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）：这项研究的总体目标是开发具有高特异性的新型DNA调节药物释放纳米颗粒（DDRNP），该药物可以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，对包括癌症在内的各种疾病的新型诊断，成像和治疗剂的开发表现出了希望。有效地临床应用纳米治疗或纳米成像剂的一个主要障碍是缺乏高亲和力和高特异性靶向配体，这些配体可以将这些纳米药物用于肿瘤或器官靶位，并具有高效率的体内。目前，需要对未来纳米药物的替代交付方法和靶向靶向。我们最近报道了（Peng，2006年），使用多种多样的和高度重点的单孔（oboc）组合型组合图库来鉴定针对激活的1421整合素的高亲和力（IC50 = 2 PM）对激活的1421整合素的鉴定，并鉴定出与高弹性射击方法相结合的。我们进一步证明，LLP2A能够在鼠异种移植模型中与近红外荧光染料结合时，能够以高灵敏度和特异性表达淋巴瘤。另外，它还与许多肿瘤类型的血管结合。我们还报道了靶向配体的卵巢癌（OA02）与具有高特异性结合的卵巢癌（OA02）的鉴定（Aina，2005a）。体内光学（AINA，2005b）和PET（AINA，2007）成像研究已证实其癌症的靶向潜力。最近，我们能够证明这种和相关的配体可以靶向具有高特异性的恶性黑色素瘤（请参阅初步数据部分）。蒽环类药物是一种用于治疗癌症（包括黑色素瘤）的有效DNA插入药物，但其治疗功效受到其毒性和缺乏特异性的限制。我们正在设想，可以利用它们的有效dsDNA插入来开发新的药物递送范式，通过创建短邻氨基苯基克林的DSDNA序列作为药物载体，从而触发抗癌药的局部释放。载有蒽环类dsDNA序列和OA02/LLP2A靶向配体的磁性纳米颗粒（MNP）将有选择地交付给癌症组织。 MNP将将外部高频电磁场（射频或RF加热）转导为局部热输出，从而导致dsDNA变性并伴随着原位药物释放。我们的假设是，与靶向配体的黑色素瘤相结合的DNA调节的药物释放概念将作为I期，II和III期黑色素瘤患者的辅助治疗，以及针对患有更晚期疾病的患者的辅助治疗。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型的纳米治疗方法。本应用的具体目的如下：目标1：开发，准备和表征DNA调节的药物释放纳米颗粒（DDRNP）（DDRNP），该纳米颗粒（DDRNP）用OA02（靶向配体的黑色素瘤）和/或LLP2A（肿瘤血液血管靶向配体）装饰。 AIM 2：评估DDRNP中阿霉素（DOX）的体外释放的RF和抗癌作用。目标3：评估黑色素瘤鼠内异种移植模型中DDRNP的生物分布和肿瘤内分布。标题：DNA调节的药物从黑色素瘤靶向NP项目叙事叙事短暂性DSDNA序列的释放可以用作药物载体，从而使其热变性触发抗癌药的局部释放。载有蒽环类dsDNA序列和OA02/LLP2A靶向配体的磁性纳米颗粒（MNP）将有选择地交付给癌症组织。 MNP将将外部高频电磁场（射频或RF加热）转导为局部热输出，从而导致dsDNA变性并伴随着原位药物释放。我们的假设是，与靶向配体的黑色素瘤相结合的DNA调节的药物释放概念将作为I期，II和III期黑色素瘤患者的辅助治疗，以及针对患有更晚期疾病的患者的辅助治疗。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型的纳米治疗方法。