NANOTEMPLATE ENGINEERING OF CELL-SPECIFIC NANOPARTICLES

描述（由申请人提供）：我们研究的总体目标是 设计含有药物的组织和细胞特异性纳米颗粒， 克服了现有技术的局限性， 颗粒载体。 这项为期24个月的R21研究计划的具体目标是 为了证明含有相关药物的靶向固体纳米颗粒 分子可以从新型微乳液前体 （“纳米模板”）使用快速、可再现和经济的方法， 这些工程纳米粒子可以靶向特定的组织和细胞， 体内。 含有乙酰丙酮钆的肿瘤特异性纳米颗粒 （GdAcAc）将被改造为靶向实体肿瘤的中子捕获 治疗（NCT）。 含有重组神经的脑特异性纳米颗粒 生长因子和重组胶质源性神经营养因子 将被设计成针对血脑屏障来治疗或预防 脑疾病。 R21的具体目标是：1）证明 三种药物分子，乙酰丙酮钆（GdAcAc），重组 （3）神经生长因子（NGF）和重组胶质源性神经营养因子 GDNF可以包埋在纳米颗粒（< 100 nm）中， 微乳液前体，并且这些药物分子保持稳定，2） 将细胞特异性配体并入工程化固体的表面上 用于靶向实体瘤（叶酸）和脑（胆碱）的纳米颗粒， 证明靶向纳米颗粒的细胞特异性识别， 体外或原位，和3）进行体内生物分布和外部伽马 放射性造影研究证明组织和细胞特异性沉积 在实体瘤（GdAcAc）和脑中含有药物的放射性标记的纳米颗粒 (NGF GDNF）。 R21阶段的军事成就，特别是 与Gd的肿瘤摄取百分比和NGF的脑摄取百分比相关的那些 和GDNF，将导致治疗上的 这些分子在这些相应组织中的相关浓度。 的 36-R33期将分为三个治疗项目，具体如下： 1)脑靶向神经生长因子或胶质细胞源性神经营养因子纳米粒的治疗作用 在中风的MCAO-大鼠模型中，2）脑靶向的 含有GDNF的纳米颗粒在帕金森病的MPTP-小鼠模型中， 和3）使用肿瘤靶向钆纳米颗粒的中子捕获疗法 在小鼠肿瘤模型中。理想情况下，这些治疗研究的数据可能有助于 将这些创新的纳米技术推向临床研究。

DESCRIPTION (provided by applicant): The overall goal of our research is to engineer tissue- and cell-specific nanoparticles containing drugs that overcome limitations of existing technologies used to make sub-micron particulate carriers. The specific goal of this 24-month R21 Research Plan is to demonstrate that targeted solid nanoparticles containing relevant drug molecules can be engineered from novel microemulsion precursors (`nanotemplates') using a rapid, reproducible, and economical process and that these engineered nanoparticles can be targeted to specific tissues and cells in-vivo. Tumor-specific nanoparticles containing gadolinium acetylacetonate (GdAcAc) will be engineered to target to solid tumors for neutroncapture therapy (NCT). Brain-specific nanoparticles containing recombinant nerve growth factor (rNGF) and recombinant glial-derived neurotrophic factor (rGDNF) will be engineered to target the blood-brain barrier to treat or prevent diseases of the brain. The Specific Aims of the R21 are to: 1) demonstrate that three drug molecules, gadolinium acetylacetonate (GdAcAc), recombinant (3-nerve growth factor (NGF), and recombinant glial-derived neurotrophic factor (GDNF) can be entrapped in nanoparticles (< 100 nm) engineered from microemulsion precursors and that these drug molecules remain stable, 2) Incorporate cell-specific ligands on the surface of the engineered solid nanoparticles for targeting solid tumors (folate) and the brain (choline) and demonstrate cell-specific recognition of targeted nanoparticles either in-vitro or in-situ, and 3) perform in-vivo biodistribution and external gamma scintigraphy studies to demonstrate tissue and cell-specific deposition of radiolabeled nanoparticles containing drug in solid tumors (GdAcAc) and brain (NGF and GDNF). The achievement of Milestones in the R21 phase, particularly those relating to percent tumor uptake of Gd and percent brain uptake of NGF and GDNF after systemic administration, will result in therapeutically relevant concentrations of these molecules in these respective tissues. The 36-month R33 phase will be divided into three therapeutic projects as follows: 1) Therapeutic Effect of Brain-Targeted Nanoparticles Containing NGF or GDNF in the MCAO-Rat Model for Stroke, 2) Therapeutic Effect of Brain-Targeted Nanoparticles Containing GDNF in the MPTP-Mouse Model of Parkinson's Disease, and 3) Neutron Capture Therapy using Tumor-Targeted Gadolinium Nanoparticles in a Mouse Tumor Model. Ideally, data from these therapeutic studies may help to advance these innovative nanotechnologies toward clinical investigation.