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

Journal of Experimental & Clinical Cancer Research

Barbara Blouw¹  Lucia Minoli²  David W. Kang³  Marina Meroni⁴  Luca Porcu⁴  Massimo Zucchetti⁴  Nicolò Panini⁴  Paolo Ubezio⁴  Marika Colombo⁴  Roberta Frapolli⁴  Ilaria Fuso Nerini⁵  Lavinia Morosi⁵  Maurizio D’Incalci⁶  Enrico Davoli⁷ 

[1] Biocept, San Diego, California, USA;Department of Veterinary Medicine, University of Milan, Lodi, Italy;Mouse and Animal Pathology Laboratory (MAPLab), Fondazione UniMi, Milan, Italy;Halozyme Therapeutics, San Diego, California, USA;Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, via M. Negri 2, 20156, Milan, Italy;Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, via M. Negri 2, 20156, Milan, Italy;Present address: IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy;Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology, via M. Negri 2, 20156, Milan, Italy;Present address: IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy;Present address: Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy;Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Laboratory of Mass Spectrometry, Milan, Italy;

关键词: Mass spectrometry imaging;    Drug distribution;    Extracellular matrix;    Hyaluronan;    Solid tumours;   

DOI  :  10.1186/s13046-021-02070-x

来源: Springer

【 摘 要 】

BackgroundScarce 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.MethodsWe 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.ResultsPre-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.ConclusionRemodelling 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.

【 授权许可】

CC BY