title: Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy.
abstract: 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.
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Junjie
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Pelin K
authors.initials: PK
authors.lastname: Lemons
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Dimitrios C
authors.initials: DC
authors.lastname: Arhontoulis
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Wilbur B
authors.initials: WB
authors.lastname: Bowne
authors.affiliation: Department of Materials Science and Engineering, and ‡School of Biomedical Engineering, Science and Health Systems, Drexel University , Philadelphia, Pennsylvania 19104, United States.|Department of Surgery, Drexel University , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000737:chemistry*; D064596:Isografts; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011091:Polyesters; D011994:Recombinant Proteins; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; D004317:Doxorubicin; D006821:Hyaluronoglucosaminidase
keywords: Extracellular matrix; appoptosis; drug release; heterogeneous; hyaluronan