Tumor associated macrophages (TAMs) are widely implicated in cancer progression, and TAM levels can influence drug responses, particularly to immunotherapy and nanomedicines. However, it has been difficult to quantify total TAM numbers and their dynamic spatiotemporal distribution in a non-invasive and translationally relevant manner. Here, we address this need by developing a pharmacokinetically optimized, 64Cu-labeled polyglucose nanoparticle (Macrin) for quantitative positron emission tomography (PET) imaging of macrophages in tumors. By combining PET with high resolution in vivo confocal microscopy and ex vivo imaging of optically cleared tissue, we found that Macrin was taken up by macrophages with >90% selectivity. Uptake correlated with the content of macrophages in both healthy tissue and tumors (R2 > 0.9), and showed striking heterogeneity in the TAM content of an orthotopic and immunocompetent mouse model of lung carcinoma. In a proof-of-principle application, we imaged Macrin to monitor the macrophage response to neo-adjuvant therapy, using a panel of chemotherapeutic and γ-irradiation regimens. Multiple treatments elicited 180–650% increase in TAMs. Imaging identified especially TAM-rich tumors thought to exhibit enhanced permeability and retention of nanotherapeutics. Indeed, these TAM-rich tumors accumulated >700% higher amounts of a model poly(D,L-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) therapeutic nanoparticle compared to TAM-deficient tumors, suggesting that imaging may guide patient selection into nanomedicine trials. In an orthotopic breast cancer model, chemoradiation enhanced TAM and Macrin accumulation in tumors, which corresponded to the improved delivery and efficacy of two model nanotherapies, PEGylated liposomal doxorubicin and a TAM-targeted nanoformulation of the toll-like receptor 7/8 agonist resiquimod (R848). Thus, Macrin imaging offers a selective and translational means to quantify TAMs and inform therapeutic decisions.
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.
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