long-term immune response on both primary and distant tumors by activating the cGAS-STING pathway. Overall, this nano-delivery system with cationic chemotherapeutic drugs can greatly enhance DNA damage and activate immunity, hence providing a promising strategy for enhanced chemo-immunotherapy.

Disulfide-containing polymer delivery of C527 and a Platinum(IV) prodrug selectively inhibited protein ubiquitination and tumor growth on cisplatin resistant and patient-derived liver cancer models

“…In order to deliver C527 for intracellular release, a GSH sensitive polymer (poly (2-HD-co-HPMDA)-mPEG, PHHM) with disulfide bonds in the polymer main chain was synthesized, and Pt (IV)–C12 was also synthesized ( Scheme S1 , Figs. S4 and S5 ) [ 22 ].…”

“…Platinum anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, are the first-line anticancer alkylating agents in clinic practice [ 20 , 21 ]. These drugs can cause DNA damage and induce cell apoptosis by cross-linking with DNAs in cancer cells [ 22 , 23 ]. Unfortunately, the DNA repair machinary is powerful in cancer cells, resulting in resistance to platinum drugs [ 24 , 25 ].…”

Glutathione‐Responsive Nanoparticles of Camptothecin Prodrug for Cancer Therapy

“…Currently, the tumor immune microenvironment has shown a great influence on cancer therapy. [ 21 ] Increasing effective immune responses is one of the most critical approaches to reprogram the tumor immunosuppressive microenvironment. Activation of cGAS‐STING selectively could stimulate antigen‐presenting cells to initiate and activate tumor antigen‐specific T cells to infiltrate tumors.…”

“…As shown in Figure 3 B , the supernatant of CT26 cells treated with S‐NP‐CPT significantly stimulated DC 2.4 cells to increase the expression of STING, phosphorylated STING (p‐STING), IRF‐3, and TBK‐1, indicating that CT26 cells treated with S‐NP‐CPT could activate the STING pathway of DCs. [ 21 ] Flow cytometry was further applied to detect surface markers of DCs. [ 23 ] As shown in Figure 3A , after incubation CT26 cells with S‐NP‐CPT, the expression levels of the costimulatory molecules CD80, CD86, and MHC‐II on the surface of DC 2.4 cells increased significantly, indicating the activation of DC 2.4 cells.…”

Transforming Cold Tumors into Hot Ones with a Metal–Organic Framework-Based Biomimetic Nanosystem for Enhanced Immunotherapy

“…The cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway suppresses tumors induced by DNA damage and activates the innate immune response, which is indispensable for antitumor immune responses. , During STING trafficking, cyclic GMP-AMP (cGAMP) can serve as a secondary messenger that contributes to the transcription of IRF3 and NF-κB, facilitating type I interferon (IFN) secretion . In addition, the cGAS/STING pathway is essential to activate natural killer cells (NKs) to disrupt the growth of T cell-resistant (cold) tumors, , and preclinical studies with STING agonists have been undertaken because of the impressive CTL-mediated antitumor immunity. − However, rapid enzymatic degradation, low water solubility, and poor cellular internalization often limit the therapy of STING agonists. − To circumvent these issues, the use of novel mono- or combination agents and strategies that target the cGAS/STING pathway may enhance the currently limited immunotherapies for tumors.…”