Histidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors

Abstract

Tumors are characterized by leaky blood vessels, and by an abnormal and heterogeneous vascular network. These pathophysiological characteristics contribute to the enhanced permeability and retention (EPR) effect, which is one of the key rationales for developing tumor-targeted drug delivery systems. Vessel abnormality and heterogeneity, however, which typically result from excessive pro-angiogenic signaling, can also hinder efficient drug delivery to and into tumors. Using histidine-rich glycoprotein (HRG) knockout and wild type mice, and HRG-overexpressing and normal t241 fibrosarcoma cells, we evaluated the effect of genetically induced and macrophage-mediated vascular normalization on the tumor accumulation and penetration of 10-20 nm-sized polymeric drug carriers based on poly(N-(2-hydroxypropyl)methacrylamide). Multimodal and multiscale optical imaging was employed to show that normalizing the tumor vasculature improves the accumulation of fluorophore-labeled polymers in tumors, and promotes their penetration out of tumor blood vessels deep into the interstitium.

Smart cancer nanomedicine

“…As an alternative to companion nanodiagnostics and nanotheranostics, clinically established (but intuitively significantly less specific) 'standard' imaging protocols could be considered to predict the accumulation and efficacy of passively targeted cancer nanomedicines, such as dynamic contrast-enhanced MRI 39 , CT 40 and ultrasound 41 . Furthermore, future analyses should set out to evaluate if histopathological assessment of tumour biopsies can help to stratify responders from non-responders.…”

Recent Advances in Tumor Targeting via EPR Effect for Cancer Treatment

“…The direct permeability enhancement by various methods has been explored that take advantage of the EPR effect and facilitate the delivery of drugs/macromolecules inside tumors. Examples include the selective inhibition of angiotensin-converting enzymes [ 86 , 87 ], generation of NO or CO within tumors [ 56 , 87 , 88 ], blockage of VEGF and other angiogenic signaling factors [ 89 , 90 , 91 ], inhibition of pericyte recruitment and BM activation [ 92 , 93 ], and image guiding systems [ 94 ].…”

Fluorescence Imaging as a Tool in Preclinical Evaluation of Polymer-Based Nano-DDS Systems Intended for Cancer Treatment

“…Thus, the FMT/CT technique in combination with targeted imaging might become a promising tool for assessments of an early therapeutic response. Recently, HPMA polymer conjugates labelled by fluorophores ATTO 488-NH 2 and Dy750-NH 2 were employed to show that normalizing the tumour vasculature improves the accumulation of polymer carriers in tumours, and promotes their penetration out of tumour blood vessels deep into the interstitium [125].…”