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.

Complex interplay between tumor microenvironment and cancer therapy

“…Inspired by the findings, recombinant human HAase PH20 was conjugated on the surface of poly (lactic-co-glycolic acid) (PLGA) NPs to modulate ECM. The study revealed that PH20 conjugated NPs treatment achieved significantly improved distribution of NPs in 4T1 breast cancer xenograft mice due to ECM degradation and increased interstitial diffusion in solid tumors [148]. Interestingly, delivery of the NPs could also increase tumor vessel density, thereby increasing drug delivery efficacy and enhancing therapeutic effects [149].…”

Smart nanoparticles improve therapy for drug-resistant tumors by overcoming pathophysiological barriers

“…However, HA that has been the systemically injected is subject to enzyme degradation while circulating and tends to induce muscle spasms and thromboembolism, as reported in clinical studies [47] . Very recently, Cheng et al demonstrated that the HA modification of drug-loaded NPs improved the efficacy of drug delivery by degrading the HA of the tumoral stroma [48] . In this study, rHuPH20 was employed to modify the surface of drugloaded poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs (PLGA-PEG-NPs).…”

Magnetic Nanoparticles for Precision Oncology: Theranostic Magnetic Iron Oxide Nanoparticles for Image-Guided and Targeted Cancer Therapy

“…At present, liposomes and polymeric nanoparticles are commonly used nanoparticle drug carriers and several of them have been approved by the US FDA for human use [9,10]. However, converting those nanoparticles into theranostic nanoparticles requires incorporation of imaging agents into the nanoparticles, such as radioactive, optical and MRI contrasts [6,[11][12][13]. Following administration, those nanoparticle drug carriers loaded with imaging agents can be broken-down in vivo and subsequently release contrast agents, resulting in different tissue distributions for the imaging contrasts and the drug carriers.…”