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Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles
Author(s) -
Evans Michael A.,
Shields C. Wyatt,
Krishnan Vinu,
Wang Lily LiWen,
Zhao Zhongmin,
Ukidve Anvay,
Lewandowski Michael,
Gao Yongsheng,
Mitragotri Samir
Publication year - 2020
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.201900162
Subject(s) - tirapazamine , prodrug , hypoxia (environmental) , in vivo , drug delivery , in vitro , tumor hypoxia , penetration (warfare) , chemistry , cancer research , drug , pharmacology , cytotoxicity , medicine , biology , biochemistry , radiation therapy , microbiology and biotechnology , organic chemistry , operations research , oxygen , engineering
Hypoxia‐activated prodrugs (HAPs) have tremendous clinical potential due to their selective toxicity toward poorly oxygenated tissues, which is a hallmark of solid tumors. Despite their promising results in vitro, HAPs have failed to make a clinical impact. This is largely because tumor hypoxia is located far from blood vessels, making it difficult for HAPs to accumulate in therapeutically sufficient concentrations. Here, a generalized strategy to overcome this barrier by employing macrophages as drug carriers to enhance the penetration and accumulation of HAPs deep in solid tumors is reported. The system leverages the chemotactic and phagocytic abilities of macrophages to improve delivery of nanoparticles encapsulating a model HAP, tirapazamine (TPZ), to the hypoxic regions of solid tumors. A sequence of in vitro assays is used to refine the properties of the system by minimizing carrier cell toxicity while maximizing therapeutic efficacy. It is demonstrated in vivo that the system improves drug accumulation in hypoxic areas of 4T1 breast tumors and slows their growth by itself and in combination with irinotecan. The results provide early evidence that macrophages can significantly improve the transport and efficacy of HAPs by improving their tumor penetration, highlighting a potential strategy to advance them into the clinic.