DNA-modulated release of drug from melanoma targeting NP

DNA 调节的黑色素瘤药物释放靶向 NP

• 批准号: 7508835
• 负责人: KIT S LAM
• 金额: $ 17.1万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7508835
• 关键词: Adjuvant Therapy; Affinity; Anthracycline Antibiotics; Anthracyclines; Antineoplastic Agents; Binding; Biodistribution; Blood Vessels; Cell Line; Class; DNA; Data; Development; Diagnostic Imaging; Disease; Doxorubicin; Doxorubicin-DNA Complex; Drug Carriers; Drug Delivery Systems; Drug usage; Electromagnetic Fields; Endothelial Cells; Fluorescent Dyes; Frequencies; Future; Goals; Heating; Image; In Situ; In Vitro; Integrins; Libraries; Ligands; Literature; Localized; Lymphoma; Magnetism; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Mus; Nanotechnology; Neoplasms in Vascular Tissue; Optics; Organ; Output; Palliative Care; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; RGD (sequence); Reporting; Research; Screening procedure; Sensitivity and Specificity; Site; Specificity; Staging; Therapeutic Agents; Time; Tissues; Title; Toxic effect; Treatment Efficacy; Work; Xenograft Model; cancer therapy; cancer type; clinical application; combinatorial; concept; design; in vivo; intercalation; melanoma; nanoimaging; nanomedicine; nanoparticle; nanotherapeutic; novel; novel diagnostics; peptidomimetics; radiofrequency; targeted delivery; tumor

DESCRIPTION (provided by applicant): The overall goal of this research is to develop novel DNA-modulated drug release nanoparticles (DDRNP) that can target and treat melanoma, or other type of cancer, with high specificity. Nanotechnology is an emerging field that has shown promise for the development of novel diagnostic, imaging and therapeutic agents for a variety of diseases, including cancer. One major obstacle to the effective clinical application of nano-therapeutic or nano-imaging agents is the lack of high affinity and high specificity targeting ligands that can deliver these nanomedicines to the tumor or organ target site with high efficiency in vivo. There are presently needs for alternative methods of delivery and targeting for future nanomedicines. We have recently reported (Peng, 2006) the identification of a high-affinity (IC50=2 pM) peptidomimetic ligand (LLP2A) against activated 1421 integrin using both diverse and highly focused one-bead one-compound (OBOC) combinatorial peptidomimetic libraries in conjunction with a high stringency screening method. We further demonstrated that LLP2A is able to image 1421- expressing lymphomas with high sensitivity and specificity when conjugated to a near infrared fluorescent dye in a murine xenograft model. In addition, it also binds to the growing blood vessels of many tumor types. We have also reported the identification of an ovarian cancer targeting ligand (OA02) that bind to 1321 integrin with high specificity (Aina, 2005a). In vivo optical (Aina, 2005b) and PET (Aina, 2007) imaging studies have confirmed its cancer targeting potential. Very recently, we were able to demonstrate that this and related ligands can target malignant melanoma with high specificity (see Preliminary Data section). Anthracyclines are a class of potent DNA intercalating drugs used for treatment of cancer, including melanoma, but their therapeutic efficacy is limited by their toxicity and lack of specificity. We are envisaging that their efficient dsDNA intercalation can be exploited to develop a new drug delivery paradigm by creating short anthracycline-laden dsDNA sequences as drug carriers whereby their thermal denaturation triggers the localized release of the anticancer drug. Magnetic nanoparticles (MNPs) carrying both anthracycline-loaded dsDNA sequences and OA02/LLP2A targeting ligands will be delivered selectively to cancer tissues. An external high frequency electromagnetic field (radiofrequency or RF heating) will be transduced by the MNP to a localized thermal output causing dsDNA denaturation and concomitant in situ drug release. Our hypothesis is that the DNA-modulated drug release concept applied in conjunction to melanoma targeting ligands, will be useful as adjuvant therapy for stage I, II, and III melanoma patients, and as palliative therapy for patients with more advanced disease. In this R21 application we shall develop this novel nanotherapeutic approach in a melanoma xenograft model. The specific aims of this application are as follows: Aim 1: To develop, prepare, and characterize DNA-modulated drug release nanoparticles (DDRNP) decorated with OA02 (a melanoma targeting ligand), and/or LLP2A (a tumor blood vessel targeting ligand). Aim 2: To evaluate the RF triggered in vitro release and anti-cancer effects of doxorubicin (DOX) from DDRNP. Aim 3: To evaluate the biodistribution and intratumoral distribution of DDRNPs in the murine xenograft model for melanoma. Title: DNA-modulated release of drug from melanoma targeting NP Project Narrative Short anthracycline-laden dsDNA sequences can be used as drug carriers whereby their thermal denaturation triggers the localized release of the anticancer drug. Magnetic nanoparticles (MNPs) carrying both anthracycline-loaded dsDNA sequences and OA02/LLP2A targeting ligands will be delivered selectively to cancer tissues. An external high frequency electromagnetic field (radiofrequency or RF heating) will be transduced by the MNP to a localized thermal output causing dsDNA denaturation and concomitant in situ drug release. Our hypothesis is that the DNA-modulated drug release concept applied in conjunction to melanoma targeting ligands, will be useful as adjuvant therapy for stage I, II, and III melanoma patients, and as palliative therapy for patients with more advanced disease. In this R21 application we shall develop this novel nanotherapeutic approach in a melanoma xenograft model.

