Gold Nanoparticle Delivery to Solid Tumors by Macrophage Depletion, Hypoxia Inhibition, and Collagen Degradation

The delivery of nanomaterials (NMs) to solid tumors remains a heavily researched topic, and while significant efforts have been aimed at optimizing NM design for active tumor targeting, it has become clear that the aberrant and heterogeneous nature of the tumor microenvironment (TME) serves as a physical barrier to NM uptake by tumor cells. In our previous work, we show that NM delivery efficacy is dependent on NM size and is linked to various TME parameters, with the levels of tumor-associated macrophages (TAMs) and hypoxia, and density of the extracellular matrix (ECM) having the largest impact. In this study, we examined the effect of modulating these three components on the delivery of 20 and 60 nm gold nanoparticles (Au NPs) to the tumor in view of various TME parameters, including tumor size, necrosis, hypoxia, ECM density, blood vessel area and maturity, as well as different cell populations within the TME. While TAM depletion led to significant improvements in tumor vasculature maturity and coverage and increased NP uptake by cancer cells, it had no significant effect on overall NP delivery efficacy, possibly due to the failure of completely removing Kupffer cells. Additionally, reduction of hypoxia using acriflavine, a potent inhibitor of HIF-1α, was expected to improve NP delivery, but the results were also not significant. However, ECM breakdown using both acriflavine and collagenase led to significant improvements in NP delivery, especially for the larger NPs, although collagenase treatment alone resulted in increased tumor cell intravasation and metastasis. This study highlights the complexity and heterogeneity of the TME and the difficulties in optimizing NP delivery to solid tumors.