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Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2021 | Research

PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models

Authors: Lavinia Morosi, Marina Meroni, Paolo Ubezio, Ilaria Fuso Nerini, Lucia Minoli, Luca Porcu, Nicolò Panini, Marika Colombo, Barbara Blouw, David W. Kang, Enrico Davoli, Massimo Zucchetti, Maurizio D’Incalci, Roberta Frapolli

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs.

Methods

We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry.

Results

Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model.

Conclusion

Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.

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Title: PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models
Authors: Lavinia Morosi
Marina Meroni
Paolo Ubezio
Ilaria Fuso Nerini
Lucia Minoli
Luca Porcu
Nicolò Panini
Marika Colombo
Barbara Blouw
David W. Kang
Enrico Davoli
Massimo Zucchetti
Maurizio D’Incalci
Roberta Frapolli
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02070-x

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Abstract

Background

Methods

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Conclusion

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