Palladium-activated prodrug therapy: a novel focal therapy for localised cancers of unmet need

尽管在早期癌症的诊断和治疗方面取得了重大进展，但在为被诊断为局部晚期或转移性肿瘤的患者开发有效的治疗方法方面，威胁生命的风险和治疗挑战仍然最高。对于大多数局部肿瘤，目前的治疗方法是手术切除，然后通常是辅助性放射治疗和/或化疗。这种疗法在癌症任何阶段的潜在益处必须与可能严重损害患者生活质量的不良影响进行权衡。不幸的是，即使用辅助化疗来治疗一些侵袭性癌症，如多形性胶质母细胞瘤，中位生存期也只提高了大约2个月，而相关的副作用非常严重。此外，对于局限性前列腺癌，在最佳治疗方案上仍存在重大争议。由于现有治疗(手术或放射治疗)的副作用(大小便失禁、阳萎、肠道问题)，目前的护理标准是积极监测，包括定期医院检查(例如前列腺活检和核磁共振扫描)，目的是推迟干预。由于缺乏在治疗效果和相关毒性之间提供更好平衡的治疗方法，这些癌症中的许多最终演变为更具侵袭性的形式，增加了过早死亡的风险。因此，需要的是新的药物输送策略，能够减少治疗的副作用，同时最大限度地提高治疗效果。为了为这些局部癌症提供更安全和更有效的策略，我们设计了一种新的治疗方法，允许仅将药物活性集中在癌症区域，从而减少与化疗相关的严重不良反应。这项技术基于爱丁堡大学爱丁堡癌症研究中心首创的一项新策略，该策略通过使用由一种名为钯的元素制成的固体金属设备，实现对化疗地点的完全控制。这种金属对患者是完全安全的(它已经被用于牙科)，可以被塑造成可植入的设备，并具有特殊的化学性质，促进抗癌药物的局部释放。通过植入局部肿瘤内，口服给药的前体只有在与钯设备相互作用时才会在癌症部位变得“活跃”。考虑到这种设备的可重用性，这种治疗可以重复必要的次数。这种新方法独特的调节能力不仅将减少药物在健康器官中的存在，还将有助于根据疾病的进展和严重程度实施个性化治疗，从而减少副作用，最大限度地发挥治疗效果。由于其新颖性，这种医疗技术将通过改善患有无法治疗的肿瘤患者的生活质量和预期寿命，在制药部门产生重大影响，进而在NHS和英国乃至世界各地的人民中产生重大影响。

Despite significant advances in the diagnosis and treatment of the earliest stages of cancer, the highest life-threatening risks and therapeutic challenges still remain in developing effective treatment of patients diagnosed with locally advanced or metastatic tumours. For most localised tumours the current treatment is surgical resection, often followed by adjuvant radiotherapy and/or chemotherapy. The potential benefit of such therapies in any stage of the cancer must be weighed against possible adverse effects that can severely impair a patient's quality of life. Unfortunately, even with adjuvant chemotherapy to treat some aggressive cancers like glioblastoma multiforme, the median survival is only improved around 2 months, while associated side effects are very severe. In addition, for localised prostate cancer, significant controversy remains on the optimal treatment options. Due to side effects (incontinence, impotence, bowel problems) of existing treatments (surgery or radiotherapy), current standard of care is active surveillance consisting of regular hospital tests (e.g. prostate biopsies and MRI scans), aimed at deferring intervention. Because of the lack of therapies providing a better balance between treatment efficacy and related toxicities, many of these cancers eventually evolve into a more aggressive form with increased risk of pre-mature death. Therefore, what is needed then are novel drug delivery strategies that can reduce the side effect profile of the treatment whilst maximising therapeutic efficacy. To provide a safer and more effective strategy to those localised cancers, we have devised a novel therapeutic approach that will allow concentrating drug activity only at the cancer area, thereby reducing the severe adverse effects associated with chemotherapy. The technology is based on a novel strategy pioneered at the Edinburgh Cancer Research Centre at the University of Edinburgh that enables full control over where chemotherapy takes action through the use of solid metal devices made of an element called palladium. This metal, which is completely safe to patients (it is already employed in dentistry), can be shaped into implantable devices and possesses exceptional chemical properties that facilitate the local release of anticancer drugs. By implantation inside localised tumour, orally-given drug precursors will only become "active" at the cancer site upon interaction with the palladium device. Given the reusability of this device, this treatment could be repeated as many times as necessary. The unique modulatory capabilities of this novel approach will not only reduce drug presence in healthy organs but will also facilitate personalized treatments to be implemented according to the progression and severity of the disease, thereby reducing side effects and maximizing the efficacy of the therapy. Due to its novelty, such healthcare technology will make a major impact in the Pharma sector and, in turn, in the NHS and people of the UK and worldwide by improving the quality of life and life expectancy of patients suffering from untreatable tumours.