Stimuli-Responsive Nanoscale Hydrogels For The Improved Delivery Of Chemotherapeutic Agents
| dc.contributor | Rosales, Adrianne | |
| dc.contributor.advisor | Peppas, Nicholas | |
| dc.creator | Shearer, Alexander | |
| dc.date.accessioned | 2019-08-08T17:06:47Z | |
| dc.date.available | 2019-08-08T17:06:47Z | |
| dc.date.issued | 2019-05-01 | |
| dc.description.abstract | Cancer represents one of the largest public health concerns in the world. Current treatment methods for cancer – namely, chemotherapy – possess serious limitations, most notably the nonspecific biodistribution of the cytotoxic drugs, which leads to diminished drug efficacy and undesirable side effects. However, nanomedicines have recently demonstrated great promise in improving the target specificity of chemotherapeutic drugs and thus drug efficacy. Nanomedicines can be designed with ideal properties for drug delivery, and they are able to preferentially accumulate in the diseased site by the enhanced permeability and retention (EPR) effect. However, there are still numerous biological barriers to drug delivery that need to be considered when designing these nanomedicines. In order to overcome these barriers, the nanomedicines or nanoparticles must be rationally designed. By tuning such properties as size, shape, elasticity, hydrophobicity, and surface charge – these nanoparticles can be passively targeted to the diseased site, and even into the cancerous cells. However, it is also beneficial to actively target tumors by functionalizing the particles with target ligands that can preferentially bind to unique or overexpressed receptors or molecules at the tumor site, thereby improving target specificity, as well as facilitating uptake of the nanoparticles by the cell. In the original work of this thesis, the use of pH-sensitive nanogels as drug delivery agents for ovarian cancer was investigated. There were three aims of this investigation: (1) to elucidate the mechanism of internalization in order to determine if endosomal acidification could be leveraged to facilitate cytosolic delivery of the drug payload, (2) to evaluate the effect of stealth coating (PEG) surface density on cellular uptake, (3) and – expecting that the presence of a stealth coating would impede uptake – to design a stimuli responsive peptide linker that would facilitate the shedding of the stealth coating in the presence of a key enzyme that is over expressed in cancer cells – thereby improving uptake. Ultimately, it was determined that the nanogels were internalized via a clathrin-mediated endocytosis process. As a result, these nanogels can, in fact, leverage endosomal acidification to induce nanoparticle swelling, endosomal rupture, and cytosolic delivery. Additionally, particles with no PEG conjugated to the surface exhibited about 90% uptake, but this uptake diminished to about 10% or lower for particles with a PEG content of 10 mol% or higher, showing that the increase in PEG content severely hindered cellular uptake. However, nanoparticles with the enzyme degradable crosslinker that functionalized the PEG to the particle surfaces were successfully synthesized, and it was seen that – in the presence of the enzyme – shedding of the stealth coating was, in fact, observed, and uptake levels returned to those of the particles without PEG coatings. Therefore, it can be concluded that nanogels were rationally designed and successfully synthesized that possessed a multitude of functionalities, each of which contributed to the capacity of the nanogels to delivery drugs to a specific target with a controlled release of the drug payload. | |
| dc.identifier.uri | https://hdl.handle.net/2152/75507 | |
| dc.identifier.uri | http://dx.doi.org/10.26153/tsw/2612 | |
| dc.relation.ispartof | Plan II Honors Theses - Openly Available | |
| dc.rights.restriction | open | |
| dc.subject | Plan II Honors Thesis | |
| dc.subject | biomaterials | |
| dc.subject | drug delivery | |
| dc.subject | nanoparticles | |
| dc.title | Stimuli-Responsive Nanoscale Hydrogels For The Improved Delivery Of Chemotherapeutic Agents |
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