Disulfide Bond-Based SN38 Prodrug Nanoassemblies with High Drug Loading and Reduction-Triggered Drug Release for Pancreatic Cancer Therapy

Abstract

Purpose Chemotherapy is a significant and effective therapeutic strategy that is frequently utilized in the treatment of cancer. Small molecular prodrug-based nanoassemblies (SMPDNAs) combine the benefits of both prodrugs and nanomedicine into a single nanoassembly with high drug loading, increased stability, and improved biocompatibility. Methods In this study, a disulfide bond inserted 7-ethyl-10-hydroxycamptothecin (SN38) prodrug was rationally designed and then used to prepare nanoassemblies (SNSS NAs) that were selectively activated by rich glutathione (GSH) in the tumor site. The characterization of SNSS NAs and the in vitro and in vivo evaluation of their antitumor effect on a pancreatic cancer model were performed. Results In vitro findings demonstrated that SNSS NAs exhibited GSH-induced SN38 release and cytotoxicity. SNSS NAs have demonstrated a passive targeting effect on tumor tissues, a superior antitumor effect compared to irinotecan (CPT-11), and satisfactory biocompatibility with double dosage treatment. Conclusion The SNSS NAs developed in this study provide a new method for the preparation of SN38-based nano-delivery systems with improved antitumor effect and biosafety.

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

“…For the preparation of nanobinders (NBs), several parameters must be thoughtfully considered, including their stability over time, the percentage of tEB functionalization to allow proper binding with HSA, and the Nlg/Ptx ratio, which should be in favor of Nlg ( Sonpavde et al, 2020 ). Moreover, it is established that homodimeric disulfide prodrugs, such as Nlg dimer, i.e., NlgD ( Figure 1 ; Supplementary Material ), ( Feng et al, 2018 ) can enhance the stability of prodrug-based nanoassemblies and facilitate the reduction-responsive release of active drugs ( Zhou et al, 2021 ; Liu et al, 2022 ; Zhong et al, 2023 ). Therefore, to achieve greater flexibility in the composition of NBs concerning stability and drug ratio, we chose to synthesize a monomeric HSA-binding analogue of Nlg, i.e., nMAC ( Scheme 3 ), to be combined with pMACs and NlgD (see § 3.4).…”

pH-Sensitive Nanodrug Self-Assembled from Aliphatic 5-Fluorouracil Derivative and Doxorubicin for Synergistic Cancer Therapy

“…pH-dependent degradation of ortho ester linkages in NP2 was determined using 1 H NMR. The in vitro release of DOX and 5FU from NPs/DOX was measured by a dialysis method . These detailed methods are described in the Supporting Information.…”

“…The in vitro release of DOX and 5FU from NPs/DOX was measured by a dialysis method. 26 These detailed methods are described in the Supporting Information.…”

Research Progress of SN38 Drug Delivery System in Cancer Treatment

“…In vivo experiments in 4T1 tumor-bearing model revealed that the tumor weight was significantly lower in the administration group mice than in the saline group, and the SN38-SS-PC liposome group had the lowest tumor weight with a tumor inhibition rate (TIR) of approximately 53.3%, which was significantly higher than that of irinotecan at 11.7%. Zhong et al 97 inserted disulfide bonds into SN38 and used it to prepare GSH responsive nanoassemblies (SNSS NAs). SNSS NAs were able to increase the absorption of Panc-2 and BxPC-3 cells when compared to free SN38, and in vitro cellular uptake demonstrated that SNSS NAs were internalized via a clathrin-mediated exocytosis pathway.…”