Nanoparticles Functionalized with Collagenase Exhibit Improved Tumor Accumulation in a Murine Xenograft Model

Abstract

Nanoparticles have garnered widespread interest for both the imaging and treatment of cancer due to their unique and tunable pharmacokinetics and their ability to carry a high payload of diverse compounds. However, despite these favorable attributes, the extent of tumor accumulation can be severely restricted due to the dense stroma surrounding the often-permeable blood vessel wall and high intratumoral pressure. In this study, we investigated whether modifying the surface of pegylated gold nanoparticles (AuNPs) with collagenase could improve the accumulation of nanoparticles within a murine tumor xenograft. It was determined that collagenase remains active after surface conjugation and the presence of collagenase has no measureable effect on cell proliferation in vitro. Following intravenous injection, the largest fractions of collagenase-labeled AuNPs were found in the liver and spleen. Histological analysis revealed no signs of toxicity in either of these organs. Blood chemistry revealed normal levels of liver enzymes, but a slightly elevated level of total bilirubin. Within the tumor, AuNPs labeled with collagenase exhibited a 35% increase in accumulation compared with unlabeled AuNPs. Therefore, these studies provide preliminary evidence that the functionalization of nanoparticles with collagenase represent an effective and safe approach to improve tumor accumulation.

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…Metals in the liver, kidney, brain, heart, and small intestine were measured using a SPECTRO ICP-OES (inductively coupled plasma optical emission spectrometry) system at the Department of Earth and Environmental Science of the School of Arts and Sciences of the University of Pennsylvania, as previously described (53). Samples were weighted, digested with 800 μl HNO 3 /HCl [3:1] at 70°C overnight, and diluted to a final volume of 2.5 ml for analysis.…”

Stromal barriers and strategies for the delivery of nanomedicine to desmoplastic tumors

“…Also, the pharmacokinetic profile of the coated NP proves important as well. Recent work by Ji et al examined these major concerns with enzyme coated NP platforms and confirmed the applicability of the design for improved NP diffusion [141]. …”

Tumor Stromal Disrupting Agent Enhances the Anticancer Efficacy of Docetaxel Loaded PEGylated Liposomes in Lung Cancer

“…A number of studies demonstrating the use of collagenase, hyaluronidase and lysyl oxidase to degrade tumor ECM, as a means to improve the delivery of various therapeutics have been published in last decade [39,40]. Collagenase labeled gold nanoparticle exhibited 35% higher tumor accumulation compared with unlabeled gold nanoparticles [17]. Also, it has been shown that liposomes injected 1 h after the collagenase injection, led to approximately 1.5-fold increase in tumor uptake.…”

“…Recently, there is a huge interest in drug or enzyme reducing the collagen density in tumor, which has the collateral effect of decreasing tumor interstitial fluid pressure (TIFP) thereby facilitating higher drug/nanocarrier penetration. Few researchers have showed enhanced uptake of antibody, virus or nanocarriers in tumor tissues by disrupting stromal barrier using bacterial collagenase, relaxin or TGF-β1 inhibitors [15][16][17]. In our previous report, we have demonstrated that inhalable telmisartan reduced collagen level in lung tumors and enhanced uptake of fluorescent polystyrene nanoparticles.…”