A Lysosome-Targeting Self-Condensation Prodrug-Nanoplatform System for Addressing Drug Resistance of Cancer

Abstract

Lysosome-targeting self-assembling prodrugs had emerged as an attractive approach to overcome the acquisition of resistance to chemotherapeutics by inhibiting lysosomal sequestration. Taking advantage of lysosomal acidification induced intracellular hydrolytic condensation, we developed a lysosomaltargeting self-condensation prodrug-nanoplatform (LTSPN) system for overcoming lysosome-mediated drug resistance. Briefly, the designed hydroxycamptothecine (HCPT)-silane conjugates self-assembled into silane-based nanoparticles, which were taken up into lysosomes by tumor cells. Subsequently, the integrity of the lysosomal membrane was destructed because of the acid-triggered release of alcohol, wherein the nanoparticles self-condensed into silicon particles outside the lysosome through intracellular hydrolytic condensation. Significantly, the LTSPN system reduced the half-maximal inhibitory concentration (IC 50 ) of HCPT by approximately 4 times. Furthermore, the LTSPN system realized improved control of large established tumors and reduced regrowth of residual tumors in several drug-resistant tumor models. Our findings suggested that target destructing the integrity of the lysosomal membrane may improve the therapeutic effects of chemotherapeutics, providing a potent treatment strategy for malignancies.

Bibliometric insights into drug resistance in bladder cancer: Two decades of progress (1999–2022)

“…This includes seminal work on resistance to cisplatin and immune checkpoint blockade (ICB), where studies have identified key molecular players such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), exosome derived from cancer-associated fibroblasts (CAF-Exo), and BCAT2. Furthermore, innovative approaches to reduce drug resistance have been proposed in highly cited Chinese research, including Lysosome-targeting self-assembling prodrugs and Knockdown of IGF-IR [ [23] , [24] , [25] , [26] , [27] ]. These contributions underscore China's growing influence in the global landscape of BC drug resistance research, driven by its strategic focus on oncology and increasing integration with the international scientific community.…”

Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy

“…7 Such drug resistance remains a leading cause of treatment failure and cancer mortality. 8 Numerous studies have highlighted the critical role of lysosomes in mediating drug resistance in tumors. [9][10][11][12] The key issue is that hydrophobic and weakly basic chemotherapeutic agents are sequestered through passive ion trapping, leading to their reduced effectiveness at the target sites.…”

“…18 The first strategy involves modifying and optimizing the chemical structure of the drug, such as adding a targeting group 18 or transforming the drug into a prodrug. 8 The second strategy involves leveraging biomedical engineering technology to facilitate drug delivery, such as using nanomaterials or biological materials to encapsulate or load drugs. 19,20 However, these strategies may have unfavorable effects on the drug, such as the introduction of additional groups, which leads to compromised drug efficacy or an undesired rise in toxicity.…”

Nuclear-Targeting Lipid PtIV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure

“…NPt IV @siXkr8 effectively induced an increase in the level IFN-γ. To investigate tumor recurrence, , the tumor tissues were resected at 6 days post 3 times intravenously administered. The tumor volume curves (Figure l) of the recurrent model indicated that NPt IV @siXkr8 effectively inhibited tumor recurrence, while the mice treated with cisplatin, CPt IV , and NPt IV @siNC all experienced tumor recurrence.…”