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

虽然细胞毒性药物的组合在临床上常规地施用给癌症患者，但是纳米颗粒可以在体内或体内施用。 基于NP的组合疗法仍然代表癌症药物递送的新兴前沿。有效 联合治疗对卵巢癌特别必要，因为卵巢癌细胞通常显示 对当前临床治疗如铂类药物（顺铂）、紫杉醇和PARP抑制剂的耐药性 （PARPi），并且这些药物的游离全身给药由于极端毒性而被排除。此外，委员会认为， 铂和PARPi抗性是卵巢癌治疗中的主要挑战。NP有潜力 减少化疗的毒性，他们可以最大限度地提高疗效，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 如果一个特定的药物组合是工作，微环境响应成像策略， 可翻译的（例如，MRI是非常必要的。PI的团队开发了新型有机聚合物NP， 证明了卵巢癌联合MRI治疗的优势。这些研究启发了我们 提出的纳米粒子，其中结合联合收割机响应有机MRI处理和合理的药物组合的图像- 指导选择卵巢癌的最佳治疗方法。这项研究结合了一种新的药物-NP 和显像剂合成（来自约翰逊和Rajca），具有卵巢癌的临床专业知识 （Ghoroghchian）和生物医学成像（Jasanoff）以及基础癌症生物学和靶向（Kufe实验室）， 通过新的图像引导的基于NP的联合疗法解决卵巢癌的化疗耐药性。的 拟议的研究将为卵巢癌治疗创造一个新的范例， 治疗剂被包装在相同的无毒载体中，并选择性地递送至肿瘤和MRI， 纳米材料内的造影剂报告治疗的成功，从而允许人们选择一种 最佳药物组合和比例的个性化治疗。 假设：同时掺入多种小分子治疗剂并响应 成像标签（MRI）到多药物缀合的纳米颗粒将导致卵巢癌的新疗法， 获得性治疗耐药性的发展，并提供MRI指导的药物选择。结合 在其它已建立的和实验性的药剂中，将建立一种或多种在以下方面具有改善的活性的NP： 耐铂性疾病已经证实的安全性，药代动力学，生物分布和疗效的3-药物 用于高级别浆液性卵巢癌治疗的含有NP的药物组合将转化为新型药物组合， 在体内有效，如将通过在Pt-和 PARPi耐药卵巢癌在一个NP中包含多种药物将导致疗效增加， 与相同比例的单一药物缀合的NP和游离药物的混合物相比，降低了毒性。的 开发完全有机的MRI造影剂将确保安全性和临床可转化性。

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.