Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

Abstract

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.

Tailoring Materials for Modulation of Macrophage Fate

“…To overcome this barrier, Mitragotri and co‐workers recently developed a generalized strategy by adopting macrophages as active drug carriers to heighten the prodrug penetration and accumulation deep into the solid tumors. [ 291 ] Macrophages were able to phagocytose and internalize at large amounts the PLGA NPs loading tirapazamine prodrug. By infiltrating the hypoxic regions in the solid tumors, the tirapazamine prodrug could contribute to a potent tumoricidal effect.…”

Strategies to Overcome the Barrier of Ischemic Microenvironment in Cell Therapy of Cardiovascular Disease

“…A macrophage-mediated delivery of hypoxia-activated prodrug nanoparticles was introduced in cancer related therapy, but might be open for a wide range of different indications, especially in cardiovascular remodeling [ 47 , 50 ]. The here described mechanism of action, so called “trojan horse strategy” in cell therapy, include nanoparticle loading of macrophages and the chemotactic and phagocytic abilities of the monocyte/macrophage axis to penetrate regions of hypoxia for remodeling processes [ 50 ]. In this context, the chemokine (C–C motif) ligand 26 (CCL 26) has been investigated for hypoxia-directed migration of mononuclear cells.…”

Targeted and Non-Targeted Mechanisms for Killing Hypoxic Tumour Cells—Are There New Avenues for Treatment?

“…Recent studies have focused on overcoming the drawbacks of HAPs using nanotechnology and cellular manipulation to develop mechanisms for macrophage-mediated drug delivery of HAPs. Particularly, Evans and colleagues [126] have demonstrated the potential use of macrophages through in vitro and in vivo analyses. Through both experiments, a hydrophobic derivative of TPZ encapsulated within poly(lactic-co-glycolic) acid (PLGA) nanoparticles are contained within a macrophage and are collectively referred to as MAC-TPZ [126].…”

“…Particularly, Evans and colleagues [126] have demonstrated the potential use of macrophages through in vitro and in vivo analyses. Through both experiments, a hydrophobic derivative of TPZ encapsulated within poly(lactic-co-glycolic) acid (PLGA) nanoparticles are contained within a macrophage and are collectively referred to as MAC-TPZ [126]. Prior to conducting in vivo analyses, Evans and colleagues [126] orchestrated multiple in vitro assays to confirm the ability of macrophages to uptake TPZ.…”

“…Through both experiments, a hydrophobic derivative of TPZ encapsulated within poly(lactic-co-glycolic) acid (PLGA) nanoparticles are contained within a macrophage and are collectively referred to as MAC-TPZ [126]. Prior to conducting in vivo analyses, Evans and colleagues [126] orchestrated multiple in vitro assays to confirm the ability of macrophages to uptake TPZ. Furthermore, in vitro analyses allowed for comparing different combination lengths of carbon chains attached to TPZ in order to determine effects on nanoparticle properties, toxicity, and overall efficacy on treatment outcomes [126].…”