Nanotechnology-enabled delivery of NQO1 bioactivatable drugs.

Abstract

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 on

NAD(P)H:

quinone 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.

• Authors: Xinpeng Ma, Zachary R Moore, Gang Huang, Xiumei Huang, David A Boothman, Jinming Gao
• Journal: Journal of drug targeting (J Drug Target) Vol. 23 Issue 7-8 Pg. 672-80 ( 2015) ISSN: 1029-2330 [Electronic] England
• PMID: 26453163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Naphthoquinones
• Prodrugs
• beta-lapachone
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Drug Delivery Systems
• Drug Design
• Humans
• Maximum Tolerated Dose
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• Nanoparticles
• Nanotechnology
• Naphthoquinones (administration & dosage, chemistry, pharmacology)
• Neoplasms (drug therapy, enzymology, pathology)
• Prodrugs (administration & dosage, chemistry, pharmacology)