nn8b07954_si_001.pdf (20.03 MB)
Modular Nanoparticulate Prodrug Design Enables Efficient Treatment of Solid Tumors Using Bioorthogonal Activation
journal contribution
posted on 2018-12-14, 15:47 authored by Miles A. Miller, Hannes Mikula, Gaurav Luthria, Ran Li, Stefan Kronister, Mark Prytyskach, Rainer H. Kohler, Timothy Mitchison, Ralph WeisslederProdrug strategies
that facilitate localized and controlled activity
of small-molecule therapeutics can reduce systemic exposure and improve
pharmacokinetics, yet limitations in activation chemistry have made
it difficult to assign tunable multifunctionality to prodrugs. Here,
we present the design and application of a modular small-molecule
caging strategy that couples bioorthogonal cleavage with a self-immolative
linker and an aliphatic anchor. This strategy leverages recently discovered in vivo catalysis by a nanoencapsulated palladium compound
(Pd-NP), which mediates alloxylcarbamate cleavage and triggers release
of the activated drug. The aliphatic anchor enables >90% nanoencapsulation
efficiency of the prodrug, while also allowing >104-fold
increased cytotoxicity upon prodrug activation. We apply the strategy
to a prodrug formulation of monomethyl auristatin E (MMAE), demonstrating
its ability to target microtubules and kill cancer cells only after
selective activation by Pd-NP. Computational pharmacokinetic modeling
provides a mechanistic basis for the observation that the nanotherapeutic
prodrug strategy can lead to more selective activation in the tumor,
yet in a manner that is more sensitive to variable enhanced permeability
and retention (EPR) effects. Combination treatment with the nanoencapsulated
MMAE prodrug and Pd-NP safely blocks tumor growth, especially when
combined with a local radiation therapy regimen that is known to improve
EPR effects, and represents a conceptual step forward in prodrug design.
History
Usage metrics
Categories
Keywords
EPRPd-NPactivationmonomethyl auristatin Emediates alloxylcarbamate cleavageblocks tumor growthaliphatic anchorComputational pharmacokinetic modelingModular Nanoparticulate Prodrug Design Enables Efficient Treatmentcouples bioorthogonal cleavagenanotherapeutic prodrug strategynanoencapsulated MMAE prodrugBioorthogonal Activation Prodrug strategiesradiation therapy regimennanoencapsulated palladium compoundsmall-molecule caging strategy
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC