| dc.contributor |
Robert Langer and Omid C. Farokhzad. |
|
| dc.contributor |
Harvard--MIT Program in Health Sciences and Technology. |
|
| dc.contributor |
Harvard University--MIT Division of Health Sciences and Technology |
|
| dc.creator |
Radovic-Moreno, Aleksandar Filip |
|
| dc.date |
2013-06-17T19:50:36Z |
|
| dc.date |
2013-06-17T19:50:36Z |
|
| dc.date |
2013 |
|
| dc.date |
2013 |
|
| dc.date.accessioned |
2022-05-04T06:26:25Z |
|
| dc.date.available |
2022-05-04T06:26:25Z |
|
| dc.identifier |
http://hdl.handle.net/1721.1/79250 |
|
| dc.identifier |
846480801 |
|
| dc.identifier.uri |
http://localhost:8080/xmlui/handle/CUHPOERS/2932 |
|
| dc.description |
Thesis (Ph. D. in Chemical and Biomedical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2013. |
|
| dc.description |
Cataloged from PDF version of thesis. |
|
| dc.description |
Includes bibliographical references. |
|
| dc.description |
Bacterial infections continue to be a significant concern particularly in healthcare settings and in the developing world. Current challenges include the increasing spread of drug resistant (DR) organisms, the side effects of antibiotic therapy, the negative consequences of clearing the commensal bacterial flora, and difficulties in developing prophylactic vaccines. This thesis was an investigation of the potential of a class of polymeric nanoparticles (NP) to contribute to the management of bacterial infections. More specifically, steps were taken towards using these NPs (1) to achieve greater spatiotemporal control over drug therapy by more targeted antibiotic delivery to bacteria, and (2) to develop a prophylactic vaccine formulation against the common bacterial sexually transmitted disease (STD) caused by Chlamydia trachomatis. In the first part, we synthesized polymeric NPs containing poly(lactic-co-glycolic acid)- block-poly(L-histidine)-block-poly(ethylene glycol) (PLGA-PLH-PEG). We show that these NPs are able to bind to bacteria under model acidic infection conditions and are able to encapsulate and deliver vancomycin to inhibit the growth of Staphylococcus aureus bacteria in vitro. Further work showed that the PLGA-PLH-PEG-based NPs demonstrated the potential for competition for binding bacteria at a site of infection from soluble protein and model phagocytic and tissue-resident cells in a NP composition dependent manner. The NPs demonstrated low toxicity in vitro, were well tolerated by mice in vivo, and circulated in the blood on timescales comparable to control PLGA-PEG NPs. In the second part, we used PLGA-PLH-PEG-based NPs to design a prophylactic vaccine against the obligate intracellular bacterium Chlamydia trachomatis, the most common cause of bacterial STD in the world. Currently, no vaccines against this pathogen are approved for use in humans. We first formulated NPs encapsulating the TLR7 agonist R848 conjugated to poly(lactic acid) (R848-PLA) in PLGA-PLH-PEG-based NPs, then incubated these R848-NPs with UV-inactivated C. trachomatis bacteria in acidity, forming a construct. Mice immunized with this vaccine via genital or intranasal routes demonstrated protection from genital infection post immunization in a primarily CD4⁺ T cell-dependent manner. These results may suggest avenues for future work in designing and developing more targeted drug therapies or vaccine formulations for managing bacterial infections using polymeric nanoparticles. |
|
| dc.description |
by Aleksandar Filip Radovic-Moreno. |
|
| dc.description |
Ph.D.in Chemical and Biomedical Engineering |
|
| dc.format |
217 p. |
|
| dc.format |
application/pdf |
|
| dc.language |
eng |
|
| dc.publisher |
Massachusetts Institute of Technology |
|
| dc.rights |
M.I.T. theses are protected by
copyright. They may be viewed from this source for any purpose, but
reproduction or distribution in any format is prohibited without written
permission. See provided URL for inquiries about permission. |
|
| dc.rights |
http://dspace.mit.edu/handle/1721.1/7582 |
|
| dc.subject |
Harvard--MIT Program in Health Sciences and Technology. |
|
| dc.title |
Bacteria-targeting nanoparticles for managing infections |
|
| dc.type |
Thesis |
|