Tuning the efficacy of esterase-activatable prodrug nanoparticles for the treatment of colorectal malignancies

Wang, Yuchen; Xie, Haiyang; Ying, Kangkang; Xie, Binbin; Chen, Xiaona; Yang, Bing; Jin, Jiahui; Wan, Jianqin; Li, Tongyu; Han, Weidong; Shi-jiang, Fang; Wang, Hangxiang

doi:10.1016/j.biomaterials.2021.120705

Cited by 56 publications

(49 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 D). These data were in accordance with the mode of action of cisplatin and SN38, both of which cause double-strand DNA breakage during DNA synthesis and arrest cells in S and G 2 phases [ 38 , 42 ]. Hence, SN38-NP appeared to produce a specific synergistic combination with Pt (IV) -NP to impose DNA damage against cisplatin-resistant cells.…”

Section: Resultssupporting

confidence: 81%

See 1 more Smart Citation

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy

Shi

Yao

et al. 2022

Biomater Res

Self Cite

View full text Add to dashboard Cite

Background Combinatorial systemic chemotherapy is a powerful treatment paradigm against cancer, but it is fraught with problems due to the emergence of chemoresistance and additive systemic toxicity. In addition, coadministration of individual drugs suffers from uncontrollable pharmacokinetics and biodistribution, resulting in suboptimal combination synergy. Methods Toward the goal of addressing these unmet medical issues, we describe a unique strategy to integrate multiple structurally disparate drugs into a self-assembling nanococktail platform. Conjugation of a polyunsaturated fatty acid (e.g., linoleic acid) with two chemotherapies generated prodrug entities that were miscible with tunable drug ratios for aqueous self-assembly. In vitro and in vivo assays were performed to investigate the mechanism of combinatorial nanococktails in mitigating chemoresistance and the efficacy of nanotherapy. Results The coassembled nanoparticle cocktails were feasibly fabricated and further refined with an amphiphilic matrix to form a systemically injectable and PEGylated nanomedicine with minimal excipients. The drug ratio incorporated into the nanococktails was optimized and carefully examined in lung cancer cells to maximize therapeutic synergy. Mechanistically, subjugated resistance by nanococktail therapy was achieved through the altered cellular uptake pathway and compromised DNA repair via the ATM/Chk2/p53 cascade. In mice harboring cisplatin-resistant lung tumor xenografts, administration of the nanococktail outperformed free drug combinations in terms of antitumor efficacy and drug tolerability. Conclusion Overall, our study provides a facile and cost-effective approach for the generation of cytotoxic nanoparticles to synergistically treat chemoresistant cancers.

show abstract

Section: Resultssupporting

confidence: 81%

“…The camptothecin derivative SN38 exerts its cytotoxicity through the inhibition of nuclear DNA topoisomerase I (TOP1), thus leading to increased DNA double-strand breaks (DSBs) in a different mode of action [ 38 ]. Hence, we speculated that integrating SN38 into platinum nanoparticles could yield therapeutic synergy in resistant cells.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy

Shi

Yao

et al. 2022

Biomater Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…The severity of bloody diarrhea was monitored by a BASO fecal OB-II kit according to the manufacturer's protocol on days 2, 4, 6 and 7. 4,5 Organs, including the liver, heart, lung, spleen, kidney and ileum, were collected from mice on day 7 to further assess the side effects of Chol-SN38@LP in mouse organs. Blood samples (n ¼ 6 per group) were also collected at 7 days post administration to evaluate hepatorenal toxicity.…”

Section: Evaluation Of In Vivo Drug Toxicitymentioning

confidence: 99%

“…SN38 (7-ethyl-10-hydroxycamptothecin), an active metabolite of irinotecan , is a potent inhibitor of DNA topoisomerase I [1][2][3]. SN38 exhibits 100to 1000-fold higher potency than its prodrug CPT-11 against a broad spectrum of cancer in in vitro cytotoxicity tests [4,5]. In the body, only a small percentage of CPT-11 is hepatically metabolized and converted to active SN38 (2-8%) due to its low carboxyl esterase (CES) substrate affinity [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] SN38 exhibits 100-to 1000-fold higher potency than its prodrug CPT-11 against a broad spectrum of cancer in in vitro cytotoxicity tests. 4,5 In the body, only a small percentage of CPT-11 is hepatically metabolized and converted to active SN38 (2-8%) due to its low carboxyl esterase (CES) substrate affinity. 6,7 In addition, in the clinics, less than 1% of the total injected dose of CPT-11 reaches tumors because of nonspecic distribution as well as rapid metabolism and clearance.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An esterase-activatable prodrug formulated liposome strategy: potentiating the anticancer therapeutic efficacy and drug safety

Shi

et al. 2022

Nanoscale Adv.

Self Cite

View full text Add to dashboard Cite

show abstract

Enzymatically Activatable Polymers for Disease Diagnosis and Treatment

Ma,

Shi,

Zhang

et al. 2023

Advanced Materials

View full text Add to dashboard Cite

The irregular expression or activity of enzymes in the human body leads to various pathological disorders and can therefore be used as an intrinsic trigger for more precise identification of disease foci and controlled release of diagnostics and therapeutics, leading to improved diagnostic accuracy, sensitivity, and therapeutic efficacy while reducing systemic toxicity. Advanced synthesis strategies enable the preparation of polymers with enzymatically activatable skeletons or side chains, while understanding enzymatically responsive mechanisms promotes rational incorporation of activatable units and predictions of the release profile of diagnostics and therapeutics, ultimately leading to promising applications in disease diagnosis and treatment with superior biocompatibility and efficiency. By overcoming the challenges, new opportunities will emerge to inspire researchers to develop more efficient, safer, and clinically reliable enzymatically activatable polymeric carriers as well as prodrugs.

show abstract

Tuning the efficacy of esterase-activatable prodrug nanoparticles for the treatment of colorectal malignancies

Cited by 56 publications

References 48 publications

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy

An esterase-activatable prodrug formulated liposome strategy: potentiating the anticancer therapeutic efficacy and drug safety

Enzymatically Activatable Polymers for Disease Diagnosis and Treatment

Contact Info

Product

Resources

About