Organic nanoparticles for dual MRI-guided therapeutic selection and ovarian cancer drug delivery

尽管临床上癌症患者常规使用细胞毒性药物的组合，但纳米颗粒 基于(NP)的联合治疗仍然是癌症药物输送的一个新兴前沿。有效 联合治疗对卵巢癌尤其必要，因为卵巢癌细胞经常表现为 对当前临床治疗的耐药性，如铂类药物(顺铂)、紫杉醇和PARP抑制剂 (PARPI)，这些药物的系统免费给药是由于极端的毒性而无法实现的。此外， 铂和PARPI耐药是卵巢癌治疗中的一大挑战。核动力源有可能 减少化疗的毒性，他们可以通过以下方式最大限度地提高疗效并克服耐药性 合理的药物选择，同时针对几个不同的DNA修复途径。为了确定 如果一种特定的药物组合有效，临床上使用的微环境响应型成像策略 可翻译的(例如，核磁共振)是非常需要的。PI的团队已经开发出新型有机聚合物纳米粒子 在卵巢癌联合治疗和MRI方面显示出优势。这些研究启发了我们 提出的NPs，它结合了响应性的有机MRI处理和合理的药物组合来成像- 卵巢癌最佳治疗方法的指导选择。这项拟议的研究结合了一种新型药物-NP 和显像剂合成(来自Johnson和Rajca)，具有卵巢癌的临床专长 (Ghoroghchian)和生物医学成像(Jasanoff)和基础癌症生物学和靶向(Kufe实验室) 通过新的图像引导的NP为基础的联合疗法解决卵巢癌的化疗耐药性问题。这个 拟议中的研究将为卵巢癌治疗创造一种新的范式，即几种 治疗剂包装在相同的无毒载体中，并选择性地输送到肿瘤和核磁共振 纳米材料内的造影剂报告了治疗的成功，从而允许人们选择 个体化治疗的最佳药物组合和比例。 假设：多种小分子治疗药物同时并入并有反应 将成像标签(MRI)植入多药物结合的纳米粒子将导致卵巢癌的新疗法，从而延缓卵巢癌的发生 获得性治疗耐药性的发展，并为MRI引导的药物选择提供依据。结合使用 其他已建立的和实验的试剂，将建立一个或多个NPs，并在 抗铂疾病。已证实的安全性、药代动力学、生物分布和疗效 含有用于高级别浆液性卵巢癌治疗的NPs将转化为新的药物组合，这些药物组合 体内有效，将通过患者来源的原位异种移植模型的活性来证明。 耐PARPI的卵巢癌。在一个NP中包含多种药物将提高疗效和 与相同比例的单一药物结合纳米粒和游离药物的混合物相比，毒性降低。这个 全有机磁共振造影剂的开发将确保安全性和临床可转移性。

Though combinations of cytotoxic drugs are routinely administered to cancer patients in the clinic, nanoparticle (NP)-based combination therapy still represents an emerging frontier in cancer drug delivery. Effective combination therapies are particularly necessary for ovarian cancer, as ovarian cancer cells often display resistance to current clinical therapies such as platinum agents (cisplatin), paclitaxel, and PARP inhibitors (PARPi), and systemic administration of these drugs in free from is precluded by extreme toxicity. Furthermore, platinum and PARPi resistance is a major challenge in ovarian cancer therapy. NPs have the potential to reduce the toxicity of chemotherapy, and they could maximize efficacy and overcome resistance through rational drug choices that target several disparate DNA repair pathways simultaneously. In order to determine if a particular drug combination is working, microenvironment-responsive imaging strategies that are clinically translatable (e.g., MRI) are critically needed. The PI’s group has developed novel organic polymer NPs with demonstrated advantages in combination ovarian cancer therapy as well as MRI. These studies inspired our proposed NPs, which combine responsive organic MRI handles and rational drug combinations for image- guided selection of optimal therapies for ovarian cancer. The proposed research combines a novel drug-NP and imaging agent synthesis (from Johnson and Rajca) with clinical expertise in ovarian cancer (Ghoroghchian) and biomedical imaging (Jasanoff) and fundamental cancer biology and targeting (Kufe lab) to address chemoresistance in ovarian cancer through novel image-guided NP-based combination therapies. The proposed research will create a new paradigm for ovarian cancer therapy, whereby combinations of several therapeutic agents are packaged within the same non-toxic carrier and delivered selectively to tumors and MRI contrast agents within the nanomaterial report on the success of the therapy, thus allowing one to select an optimum drug combination and ratio for personalized therapy. HYPOTHESIS: Simultaneous incorporation of multiple small-molecule therapeutic agents and responsive imaging tags (MRI) into multi-drug-conjugated NPs will lead to novel therapies for ovarian cancer that delay the development of acquired therapeutic resistance and provide for MRI-guided drug selection. In combination with other established and experimental agents, one or more NPs will be established with improved activity in platinum-resistant disease. The already proven safety, pharmacokinetics, biodistribution, and efficacy of 3-drug containing NPs for high-grade serous ovarian cancer therapy will translate to novel drug combinations that are effective in vivo, as will be demonstrated by activity in orthotopic patient-derived xenograft models of Pt- and PARPi-resistant ovarian cancer. Inclusion of multiple drugs in one NP will lead to increased efficacy and decreased toxicity compared to mixtures of single-drug-conjugated NPs and free drugs at the same ratios. The development of entirely organic MRI contrast agents will ensure safety and clinical translatability.