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）：本研究的总体目的是开发基于多功能核-壳层状双氢氧化物纳米颗粒（LDHN）的纳米载体，用于晚期癌症的靶向消融和成像。这种新型的非聚合物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，用于使递送的纳米载体成像和用于消融癌细胞，2）在陶瓷LDH壳内插入诱导肿瘤坏死的化疗药物（基因毒素）或siRNA，和3）用于靶向癌细胞的官能化最外表面。据推测，在单一生物相容性纳米级递送平台上结合靶向、成像和消融/化疗能力是前列腺癌治疗的有力方法，直接应用于治疗残留和转移性疾病。无机陶瓷由于其固有的生物相容性和在生理环境中的稳定性而在生物应用中具有吸引力的材料。LDH纳米颗粒是一类具有通式M2+1-xM 3 +x（OH）2的无机陶瓷。（An-）x/n·mH 2 O，其中M2+为二价阳离子，M3+为三价阳离子，An-为n价层间阴离子。其独特的结构容易允许通过离子交换插入各种阴离子性骨质疏松诱导治疗剂。在本申请中，我们将采用基于LDH的核-壳纳米载体用于将阴离子治疗剂（缀合的阿霉素和抗bcl-2 siRNA）靶向递送至前列腺癌细胞。核心将由荧光半导体量子点和银纳米棒组成，分别用于荧光和近红外（NIR）成像。Ag核-LDH壳结构将具有通过使用纵向等离子体共振模式对癌细胞进行热消融的附加属性。前列腺特异性膜抗原（PSMA）是一种在前列腺癌疾病的所有阶段过表达的细胞表面受体，因此适用于靶向恶性前列腺癌细胞。靶向PSMA的双分子（肽和抗体）将与表面活化的LDHN缀合，以特异性靶向恶性前列腺细胞。该平台将在体外评估LDHN中嵌入药物向前列腺癌细胞系和非恶性细胞的靶向递送。我们这项奋进的具体目标是：1：合成和表征的核壳层状双氢氧化物纳米粒子（LDHN）与控制的大小和窄的尺寸分布;与半导体量子点和银纳米棒的核心，同时成像和治疗，2。LDHN的表面活化，以及聚（乙二醇）（PEG）和前列腺靶向生物分子（PTB）在LDHN上的缀合，3）化学治疗分子在LDHN结构内的嵌入，以及3.体外评价以确定PTB-LDHN纳米载体的摄取、细胞内定位、功效、选择性、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学和工程方面的互补经验，用于设计，生成，表征和体外评估多功能核壳LDHN纳米载体作为前列腺癌治疗剂。拟议研究的成功完成将为晚期前列腺癌疾病带来具有内置冗余和成像的新型靶向治疗方法，并可以作为其他转移性癌的治疗输送和成像的通用平台。 项目叙述：我们合作研究的目标是开发靶向多功能核壳层状双氢氧化物（LDH）纳米载体，用于晚期癌症疾病的靶向破坏和光学成像。为此，我们进行了设计，合成和表征的核壳LDH纳米粒子。虽然核将由荧光量子点或近红外（NIR）活性银（Ag）纳米棒组成，但层状双金属氢氧化物的壳将具有插入其结构内的诱导凋亡的基因毒素和siRNA。除了肿瘤诱导分子之外，在基于Ag纳米棒的核-壳纳米颗粒的情况下，还将通过热消融促进癌细胞破坏，从而导致双重治疗。靶向癌细胞的生物分子（肽和抗体）将与LDH壳的最外层缀合，从而在单个递送平台上产生具有靶向、成像和双重治疗能力（消融和化疗）的多功能纳米载体。将使用人前列腺癌细胞系和未转化的前列腺上皮细胞对核-壳LDH纳米载体的细胞毒性、细胞死亡机制和选择性进行广泛的体外评价，以评价这些新型纳米载体的功效。