描述（由申请人提供）：本研究的总体目标是开发新型 DNA 调节药物释放纳米粒子 (DDRNP)，它可以高度特异性地靶向和治疗黑色素瘤或其他类型的癌症。纳米技术是一个新兴领域，有望开发出针对包括癌症在内的多种疾病的新型诊断、成像和治疗药物。纳米治疗剂或纳米成像剂有效临床应用的一个主要障碍是缺乏高亲和力和高特异性的靶向配体，这些配体可以在体内高效地将这些纳米药物递送到肿瘤或器官靶位点。目前，未来的纳米药物需要替代的递送和靶向方法。我们最近报道（Peng，2006）使用多样化和高度集中的单珠一化合物（OBOC）组合肽模拟文库，鉴定了针对激活的 1421 整联蛋白的高亲和力（IC50 = 2 pM）肽模拟配体（LLP2A）与高严格筛选方法相结合。我们进一步证明，当在小鼠异种移植模型中与近红外荧光染料结合时，LLP2A 能够以高灵敏度和特异性对表达 1421 的淋巴瘤进行成像。此外，它还与许多肿瘤类型的生长血管结合。我们还报道了一种卵巢癌靶向配体 (OA02) 的鉴定，该配体与 1321 整合素具有高特异性结合 (Aina, 2005a)。体内光学（Aina，2005b）和 PET（Aina，2007）成像研究已证实其癌症靶向潜力。最近，我们能够证明这种配体和相关配体可以高度特异性地靶向恶性黑色素瘤（参见初步数据部分）。蒽环类药物是一类有效的 DNA 嵌入药物，用于治疗包括黑色素瘤在内的癌症，但其治疗效果因其毒性和缺乏特异性而受到限制。我们设想，通过创建短的载有蒽环类药物的 dsDNA 序列作为药物载体，可以利用它们有效的 dsDNA 嵌入来开发新的药物递送范例，从而使它们的热变性触发抗癌药物的局部释放。携带蒽环类双链 DNA 序列和 OA02/LLP2A 靶向配体的磁性纳米粒子 (MNP) 将选择性地递送至癌症组织。外部高频电磁场（射频或 RF 加热）将由 MNP 转换为局部热输出，导致 dsDNA 变性并伴随原位药物释放。我们的假设是，与黑色素瘤靶向配体结合应用的 DNA 调节药物释放概念将可用作 I、II 和 III 期黑色素瘤患者的辅助治疗，以及作为更晚期疾病患者的姑息治疗。在此 R21 应用中，我们将在黑色素瘤异种移植模型中开发这种新颖的纳米治疗方法。本申请的具体目标如下： 目标 1：开发、制备和表征用 OA02（黑色素瘤靶向配体）和/或 LLP2A（肿瘤血管靶向配体）修饰的 DNA 调节药物释放纳米颗粒（DDRNP） ）。目标 2：评估 RF 触发 DDRNP 中阿霉素 (DOX) 的体外释放和抗癌作用。目标 3：评估 DDRNP 在黑色素瘤小鼠异种移植模型中的生物分布和瘤内分布。标题：DNA 调节药物从黑色素瘤中释放，靶向 NP 项目叙述 含有蒽环类药物的短双链 DNA 序列可用作药物载体，通过其热变性触发抗癌药物的局部释放。携带蒽环类双链 DNA 序列和 OA02/LLP2A 靶向配体的磁性纳米粒子 (MNP) 将选择性地递送至癌症组织。外部高频电磁场（射频或 RF 加热）将由 MNP 转换为局部热输出，导致 dsDNA 变性并伴随原位药物释放。我们的假设是，与黑色素瘤靶向配体结合应用的 DNA 调节药物释放概念将可用作 I、II 和 III 期黑色素瘤患者的辅助治疗，以及作为更晚期疾病患者的姑息治疗。在此 R21 应用中，我们将在黑色素瘤异种移植模型中开发这种新颖的纳米治疗方法。