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Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy
Journal article   Peer reviewed

Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy

Hao Zhou, Zhiyuan Fan, Junjie Deng, Pelin K Lemons, Dimitrios C Arhontoulis, Wilbur B Bowne and Hao Cheng
Nano letters, v 16(5), pp 3268-3277
11 May 2016
DOI: https://doi.org/10.1021/acs.nanolett.6b00820
PMID: 27057591
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects Cell Line, Tumor Cell Survival - drug effects Dose-Response Relationship, Drug Doxorubicin - chemistry Doxorubicin - pharmacology Doxorubicin - therapeutic use Drug Carriers - chemistry Drug Liberation Extracellular Matrix - metabolism Female Humans Hyaluronoglucosaminidase - chemistry Isografts Mammary Neoplasms, Animal - drug therapy Mice, Inbred BALB C Nanoparticles - chemistry Particle Size Polyesters - chemistry Polyethylene Glycols - chemistry Recombinant Proteins - chemistry Tissue Distribution
One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood.

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265 citations in Web of Science
266 citations in Scopus

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Web of Science research areas
Chemistry, Multidisciplinary
Chemistry, Physical
Materials Science, Multidisciplinary
Nanoscience & Nanotechnology
Physics, Applied
Physics, Condensed Matter
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