Synthesis and Evaluation of Camptothecin Antibody–Drug Conjugates

Li, Wei; Veale, Karen; Qiu, Qinghua; Sinkevicius, Kerstin W.; Maloney, Erin K.; Costoplus, Juliet A.; Lau, Justin Kai-Chi; Evans, Helen L.; Setiady, Yulius Y.; Ab, Olga; Abbott, Stephen M.; Lee, Jenny; Wisitpitthaya, Somsinee; Skaletskaya, Anna; Wang, Lintao; Keating, Thomas A.; Chari, Ravi; Widdison, Wayne C.

doi:10.1021/acsmedchemlett.9b00301

Cited by 23 publications

(14 citation statements)

References 28 publications

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“…Latest researches focused on less cytotoxic drugs, with a lower IC50, but whose activity could have been enhanced exploiting different strategies such as an increased DAR or the bystander effect. Among them, the most promising new class of payload is represented by camptothecins, a well-known class of anticancer agents targeting topoisomerase I (TOP1) [ 13 ]. Sacituzumab govitecan is a recently approved ADC conjugating an anti-Trop2 antibody with SN-38, the active metabolite of irinotecan.…”

Section: Introductionmentioning

confidence: 99%

Antibody–drug conjugates in solid tumors: a look into novel targets

2021

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Antibody–drug conjugates (ADCs) are a relatively new class of anticancer agents designed to merge the selectivity of monoclonal antibodies with cell killing properties of chemotherapy. They are commonly described as the “Trojan Horses” of therapeutic armamentarium, because of their capability of directly conveying cytotoxic drug (payloads) into the tumor space, thus transforming chemotherapy into a targeted agent. Three novel ADCs have been recently approved, i.e., trastuzumab deruxtecan, sacituzumab govitecan and enfortumab vedotin, respectively, targeting HER2, Trop2 and Nectin4. Thanks to progressive advances in engineering technologies these drugs rely on, the spectrum of diseases sensitive to these drugs as well as their indications are in continuous expansion. Several novel ADCs are under evaluation, exploring new potential targets along with innovative payloads. This review aims at providing a summary of the technology behind these compounds and at presenting the latest ADCs approved in solid tumors, as well as at describing novel targets for ADCs under investigation and new strategies to optimize their efficacy in solid tumors.

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Section: Introductionmentioning

confidence: 99%

Antibody–drug conjugates in solid tumors: a look into novel targets

2021

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“…However, phase II studies and phase III studies do not show ideal antitumor effects due to the ineffective delivery of drugs to tumor tissues . For the past two years, DS-8201a, an antibody drug conjugate (ADC), using Exatecan derivatives Dxd as effector molecules, has been on the market, resulting in drug delivery systems of Exatecan and its derivatives receiving a lot of attention. − …”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Activated Albumin-Binding Exatecan Prodrug for Cancer Therapy

et al. 2021

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As an effective drug delivery strategy for traditional antitumor drugs, the stimulus-responsive albumin-based prodrugs are getting more and more attention. These prodrugs only release drugs in specific tumor microenvironments, which can prevent premature release of the drug in the circulation. Tumor hypoxia is a fundamental feature of the solid tumor microenvironment. As a hypoxia-activated linker, the 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole can be a trigger for albumin-based prodrugs. In this study, we report the synthesis and biological evaluation of the hypoxia-activated albumin-binding prodrug Mal-azo-Exatecan . After intravenous administration, the maleimide on the side chain can rapidly bind to endogenous albumin, enabling the prodrugs to accumulate in tumors, where tumor-associated hypoxia microenvironments trigger the selective release of Exatecan . The 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole as a cleavable linker has high plasma stability and does not cause Exatecan release from HSA-azo-Exatecan during circulation in vivo , avoiding systemic side effects caused by Exatecan .

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“…However, because of the low solubility of this molecule in water and most organic solvents and the active carboxylic acid derivatives produced by the cleavage of the lactone ring can cause hemorrhagic cystitis and muscle toxicity. Therefore, highly stable and biocompatible nanocarriers are very important for the delivery and release of CPT. − HNU-43 takes the advantage of high porosity, but which is unstable in water. In contrast, HNU-43(T) obtained by the drying process shows very good water stability, and traces of Zn 2+ and organic ligands are very harmless or even harmless to the human body.…”

Section: Resultsmentioning

confidence: 99%

Single-Crystal to Single-Crystal Transformation of Metal–Organic Framework Nanoparticles for Encapsulation and pH-Stimulated Release of Camptothecin

Yang

Ren

Yang

et al. 2021

ACS Appl. Nano Mater.

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The phenomenon of single-crystal to single-crystal transformation and the performance change along with the transformation have been widely discovered, whereas the efficient utilization of the crystal transformation process is less reported. Herein, we present an interesting thermally driven single-crystal to single-crystal transformation of HNU-43. During transformation, the effective encapsulation of camptothecin (CPT) has been achieved as CPT-HNU-43 converts into CPT-HNU-43(T), which cannot directly encapsulate CPT owing to the small channel size of HNU-43(T). Following the successful packaging, the CPT can be triggered to gradually release as pH = 6.0 which is quite close to the acid environment of cancer cells. Furthermore, CPT-HNU-43(T) nanoparticles show excellent biocompatibility, and the cancer cells can be effectively inhibited through the release of CPT.

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Synthesis and Evaluation of Camptothecin Antibody–Drug Conjugates

Cited by 23 publications

References 28 publications

Antibody–drug conjugates in solid tumors: a look into novel targets

Antibody–drug conjugates in solid tumors: a look into novel targets

Hypoxia-Activated Albumin-Binding Exatecan Prodrug for Cancer Therapy

Single-Crystal to Single-Crystal Transformation of Metal–Organic Framework Nanoparticles for Encapsulation and pH-Stimulated Release of Camptothecin

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