We report the development of a multifunctional system that has the capability to target cancer cells, as well as simultaneously image and deliver therapeutics to these targeted cells. Such a “three-in-one” technology that has integrated targeting, imaging, and drug delivery capabilities is highly desirable in the field of cancer therapy. The material that we have developed for this application is a quantum dot (QD)-polypeptide hybrid assembly system that is spontaneously formed through the self-assembly of carboxyl-functionalized QDs and poly(diethylene glycol L-lysine)-poly(L-lysine) (PEGLL-PLL) diblock copolypeptide molecules. The hybrid assemblies could be modified to target a great variety of cancer biomarkers and have potential ability to carry therapeutic agents with diverse chemical and physical properties. In addition, the QD-polypeptide assemblies have the advantage of extensive tunability and versatility that allow their properties to be tailored and optimized for a broad range of applications.
Cancer targeting can be achieved by modifying the QD-polypeptide hybrid assemblies with ligands that have affinity for certain biomarkers, which are overexpressed on cancer cells. Upon binding and uptake by the target cells through specific ligand-receptor mediated interactions, the assemblies could then allow for the simultaneous imaging of the cells and delivery of therapeutic agents to these cells. Imaging of the cells is done through detection of the QD fluorescence, and drug-delivery can be effected by loading the assembly with therapeutic agents and releasing them by means that disrupt the self-assembly.
When compared to other dual imaging and drug-delivery systems, our QD-polypeptide hybrid assemblies have the advantage of extensive tunability and versatility. To showcase the tunability of the assembly, we demonstrated how its tumor-cell binding characteristics could be modulated and optimized by changing the PEGLL x-PLLy, architecture and the self-assembly conditions. First, we showed how the level of non-specific binding of the QD-polypeptide assemblies could be modulated by changing the PEGLLx-PLLy architecture that constitutes the assembly. The PEGLLx-PLLy architecture was found to affect the zeta-potential of the assembly, which in turn controls its level of non-specific binding. Second, we demonstrated that the level of integrin-mediated binding exhibited by the c(RGD)-assemblies could be modulated by varying the charge ratio (R'). R' is a parameter that is defined as the molar ratio of QD carboxyl functional groups to the lysine (PLL) residues. It was shown previously that the charge ratio controls the size of the assembly, and we believe that the assembly size in turn affects the ligand-receptor avidity effects.
This work lays the foundation for further development of the QD-polypeptide hybrid assembly system such that we can achieve the ultimate goal of applying it as a highly tunable dual imaging and targeted drug-delivery agent. In the future, to allow for intracellular drug delivery, one can take advantage of the pH change that occurs in the endocytic pathway as the assemblies are internalized by the tumor cells. The change of pH to a relatively low value should then disrupt the electrostatic interaction that causes the self-assembly, which can in turn be expected to mediate the cytosolic delivery of the therapeutics cargo. (Abstract shortened by UMI.)
|Advisor:||Frank, Curtis W.|
|School Location:||United States -- California|
|Source:||DAI-B 71/04, Dissertation Abstracts International|
|Subjects:||Biomedical engineering, Chemical engineering, Materials science|
|Keywords:||Hybrid assemblies, Polypeptides, Quantum dots|
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