Tuesday, April 12, 2016

PLGA-PEG-Maleimide from PolySciTech used as part of developing hyaluronidase conjugated particle for enhanced tumor penetration and chemotherapy

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of polymers such as PLGA-PEG-Maleimide (PolyVivo AI020). The Maleimide cap on these polymers possesses the capability of conjugating to any thiol-bearing molecule in aqueous solution at near neutral pH with no heating by a simple Michaels-type addition. This process allows for generating nanoparticles which express a desired ligand or targeting moiety on their surface. Recently, researchers at Drexel University utilized PLGA-PEG-Maleimide from PolySciTech for developing a nanoparticle which had recombinant human hyaluronidase PH20 (rHuPH20) labelled on the surface. They found that this conjugation lead to four-times the accumulation of nanoparticles inside a 4T1 syngenic tumor model (advanced breast cancer model) as compared to unlabeled PEG-PLGA nanoparticles. This also led to enhanced performance of model chemotherapeutic doxorubicin against these tumor cells when it was encapsulated in the labeled nanoparticles as compared to conventional delivery of loose drug. Read more: Zhou, Hao, Zhiyuan Fan, Junjie Deng, Pelin K. Lemons, Dimitrios C. Arhontoulis, Wilbur B. Bowne, and Hao Cheng. "Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy." Nano Letters (2016). http://pubs.acs.org/doi/abs/10.1021/acs.nanolett.6b00820

“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 systematic 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. Keywords: Extracellular matrix; hyaluronan; appoptosis; heterogeneous; drug release”

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