Aggregation and Dendrimer Mediated Secondary Binding towards Folate BindingProtein & Fatigue Failure Mechanism of Anterior Cruciate Ligament Fracture

dendrimer drug delivery;anterior cruciate ligament injury;nanoparticle aggregation;Chemistry;Science;Chemistry

Chen, JunjieRamamoorthy, Ayyalusamy ;

University of Michigan

关键词: dendrimer drug delivery;    anterior cruciate ligament injury;    nanoparticle aggregation;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/144055/junjchen_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Drug conjugation gives many advantages such as improved targeting, solubility and retention. How conjugated drugs interact with proteins is a key question to answer in targeted drug delivery. This not only includes the interaction with the target protein, but also includes the proteins that the drug carrier may encounter during drug trafficking. Folic acid (FA) is of wide interest as a targeting agent. It provides targeting effect towards the folate receptor (FR), a commonly overexpressed protein in breast cancer and ovarian cancer. Chapter one focused on developing a conjugated tighter binder towards the soluble form of folate receptor, folate binding protein (FBP). This strategy employed a PAMAM dendrimer conjugated folic acid; the dissociation constant was improved from 20 nM of free folic acid to 2 nM of the dendrimer conjugated folic acid. The folate binding protein is a minor serum protein and is known to aggregate upon binding to folic acid. This aggregation could pose risk factors for drug delivery vectors such as the folic acid conjugated iron oxide nanoparticles. In chapter two, folate binding protein was shown to aggregate to large iron oxide nanoparticles that are conjugated to folic acid, triggering the agglomeration cascade that could drastically change the size of these nanoparticles. Chapter three addresses a question that is important to sport medicine:what leads to non-contact anterior cruciate ligament (ACL) failure? Our hypothesis was that before the ACL fracture, microdamage would have already been created by jumping and landing activities. In this chapter, paired cadaveric knees were collected and one of the pair was mechanically tested under submaximal loading to see to what extent the microdamage would be created. A hierarchical damage ranging from nanometer level to micrometer level were detected using various methods including atomic force microscopy (AFM), nanoIR, second harmonic generation (SHG) and confocal microscopy. These microdamages exhibits patterns that resemble the fractured ACL seen in the clinical patients.