Abstract
Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.
Highlights
Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding
TNPs of Pt-based anticancer agents have advanced to clinical trials[13,14], results have been mixed, presumably due to heterogeneous enhanced permeability and retention (EPR) effects in different tumours combined with limited experimental data from patients on the effectiveness of this mechanism as related to enhanced drug accumulation[15]
DNA damage (Supplementary Fig. 3), thereby validating the use of fluorescence as a surrogate marker of cellular payload content. These results provide evidence that, over the course of 24 h, TNPs accumulate in endosomes and lysosomal compartments, where the Pt pro-drug is activated through reduction to form cisplatin
Summary
Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Pt-related toxic side-effects including neurotoxicity and nephrotoxicity limit some of these approaches, indicating the need for new strategies To circumvent these problems, specialized drug-delivery mechanisms such as nanoparticles (NPs) have been introduced to enhance local drug accumulation in tumours while simultaneously mitigating systemic toxicities[4,5]. TNPs of Pt-based anticancer agents have advanced to clinical trials[13,14], results have been mixed, presumably due to heterogeneous EPR effects in different tumours combined with limited experimental data from patients on the effectiveness of this mechanism as related to enhanced drug accumulation[15]. Little experimental evidence exists that describes how this multi-step drug delivery sequence performs in vivo and within tumours, despite its critical importance to overall therapeutic outcome This lack of understanding clearly represents a bottleneck in the design and development of more efficacious therapies. This work establishes a paradigm for NP drug delivery based on the principle that TAMs can sequester TNP payload and gradually release it into the surrounding tissue, thereby serving as ‘drug depots.’
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