Nanotechnology-enabled delivery of NQO1 bioactivatable drugs
| Autor: | Xiumei Huang, David A. Boothman, Xinpeng Ma, Zachary R. Moore, Gang Huang, Jinming Gao |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Cancer chemotherapy
Maximum Tolerated Dose Pharmaceutical Science Nanotechnology Antineoplastic Agents Pharmacology Drug Delivery Systems Neoplasms medicine NAD(P)H Dehydrogenase (Quinone) Animals Humans Prodrugs Chemistry digestive oral and skin physiology Prodrug Mechanism of action Maximum tolerated dose Drug Design Drug delivery Systemic administration Nanoparticles NAD+ kinase medicine.symptom Naphthoquinones |
| Zdroj: | Journal of drug targeting. 23(7-8) |
| ISSN: | 1029-2330 |
| Popis: | Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. β-Lapachone (β-lap) is a novel anticancer agent whose mechanism of action is highly dependent onquinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of β-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of β-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of β-lap further decreases the crystallization of β-lap by introducing esterase degradable side chains to the rigid fused ring structure. β-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of β-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints. |
| Databáze: | OpenAIRE |
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