Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, Chapel Hill, NC 27599, USA.
Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Acta Biomater. 2022 Aug;148:163-170. doi: 10.1016/j.actbio.2022.06.023. Epub 2022 Jun 17.
Brachytherapy, which is the placement of radioactive seeds directly into tissue such as the prostate, is an important curative treatment for prostate cancer. By delivering a high dose of radiation from within the prostate gland, brachytherapy is an effective method of killing prostate cancer cells while limiting radiation dose to normal tissue. The main shortcomings of this treatment are: less efficacy against high grade tumor cells, acute urinary retention, and sub-acute urinary frequency and urgency. One strategy to improve brachytherapy is to incorporate therapeutics into brachytherapy. Drugs, such as docetaxel, can improve therapeutic efficacy, and dexamethasone is known to decrease urinary side effects. However, both therapeutics have high systemic side effects. To overcome this challenge, we hypothesized that we can incorporate therapeutics into the inert polymer spacers that are used to correctly space brachytherapy seeds during brachytherapy to enable local drug delivery. To accomplish this, we engineered 3D printed drug-loaded brachytherapy spacers using continuous liquid interface production (CLIP) with different surface patterns to control drug release. These devices have the same physical size as existing spacers, allowing them to easily replace commercial spacers. We examined these drug-loaded spacers using docetaxel and dexamethasone as model drugs in a murine model of prostate cancer. We found that drug-loaded spacers led to higher therapeutic efficacy for brachytherapy, and there was no discernable systemic toxicity from the drug-loaded spacers. STATEMENT OF SIGNIFICANCE: There has been high interest in the application of 3D printing to engineer novel medical devices. However, such efforts have been limited by the lack of technologies that can fabricate devices suitable for real world medical applications. In this study, we demonstrate a unique application for 3D printing to enhance brachytherapy for cancer treatment. We engineered drug-loaded brachytherapy spacers that can be fabricated using Continuous Liquid Interface Production (CLIP) 3D printing, allowing tunable printing of drug-loaded devices, and implanted intraoperatively with brachytherapy seeds. In combined chemotherapy and brachytherapy we are able to achieve greater therapeutic efficacy through local drug delivery and without systemic toxicities. We believe our work will facilitate further investigation in medical applications of 3D printing.
近距离放射治疗是将放射性粒子直接植入组织（如前列腺）的一种重要治疗方法，可有效治疗前列腺癌。通过在前列腺内提供高剂量的辐射，近距离放射治疗是一种有效杀死前列腺癌细胞的方法，同时限制对正常组织的辐射剂量。这种治疗方法的主要缺点是：对高级别肿瘤细胞的疗效较低，急性尿潴留，以及亚急性尿频和尿急。提高近距离放射治疗疗效的一种策略是将治疗药物纳入近距离放射治疗。药物，如多西他赛，可以提高治疗效果，而地塞米松已知可以减少尿路副作用。然而，这两种治疗药物都有很高的全身副作用。为了克服这一挑战，我们假设可以将治疗药物纳入在近距离放射治疗中用于正确间隔放射性粒子的惰性聚合物间隔物中，以实现局部药物输送。为此，我们使用连续液体界面生产（CLIP）技术设计了 3D 打印载药近距离放射治疗间隔物，该技术具有不同的表面图案，可控制药物释放。这些装置与现有的间隔物具有相同的物理尺寸，因此可以轻松替代商业间隔物。我们在前列腺癌的小鼠模型中使用多西他赛和地塞米松作为模型药物对这些载药间隔物进行了研究。我们发现，载药间隔物可提高近距离放射治疗的疗效，且载药间隔物没有明显的全身毒性。意义声明：将 3D 打印应用于工程新型医疗设备的应用引起了广泛关注。然而，由于缺乏能够制造适用于实际医疗应用的技术，此类努力受到了限制。在这项研究中，我们展示了 3D 打印在增强癌症治疗中的近距离放射治疗方面的独特应用。我们设计了载药近距离放射治疗间隔物，可以使用连续液体界面生产（CLIP）3D 打印技术制造，允许对载药装置进行可调节打印，并与近距离放射治疗种子一起在手术中植入。在化疗联合近距离放射治疗中，我们能够通过局部药物输送实现更大的治疗效果，而没有全身毒性。我们相信我们的工作将促进对 3D 打印在医学应用中的进一步研究。
