Rational Design and High throughput synthesis of nanocarriers for efficient drug delivery
Rational Design and High throughput synthesis of nanocarriers for efficient drug delivery
批准号:
8970069
负责人:
Juntao Luo
金额:
$25.36万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-08-01 至 2017-07-31
关键词:
AffinityAntineoplastic AgentsBindingBiocompatibleBiodistributionCell Culture TechniquesCharacteristicsChemical StructureChemistryCholic AcidsClinicalCombinatorial SynthesisComputer AssistedComputing MethodologiesData SetDevelopmentDockingDoxorubicinDrug Delivery SystemsDrug FormulationsDrug IndustryDrug StabilityEngineeringEvaluationExhibitsExperimental DesignsFaceFluorescenceFutureGoalsIn VitroInheritedLibrariesLiverMeasurableMethodologyMicellesMolecularMolecular WeightMorphologyMuscleNamesNude MiceOligonucleotidesParticle SizePeptidesPharmaceutical PreparationsPolyethylene GlycolsPolylysinePolymer ChemistryPolymersProcessPropertyRelative (related person)RoleSN-38Shelter facilitySiteSolubilitySolutionsSpectrometrySpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationStructureStructure-Activity RelationshipSystemTestingTimeToxic effectTrainingValidationVertebral columnWateranimal imagingaqueousbasecombinatorialcopolymerdesigndrug structureexperimental analysisimprovedin vivointerestnanocarriernanoformulationnanomedicinenanoparticlenanotherapeuticphysical propertypublic health relevancescreeningself assemblysimulationsuccesstheoriestumortumor xenograftvirtual
中文摘要
英文摘要
DESCRIPTION: The classic compatibility/solubility theories and molecular simulations have been applied to predict the drug loading properties of polymeric nanoconstructs. However, the success of these approaches to guide nanocarrier design is still limited. At the same time, it is challenging to synthesize a variety of nanocarriers as predicted with the precise control on structure, molecular weight and functional diversity via the conventional polymer chemistry, which further limits the systematic validation and experimental evaluation of the theoretical design. The current development of nanocarriers, especially for polymeric micelle and nanoparticles, is often a trial-error process with numerous attempts on a small subset of polymers, which frequently yield nanoparticles with less optimized drug loading properties and limited opportunity for further optimization. Inspired by the well- defined structure-activity relationship in peptide chemistry, we have developed a PEG-b-dendritic oligomer system (named telodendrimer) using stepwise peptide chemistry, which assembles into micellar nanocarrier for drug delivery. A new version of telodendrimer possesses a function-segregated structure, e.g. a hydrophilic PEG shell, a facial amphiphilic oligo-cholic acid intermediate layer o shelter the interior hydrophobic drug- binding interior core. These telodendrimers inherit the features of peptide, e.g. well-defined highly engineer- able structure, therefore providing a blueprint for both computational design and the combinatorial synthesis of the nanocarriers for systematic optimization. Our hypothesis is that engineering of the core structure of nanocarriers with the introduction of drug binding moieties will be able to optimize drug loading properties within the nanocarrier. It will be tested via the following steps: (1) A training dataset will be ued to validate the computational approach in identifying drug-binding molecules (DBMs), such as, scoring function, criteria for DBM selection, experimental validation of docking energy, etc.; (2) A enhanced natural compound library will be virtually screened against three important anticancer drugs with distinct structures, e.g. cabazitaxel, SN-38 and doxorubicin. Subsequently, the rationally designed nanocarriers will be synthesized combinatorially and characterized; (3) Drug loading properties, in vitro anticancer effects and the in vivo tumor-targeted drug delivery will be characterized to validate the computational predictions. At the end of study, we expect to elucidate the structure-property relationship (SPR) of telodendrimer nanocarriers in drug delivery and several optimized nanocarriers for SN-38, cabazitaxel and doxorubicin delivery will be developed, respectively, for the further in vivo anticancer evaluation Success in this effort is able to create a paradigm shift in the field of drug delivery. It can als benefit the pharmaceutical industry potentially by providing a reliable and predictable path for nanomedicine design and development.
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