Journal
ACS NANO
Volume 5, Issue 5, Pages 3961-3969Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn200478m
Keywords
polymer; liposome; drug delivery; pH-sensitive release; molecular modeling; arsenic trioxide
Categories
Funding
- NIH (NCI Center of Cancer Nanotechnology Excellence) [U54CA119341, 4, U54CA151880, U01CA151461, P30CA050553]
- NSF-NSEC
- NSF-MRSEC
- Keck Foundation
- state of Illinois, NASA
- Northwestern University
- NSF [CHE-0843823]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0843832] Funding Source: National Science Foundation
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Nanoscale drug delivery platforms can provide an attractive therapeutic strategy for cancer treatments, as they can substantially reduce the adverse side effects associated with toxic small-molecule anticancer agents. For enhanced therapeutic efficacy to be achieved with such platforms, a tumor-specific drug-release trigger is a critical requirement. This article reports the use of a pH-sensitive polymer network that surrounds a nanoscale liposome core to trigger the release of both encapsulated hydrophilic, membrane-impermeable Ni-II cations and amphipathic, membrane-permeable As-III anticancer agents under acidic conditions commonly encountered in hypoxic tumor tissues and late endosomes. Computational modeling studies provide clear evidence that the acid-triggered drug-release mechanism for this polymer-caged nanobin (PCN) platform arises from a pH- and temperature-responsive conformation change of the cross-linked polymer cage. As a result, the simultaneous release of both of the active agents in this multicomponent therapeutic enhances the pro-apoptotic activity of As-III while diminishing its acute toxicity, potentially reducing the undesirable side effects commonly associated with this free drug. The ability to engender acid-triggered release of drugs co-encapsulated inside a liposomal template makes drug delivery using PCN an attractive strategy for triggered drug release.
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