Molecular Targeted Agent and Immune Checkpoint Inhibitor Co-Loaded Thermosensitive Hydrogel for Synergistic Therapy of Rectal Cancer

Abstract

Molecular targeted therapy has been proved effective in treatment of rectal cancer. Up-regulated expression of programmed death ligand-1 (PD-L1) was observed after the management of molecular targeted therapy, which made the therapeutic effect discounted. Tumors with higher PD-L1 expression were more sensitive and responsive to treatment of PD-L1 inhibitor. Therefore, the combination of molecular targeted therapy and immune checkpoint blockade makes sense. In this study, the copolymers of poly (ethylene glycol)-block-poly (L-leucine) (PEG-PLLeu) were synthesized as a thermosensitive hydrogel composite for consecutive release of regorafenib (REG) and BMS202. The mechanical properties of PEG-PLLeu were investigated, confirming that PEG-PLLeu (5 wt.%) was suitable for in situ injection as drug-delivery composite at low temperature and stable after sol-gel transition at body temperature. Importantly, the double drug loaded hydrogel showed superior antitumour activity over single drugs in an orthotopic rectal cancer model (CT26-Luc). Further analysis of the tumor tissues suggested that REG upregulated the expression of PD-L1 in tumor tissues. In addition, the immunosuppressive tumor microenvironment of CT26-Luc tumor was distinctly relieved under the effect of BMS202, as characterized by increased infiltration of CD8+ T cells in tumors and enhanced secretion of antitumour cytokines (IFN-γ and TNF-α). Moreover, the drug-loaded composite showed no obvious toxicity in histological analysis. Taken together, the administration of REG and BMS202 in the PEG-PLLeu composite could induce a synergistic effect in in situ treatment of rectal cancer without obvious toxicity, and thus represented a potential strategy for enhanced in situ therapeutic modality.

Effects of GLP-1 Receptor Agonists on Biological Behavior of Colorectal Cancer Cells by Regulating PI3K/AKT/mTOR Signaling Pathway

“…In addition to significantly prolonging the overall survival of patients with advanced stage, the high specificity of targeted drugs meets the requirements of current precision treatment. However, whether they are monoclonal antibodies or signal pathway inhibitors, except for patients with natural drug resistance, the use of single drug may lead to acquired drug resistance and various serious complications ( Sadat et al, 2021 ; Teo et al, 2021 ; Huaiyu Zhang et al, 2021 ), making the treatment fail. Therefore, combined targeted drug therapy is the main alternative treatment with poor effect of single targeted drug therapy, which has important research significance for the treatment of CRC.…”

Progress in the application of hydrogels in immunotherapy of gastrointestinal tumors

“…As a thermoplastic hydrogel composite, Zhang et al. ( 2021 ) synthesized a polyethylene glycol-block-poly-L-leucine (PEGPLLeu) copolymer, which can be used for the synergistic treatment of rectal cancer with the continuous release of RCEFINI (REG) and BMS202 (PD-L1 inhibitor). At body temperature, polyethylene glycol polylactic acid microspheres are stable after sol-gel transformation.…”

“…In summary, hydrogels, as drug delivery systems, possess unique advantages in the immunotherapy of gastrointestinal tumors and offer great potential for the future development of new drugs. In this article, we review the development of hydrogel-based delivery systems and their use in immunotherapy of gastrointestinal tumors in recent years (Muraoka et al., 2019 ; Wang et al., 2020 ; Wu et al., 2021 ; Yang et al., 2021a , 2021b ; Zhang et al., 2021 ; Zhu et al., 2021) ( Table 1 ) and finally look forward to the future application prospects and challenges of hydrogel systems.…”

Progress of Research in In Situ Smart Hydrogels for Local Antitumor Therapy: A Review

“…Although poloxamers are biodegradable and biologically inert, the development of hydrogels made from poloxamers has been limited by the low viscosity and poor mechanical properties. Accordingly, significant efforts have been made to construct thermoresponsive hydrogels based on other synthetic polymers, such as PCLA-PEG-PCLA [ 42 ], PLEL [ 11 ] and PEG-PLLeu [ 43 ]. For example, Zhou et al synthesized PLEL, an amphiphilic block copolymer, from methoxypolyethylene glycol (mPEG) and d,l-lactide (LA) as a hydrogel matrix by the ring-open polymerization method [ 44 ].…”

“…The long intratumoral and peritumoral drug retention of the ERT@HMSNs PLEL hydrogel provided an impressive balance between antitumor efficacy and systemic adverse effects in a NSCLC xenograft mouse model. Zhang et al synthesized polyethylene glycol-block-poly-(L-leucine) (PEG-PLLeu) as a thermosensitive hydrogel matrix for simultaneous delivery and consecutive release of regorafenib (REG) and BMS202 [ 43 ]. The gelation temperature of the prepared PEG-PLLeu polymer is 4.6 °C, which is suitable for in situ injection.…”