Junction opener protein increases nanoparticle accumulation in solid tumors

Abstract

Carcinomas contain tight junctions that can limit the penetration and therefore therapeutic efficacy of anticancer agents, especially those delivered by nano-carrier systems. The junction opener (JO) protein is a virus-derived protein that can transiently open intercellular junctions in epithelial tumors by cleaving the junction protein desmoglein-2 (DSG2). Co-administration of JO was previously shown to significantly increase the efficacy of various monoclonal antibodies and chemotherapy drugs in murine tumor models by allowing for increased intratumoral penetration of the drugs. To investigate the size-dependent effect of JO on nanocarriers, we used PEGylated gold nanoparticles (AuNPs) of two different sizes as model drugs and investigated their biodistribution following JO protein treatment. By inductively coupled plasma mass spectrometry (ICP-MS), JO was found to significantly increase bulk tumor accumulation of AuNPs of 35nm but not 120nm particles in both medium (200-300mm) and large (500-600mm) tumors. Image analysis of tumor sections corroborates this JO-mediated increase in tumor accumulation of AuNPs. Quantitative intratumoral distribution analyses show that most nanoparticles were found within 100μm of the vasculature, and that the penetration profiles of AuNPs are not significantly affected by JO treatment at the 6h timepoint.

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency

“…The approach has been proposed to improve the penetration efficiency by simultaneous targeting the tight junctions which are widely represented in solid tumors. Several protein agents targeting intercellular tight junctions has been created and demonstrated its potency in combination with various agents [302,303,304]. This approach is of particular interest when applying targeted agents specifically binding to cell surface receptors, since the latter are often hidden under cell adhesion proteins and may be unavailable for binding.…”

Desmoglein-2 as a prognostic and biomarker in ovarian cancer

“…We have previously explored this option using an engineered form of the adenovirus subtype 3 fiber knob protein (Junction Opener or "JO"), which mediates binding to the DSG2 protein, its cleavage/ downregulation, and transient opening of epithelial junctions. 7,10,[20][21][22][23][24] In the context of ovarian cancer, several studies have found preliminary evidence of DSG2 overexpression. A proteome analysis of ovarian cancer ascites found DSG2 upregulated and suggested it as a potential biomarker for ovarian cancer.…”

Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration

“…[ 40 ] Coincidentally, virus‐derived junction opener protein also possesses the function of opening intercellular junctions transiently in epithelial tumors by cleaving junction protein desmoglein‐2, which can also be used in surface modification for tumor penetration. [ 41 ]…”