Preclinical to clinical development of the novel camptothecin nanopharmaceutical CRLX101
| Autor: | Scott Eliasof, Sonke Svenson, John L. Ryan, Marc Wolfgang, Jungyeon Hwang |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Drug Evaluation
Preclinical Pharmaceutical Science Pharmacology Polymeric nanoparticle Polyethylene Glycols Mice Pharmacokinetics In vivo Cell Line Tumor Neoplasms Camptotheca medicine Animals Humans heterocyclic compounds neoplasms Clinical Trials as Topic Cyclodextrins Chemistry Antineoplastic Agents Phytogenic Irinotecan Solubility CRLX101 Pharmacodynamics Drug delivery Nanoparticles Camptothecin Drug carrier Nanopharmaceutical medicine.drug |
| Zdroj: | Journal of controlled release : official journal of the Controlled Release Society. 153(1) |
| ISSN: | 1873-4995 |
| Popis: | Camptothecin (CPT) is a potent broad-spectrum anticancer agent that acts through inhibition of topoisomerase 1. Clinical development of CPT was unsuccessful due to poor drug solubility, insufficient in vivo stability of the active form, and toxicity. In order to address these issues, a polymeric nanoparticle comprised of cyclodextrin-poly(ethylene glycol) copolymer (CDP) conjugated to CPT (CRLX101) has been developed and Phase 2 clinical studies are ongoing. Camptothecin is conjugated to the polymer in its active form at 10–12wt.% loading. CRLX101 self-assembles in solution into nanoparticles with an apparent solubility increase of >1000-fold as compared to the parent drug camptothecin. Preclinical studies exhibited CRLX101 pharmacokinetics superior to the parent drug. Drug concentration in tumor relative to plasma and other major organs is consistent with the enhanced permeation and retention (EPR) anticipated from a nanoparticle. Significant anti-tumor activity was observed that is superior when compared to irinotecan across a broad range of xenograft models. Pharmacokinetic data are consistent with the prolonged half-life and increased AUC. The CRLX101 preclinical and clinical data confirm that CDP can address not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of CPT, but more importantly, can impart unique biological properties, that enhance pharmacodynamics and efficacy of camptothecin. |
| Databáze: | OpenAIRE |
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