Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy.

Journal Article (Journal Article)

Nanomedicine-based strategies have the potential to improve therapeutic performance of a wide range of anticancer agents. However, the successful implementation of nanoparticulate delivery systems requires the development of adequately sized nanocarriers delivering their therapeutic cargo to the target in a protected, pharmacologically active form. The present studies focused on a novel nanocarrier-based formulation strategy for SN-38, a topoisomerase I inhibitor with proven anticancer potential, whose clinical application is compromised by toxicity, poor stability and incompatibility with conventional delivery vehicles. SN-38 encapsulated in biodegradable sub-100 nm sized nanoparticles (NP) in the form of its rapidly activatable prodrug derivative with tocopherol succinate potently inhibited the growth of neuroblastoma cells in a dose- and exposure time-dependent manner, exhibiting a delayed response pattern distinct from that of free SN-38. In a xenograft model of neuroblastoma, prodrug-loaded NP caused rapid regression of established large tumors, significantly delayed tumor regrowth after treatment cessation and markedly extended animal survival. The NP formulation strategy enabled by a reversible chemical modification of the drug molecule offers a viable means for SN-38 delivery achieving sustained intratumoral drug levels and contributing to the potency and extended duration of antitumor activity, both prerequisites for effective treatment of neuroblastoma and other cancers.

Full Text

Duke Authors

Cited Authors

  • Alferiev, IS; Iyer, R; Croucher, JL; Adamo, RF; Zhang, K; Mangino, JL; Kolla, V; Fishbein, I; Brodeur, GM; Levy, RJ; Chorny, M

Published Date

  • May 2015

Published In

Volume / Issue

  • 51 /

Start / End Page

  • 22 - 29

PubMed ID

  • 25770994

Pubmed Central ID

  • PMC4361798

Electronic International Standard Serial Number (EISSN)

  • 1878-5905

International Standard Serial Number (ISSN)

  • 0142-9612

Digital Object Identifier (DOI)

  • 10.1016/j.biomaterials.2015.01.075

Language

  • eng