Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
Prostate Cancer Prostatic Dis. 2020 Jun;23(2):324-332. doi: 10.1038/s41391-019-0190-x. Epub 2019 Nov 25.
Focal therapy has emerged as a treatment option for low- to intermediate-risk localized prostate cancer (PCa) patients, to balance the risks for urinary and sexual morbidity of radical treatment with the psychological burden of active surveillance. In this context, we developed ST-4PC, an injectable, polymeric paste formulation containing docetaxel (dtx) and bicalutamide (bic) for image-guided focal therapy of PCa. The objective of this work was to evaluate the in vitro characteristics and in vivo toxicity and efficacy of ST-4PC.
In vitro drug release was evaluated using high-performance liquid chromatography. In vivo toxicity of blank- and drug-loaded ST-4PC was assessed in mice and rats. Tumor growth inhibition was evaluated in LNCaP subcutaneous (s.c.) and LNCaP-luc orthotopic xenograft models. Using the s.c. model, mice were monitored weekly for weight loss, tumor volume (TV) and serum PSA. For the orthotopic model, mice were additionally monitored for bioluminescence as measure of tumor growth.
ST-4PC demonstrated a sustained and steady release of incorporated drugs with 50% dtx and 20% bic being released after 14 days. While no systemic toxicity was observed, dose-dependent local side effects from dtx developed in the s.c. but not in the orthotopic model, illustrating the limitations of s.c. models for evaluating local cytotoxic therapy. In the s.c. model, 0.1%/4% and 0.25%/4% dtx/bic ST-4PC paste significantly reduced PSA progression, but did not have a significant inhibitory effect on TV. ST-4PC loaded with 1%/4% dtx/bic significantly reduced TV, serum PSA, and bioluminescence in the orthotopic xenograft model. Compared with drugs dissolved in DMSO, ST-4PC significantly delayed tumor growth.
Image-guided focal therapy using ST-4PC demonstrated promising inhibition of PSA progression and orthotopic tumor growth in vivo without significant toxicity, and warrants further clinical evaluation.
局部治疗已成为中低危局限性前列腺癌（PCa）患者的一种治疗选择，以平衡根治性治疗的尿和性功能障碍风险与主动监测的心理负担。在这种情况下，我们开发了 ST-4PC，一种可注射的聚合物糊剂，含有多西他赛（dtx）和比卡鲁胺（bic），用于 PCa 的图像引导聚焦治疗。本工作的目的是评估 ST-4PC 的体外特性和体内毒性和疗效。
采用高效液相色谱法评价药物体外释放情况。评估空白和载药 ST-4PC 在小鼠和大鼠体内的毒性。在 LNCaP 皮下（s.c.）和 LNCaP-luc 原位异种移植模型中评估肿瘤生长抑制作用。使用 s.c.模型，每周监测小鼠体重减轻、肿瘤体积（TV）和血清 PSA。对于原位模型，还监测小鼠的生物发光作为肿瘤生长的指标。
ST-4PC 表现出持续稳定的药物释放，14 天后释放 50%的 dtx 和 20%的 bic。虽然没有观察到系统毒性，但在 s.c.模型中观察到与 dtx 相关的剂量依赖性局部副作用，而在原位模型中没有观察到，这表明 s.c.模型在评估局部细胞毒性治疗方面存在局限性。在 s.c.模型中，0.1%/4%和 0.25%/4%的 dtx/bic ST-4PC 糊剂显著降低了 PSA 进展，但对 TV 没有显著抑制作用。载有 1%/4%的 dtx/bic 的 ST-4PC 显著降低了原位异种移植模型中的 TV、血清 PSA 和生物发光。与溶解在 DMSO 中的药物相比，ST-4PC 显著延迟了肿瘤生长。
使用 ST-4PC 的图像引导聚焦治疗在体内显示出有希望的 PSA 进展抑制和原位肿瘤生长抑制作用，且无明显毒性，值得进一步临床评估。
