Targeted Ceramic Nanovectors for Simultaneous Therapy and Imaging of Cancer

用于癌症同步治疗和成像的靶向陶瓷纳米载体

• 批准号: 7455376
• 负责人: SANDWIP Kumar DEY
• 金额: $ 23.15万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-12 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455376
• 关键词: Ablation; Adriamycin PFS; Advanced Malignant Neoplasm; Anions; Antigen Targeting; Apoptosis; Biocompatible; Biological; Biological Assay; Cations; Cell Death; Cell Surface Receptors; Cells; Ceramics; Cessation of life; Charge; Chemistry; Class; Development; Disease; Divalent Cations; Drug Delivery Systems; Engineering; Environment; Epithelial; Epithelial Cells; Ethylene Glycols; Evaluation; Generations; Glutamate Carboxypeptidase II; Goals; Hydroxide Ion; Hydroxides; Image; In Vitro; Individual; Ion Exchange; Ions; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Metals; Metastatic Carcinoma; Modality; Molecular; Molecular and Cellular Biology; Mutagens; Nodule; Non-Malignant; Outcome; PC3 cell line; Peptide antibodies; Peptides; Pharmaceutical Preparations; Physiological; Polymers; Prostate; Prostate Cancer therapy; Protein Overexpression; Purpose; Quantum Dots; Radiopharmaceuticals; Research; Research Personnel; Residual Tumors; Residual state; Semiconductors; Silver; Small Interfering RNA; Specificity; Staging; Standards of Weights and Measures; Stromal Cells; Structure; Surface; Therapeutic; Treatment Efficacy; Work; absorption; antigen binding; base; biomaterial compatibility; cancer cell; cancer imaging; chemotherapy; cytotoxicity; design; direct application; engineering design; ethylene glycol; experience; in vivo; intercalation; layered ceramics; nanoparticle; nanorod; nanoscale; nanovector; novel; optical imaging; pre-clinical; size; targeted delivery; therapeutic target; uptake

DESCRIPTION (provided by applicant): The overall purpose of this study is the development of multifunctional core-shell Layered Double Hydroxide Nanoparticle (LDHN)-based nanovectors for the targeted ablation and imaging of advanced cancer disease. This novel, non-polymeric platform will be designed to possess the following features: 1) metallic or quantum dot core/LDH ceramic shell for imaging the delivered nanovector and for ablation of cancer cells, 2) intercalated apoptosis-inducing chemotherapeutic drugs (genotoxins) or siRNA within the ceramic LDH shell, and 3) functionalized outermost surfaces for targeting cancer cells. It is hypothesized that the incorporation of targeting, imaging, and ablation/chemotherapeutic capabilities on a single biocompatible nanoscale delivery platform is a powerful approach for prostate cancer therapy, with direct application in the treatment of residual and metastatic disease. Inorganic ceramics are attractive materials for biological applications due to their inherent biocompatibility and stability in physiological environments. LDH nanoparticles are a class of inorganic ceramics that have a general formula of M2+1-xM3+x(OH)2.(An-)x/n.mH2O, where M2+ is a divalent cation, M3+ is a trivalent cation, and An- is the interlayer anion of valence n. Their unique structure readily allows the intercalation of a variety of anionic apoptosis-inducing therapeutics via ion exchange. In the present application, we will employ core-shell LDH-based nanovectors for the targeted delivery of anionic therapeutics (conjugated adriamycin and anti-bcl-2 siRNA) to prostate cancer cells. The core will consist of fluorescent semiconductor quantum dots and silver nanorods for fluorescent and near-infra red (NIR) imaging, respectively. The Ag core-LDH shell structure will have an additional attribute of hyperthermic ablation of cancer cells through the use of the longitudinal plasmon resonance mode. The Prostate-Specific Membrane Antigen (PSMA) is a cell-surface receptor over-expressed in all stages of prostate cancer disease and is therefore appropriate for targeting malignant prostate cancer cells. Bimolecular (peptides and antibodies) targeting the PSMA will be conjugated to surface-activated LDHNs in order to specifically target malignant prostate cells. The platform will be evaluated in vitro for the targeted delivery of the intercalated drugs in LDHN to prostate cancer cell lines and non-malignant cells. Our specific aims for this endeavor are: 1: Synthesis and characterization of core-shell layered double hydroxide nanoparticles (LDHN) with controlled size and narrow size distribution; with cores of semiconductor quantum dots and silver nanorods for simultaneous imaging and therapy, 2. Surface-activation of LDHN, and conjugation of poly(ethylene glycol) (PEG) and Prostate-Targeting Biomolecules (PTBs) on LDHNs, 3) Intercalation of chemotherapeutic molecules within the LDHN structure, and 3. In vitro evaluation to determine the uptake, intracellular localization, efficacy, selectivity, mechanisms of ablation, and biocompatibility of PTB- LDHN nanovectors. The team of investigators brings together complementary experience in ceramic materials engineering, polymer and surface chemistry, molecular and cellular biology, and molecular therapeutics and engineering, for the design, generation, characterization and in vitro evaluation of multifunctional core-shell LDHN nanovectors as prostate cancer therapeutics. Successful completion of the proposed research will result in novel targeted therapeutics with built-in redundancy and imaging for advanced prostate cancer disease, and can serve as a general platform for therapeutic delivery and imaging of other metastatic carcinomas. Project Narrative: The goal of our collaborative research is to develop targeted multifunctional core-shell Layered Double Hydroxide (LDH) nanovectors for the targeted destruction and optical imaging of advanced cancer disease. Towards that end, we carry out the design, synthesis, and characterization of core-shell LDH nanoparticles. While the core will consist of fluorescent quantum dots or near infra red (NIR) active silver (Ag) nanorods, the shell of layered double metal hydroxides will have apoptosis-inducing genotoxins and siRNA that are intercalated within its structure. In addition to apoptosis-inducing molecules, cancer cell destruction will also be facilitated by hyperthermic ablation in the case of Ag-nanorod based core-shell nanoparticles, resulting in dual therapy. Cancer cell targeting biomolecules (peptides and antibodies) will be conjugated to the outermost layer of the LDH shell leading to multifunctional nanovectors that possess targeting, imaging, and dual therapeutic capabilities (ablation and chemotherapy) on a single delivery platform. Extensive in vitro evaluation of cytotoxicity, mechanisms of cell death, and selectivity of the core-shell LDH nanovectors will be carried out using human prostate cancer cell lines and untransformed prostate epithelial cells in order to evaluate the efficacy of these novel nanovectors.

