Theranostic gold nanoparticles for imaged-guided radical prostatectomy and PDT ablation

 描述（由申请人提供）：前列腺癌是美国男性中最常见的诊断疾病。目前的诊断是通过评估多种数据，包括PSA血液水平和直肠指检来实现的。自从PSA检测引入以来，有更多的男性被诊断和治疗了这种疾病。诊断的前列腺癌的治疗行动过程取决于疾病的分期，并根据分期分为基本上3种干预措施：1）根治性前列腺切除术，用于前列腺内的癌症; 2）放射治疗，可用于早期和更晚期的癌症;和3）观察等待，或主动监测。根据目前的筛查和公众意识，估计约91%的前列腺癌在首次检测时被临床定位，并且这些患者可能是手术的候选人，手术仅用于局部疾病。然而，没有办法确切地知道在手术期间癌症是否局限于前列腺包膜内，并且在接受根治性前列腺切除术的患者中，大约20%由于疾病扩散到前列腺外而无法实现手术治愈。此外，手术与包括失禁和勃起功能障碍在内的显著发病率相关。需要进行更完整的子宫切除术和减少手术发病率定义了未满足的临床需求。开发一种技术，提高外科医生区分这些结构的能力，在膀胱切除术期间评估癌症的包膜外浸润，改善手术决策，消融不可切除的癌症组织，将提高护理质量。我们建议使用高度选择性的前列腺生物标志物PSMA来驱动靶向治疗诊断纳米颗粒剂与前列腺癌的结合。这种纳米颗粒含有一种光动力治疗剂，Pc 4，它既是荧光的，也是一种有效的癌症治疗剂。所提出的研究的目标是用PSMA的配体衍生化含有Pc 4的纳米颗粒，从而驱动其选择性摄取并将Pc 4递送到前列腺肿瘤中。在手术期间，Pc 4的荧光方面将被利用来在视觉上区分肿瘤与周围的正常组织，正常组织不吸收纳米颗粒。这将允许外科医生在真实的时间内决定手术干预需要有多积极，即完全去除患病组织可能引起的发病程度。在完成手术切除后，可以使用特定波长的光来激发Pc 4，导致自由基的产生和对剩余癌组织的强烈的癌症杀伤， 并不是通过手术切除的

 DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent diagnosed disease among men in the United States. Currently diagnosis is achieved through assessment of multiple data including PSA blood levels and digital rectal exams. Since the introduction of PSA testing significantly more men have been diagnosed and treated for the disease. The course of therapeutic action for diagnosed prostate cancer depends on staging of the disease and breaks down to essentially 3 interventions depending on stage: 1) Radical prostatectomy for cancers that are contained within the prostate; 2) Radiation therapy which can be used for both early and more advanced cancer; and 3) Watchful waiting, or active surveillance. With current screening and public awareness approximately 91% of prostate cancers detected are estimated to be clinically localized when first detected and potentially these patients are candidates for surgery, which is only used for localized disease. However, there is no way to know with certainty if the cancer is localized within the prostate capsule during surgery, and, of the patients that undergo radical prostatectomy, approximately 20% do not achieve surgical cures because of disease spread outside of the prostate gland. Moreover, surgery is associated with significant morbidities including incontinence and erectile dysfunction. The need to perform more complete prostatectomies and reduce surgical morbidities defines an unmet clinical need. The development of a technology that would improve the ability of the surgeon to distinguish among these structures, assess extra-capsular invasion of the cancer during prostatectomy, improve surgical decisions, and ablate cancer tissue that is not resectable, would improve quality of care. We propose to use a highly selective prostate biomarker, PSMA, to drive the binding of a targeted theranostic nanoparticle agent to prostate cancer. This nanoparticle contains a photodynamic therapeutic agent, Pc4 that is both fluorescent and a potent cancer therapeutic. The goal of the proposed studies is to derivatize the nanoparticle containing Pc4 with a ligand for PSMA, thusly driving its selective uptake and delivery of Pc4 into prostate tumors. During surgery the fluorescent aspects of Pc4 would be exploited to visually differentiate the tumor from surrounding normal tissues, which do not take up the nanoparticle. This would allow the surgeon to decide in real time how aggressive the surgical intervention need be, i.e. the degree of morbidity potentially incurred to fully remove diseased tissues. Upon completion of the surgical resection, light of a specific wavelength can be used to excite the Pc4 resulting in free radical generation and robust cancer killing of the remaining cancer tissues that were not removed by the surgical procedure.