We propose the synthesis of discrete functionalized polyester nanoparticles in selected nanoscale size dimensions via a controlled intermolecular chain cross-linking process. The novel technique establishes a practical method to form nanoparticles in which parameters, such as size, degradability, encapsulation efficiencies, can be controlled by the cross-linking of two partners, a dysfunctional linker of different chemical nature and a linear functionalized polyester precursor with an incorporated cross-linking partner, in varying percentages. By controlling the equivalents of cross-linker and the concentration of the linear polymer, we will produce particles with a narrow size distribution and a selected nanoscopic size dimension. Furthermore, the cross-linking technique yields amorphous nanoparticles in contrast to known techniques that are limited due to their products with crystalline and hydrophobic properties. In the demand for tunable and amorphous degradable particles, we will (a) synthesize nanoparticles with controlled and selected nanoscopic dimensions from functional linear polyester precursors and cross-linking units of different molecular length and polarity (b) and we will evaluate and test the control of morphologies and degradation behavior to determine also encapsulation properties and the controlled release of therapeutics. (c) And we will be test the prepared particles biocompatibility and safety with the observed release of therapeutics. This novel technology will overcome caveats of current techniques that do not allow a controlled variation of nanoparticle sizes, morphologies or encapsulation of drug molecules after nanoparticle synthesis that prevents higher drug loads.
In the proposed Aims, we will further develop a novel technique to form well-defined polyester nanoparticles in selected nanoscopic size dimensions. The technique allows adjusting the controlled release mechanism based on the density and amount of the introduced hydrophobic or hydrophilic cross-linker to facilitate nanoparticle formation. The created """"""""nanosponge"""""""" is a soluble supramolecular structure that can contain a number of functional groups for the conjugation to biologically active units. Furthermore, the particles prepared from the novel technique allow for the incorporation of therapeutics after nanoparticle formation that increases the overall drug load significantly. We will further optimize the release and degradation kinetics through a detailed study of the influence of the integrated cross-linking units based on their polarity and molecular chain length. This investigation will be accompanied by the studies to incorporate not only small molecules but also therapeutics of higher molecules weight. The toxicology studies will complete the testing of the particles for their suitability as a drug delivery platform.
| Lockhart, Jacob N; Stevens, David M; Beezer, Dain B et al. (2015) Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges. J Control Release 220:751-7 |
| Hariri, Ghazal; Edwards, Aaron D; Merrill, Tyler B et al. (2014) Sequential targeted delivery of paclitaxel and camptothecin using a cross-linked ""nanosponge"" network for lung cancer chemotherapy. Mol Pharm 11:265-75 |
| Grove, Karen; Dobish, Julia; Harth, Eva et al. (2014) Trans-meningeal drug delivery to optic nerve ganglion cell axons using a nanoparticle drug delivery system. Exp Eye Res 118:42-5 |
| Adkins, Chinessa T; Dobish, Julia N; Brown, Scott et al. (2013) Water-soluble Semiconducting Nanoparticles for Imaging. ACS Macro Lett 2:710-714 |
| Stevens, David M; Tempelaar, Sarah; Dove, Andrew P et al. (2012) Nanosponge formation from organocatalytically-synthesized poly(carbonate) copoplymers. ACS Macro Lett 1:915-918 |