描述（由申请人提供）：这项研究的总体目的是开发基于靶向消融和成像晚期癌症疾病的多功能核壳分层双氢氧化物纳米颗粒（LDHN）的纳米摩析器的发展。这个新型的非聚合平台将被设计为具有以下特征：1）金属或量子点核/LDH陶瓷壳，用于对输送的纳米植物和消融癌细胞进行成像，2）近距性凋亡诱导化学治疗药物（基因毒素）或sirna coramic ldh壳壳中的sirna和3）功能化。假设在单个生物相容性的纳米级传递平台上纳入靶向，成像和消融/化学治疗能力是前列腺癌治疗的强大方法，并直接应用了残留和转移性疾病。无机陶瓷由于生理环境中的固有生物相容性和稳定性，是生物应用的有吸引力的材料。 LDH纳米颗粒是一类无机陶瓷，具有M2+ 1-XM3+ X（OH）的一般公式。（AN-）X/N.MH2O，其中M2+是二价阳离子，M3+是三价阳离子，并且是valence n的层间阳离子。它们的独特结构易于通过离子交换来插入各种阴离子凋亡的疗法。在本应用中，我们将采用基于核心LDH的核心纳米旋齿剂来靶向递送阴离子治疗剂（共轭adrimycin和andi-BCl-2 siRNA）来前列腺癌细胞。核心将分别由荧光半导体量子点和银色纳米棒组成，分别用于荧光和近乎Infra红色（NIR）成像。 Ag Core-LDH壳结构将通过使用纵向等离子体共振模式具有癌细胞高温消融的附加属性。前列腺特异性膜抗原（PSMA）是在前列腺癌疾病的所有阶段过表达的细胞表面受体，因此适合靶向恶性前列腺癌细胞。靶向PSMA的双分子（肽和抗体）将与表面激活的LDHN共轭，以特异性地靶向恶性前列腺细胞。该平台将在体外评估，以靶向LDHN中的插入药物靶向前列腺癌细胞系和非恶性细胞。我们对这项工作的具体目的是：1：具有控制尺寸和窄尺寸分布的核壳分层双氢氧化物纳米颗粒（LDHN）的合成和表征； with cores of semiconductor quantum dots and silver nanorods for simultaneous imaging and therapy, 2. Surface-activation of LDHN, and conjugation of poly(ethylene glycol) (PEG) and Prostate-Targeting Biomolecules (PTBs) on LDHNs, 3) Intercalation of chemotherapeutic molecules within the LDHN structure, and 3. In vitro评估以确定PTB-LDHN纳米摩测的摄取，细胞内定位，疗效，消融机制和生物相容性。研究人员团队汇集了陶瓷材料工程，聚合物和表面化学，分子和细胞生物学以及分子治疗和工程学方面的互补经验，用于设计，生成，表征和体外评估多功能核心核心-shell LDHN LDHN Nanovectors作为前列腺癌的疗法。成功完成拟议的研究将导致新颖的有针对性的治疗疗法，并具有内置的冗余和成像为晚期前列腺癌疾病，并可以作为治疗性递送和成像其他转移性癌的一般平台。 项目叙述：我们的合作研究的目的是开发针对靶向破坏和晚期癌症靶向成像的靶向多功能核心分层双氢氧化物（LDH）纳米。为此，我们进行了核心壳LDH纳米颗粒的设计，合成和表征。尽管核心将由荧光量子点或接近红色（NIR）活性银（Ag）纳米棒组成，但分层双金属氢氧化物的外壳将具有凋亡诱导的基因毒素和siRNA，它们在其结构内插入。除了凋亡诱导分子外，在基于AG的基于Ag-nanorod的核心壳纳米颗粒的情况下，高温消融也将促进癌细胞的破坏，从而导致双重治疗。癌细胞靶向生物分子（肽和抗体）将与LDH壳的最外层偶联，从而导致具有靶向，成像和双重治疗能力（烧蚀和化学疗法）的多功能纳米分离器。将使用人类前列腺癌细胞系和未转化的前列腺上皮细胞进行广泛的细胞毒性，细胞死亡机制以及核心壳LDH纳米型的选择性的广泛评估。