Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

Modular Nanoparticulate Prodrug Design Enables Efficient Treatment of Solid Tumors Using Bioorthogonal Activation.

Prodrug 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.