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.
J Exp Clin Cancer Res. 2021 Sep 10;40(1):286. doi: 10.1186/s13046-021-02070-x.
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.
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.
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.
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.
实体瘤中药物渗透不足是化疗疗效有限的原因之一，这与肿瘤微环境的改变有关。异常的肿瘤细胞外基质（ECM），以及异常的血管和淋巴管、反应性基质和炎症，都会影响抗癌药物的摄取、分布和疗效。
我们研究了聚乙二醇化重组人透明质酸酶 PH20（PEGPH20）预处理降解透明质酸（HA），即 ECM 的主要成分之一，以改善抗肿瘤药物的递送并提高其治疗效果。通过监测有无 PEGPH20 预处理的情况下肿瘤生长，评估紫杉醇（PTX）在透明质酸合酶 3 过表达和野生型 SKOV3 卵巢癌模型以及 BxPC3 胰腺异种移植肿瘤模型中的抗肿瘤活性。通过高效液相色谱法和质谱成像分析在相同的肿瘤模型中评估 PTX 的药代动力学和肿瘤渗透。通过组织化学分析评估肿瘤组织形态和 HA 沉积。
PEGPH20 预处理改变了肿瘤组织形态，提高了 SKOV3/HAS3 肿瘤模型中紫杉醇的抗肿瘤活性，促进了其积累和更均匀的肿瘤内分布，通过定量和定性分析进行评估。PEGPH20 还降低了 HA 含量，尽管程度较轻，但影响了 PTX 在 BxPC3 肿瘤模型中的分布和抗肿瘤活性。
用 PEGPH20 预处理耗尽富含 HA 的肿瘤中的 HA，重塑基质，是一种提高抗癌药物在肿瘤内分布、提高疗效而不增加毒性的潜在有效策略。
