Localized and disease-selective drug delivery using adhesive hydrogels for treatment of locally advanced TNBC

Triple negative breast cancer (TNBC) is an aggressive form of cancer that represents 20% of invasive breast cancers, and about 15% are locally advanced at time of presentation. TNBC is negative for estrogen and progesterone receptor, as well as for HER2, and hence it is not treatable with common endocrine treatment such as tamoxifen or Herceptin. Systemic neoadjuvant therapy has been established as the preferred therapeutic approach for locally advanced breast cancer, downstaging the disease and preventing mastectomy. However, complications of systemic chemotherapy are devastating. Local therapy would prevent high concentrations of circulating drug and reduce off-target tissue retention. Yet, the means to attain ideal release kinetics and selective uptake remain elusive. I developed a novel class of biocompatible and biodegradable adhesive materials based on dendrimer and dextran that can coat the tumor and locally release doxorubicin in a controlled manner. Doxorubicin was conjugated to the dendritic component of the adhesive hydrogel to form a pro-drug capable of being released over time as the hydrogel degrades at a pre-programmed rate. The pro-drug was further modified with a ligand capable of sensing and discerning between healthy and cancer cells and facilitating uptake through receptor-mediated endocytosis (RME). The platform developed herein provides a paradigm shift in the way we treat cancer, in a local, selective and targeted manner, to impart optimal clinical outcome.

Department dc:contributor.department

Harvard--MIT Program in Health Sciences and Technology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2016

Author dc:creator

• Oliva Jorge, Nuria

Advisor dc:contributor.advisor

• Elazer R. Edelman and Natalie Artzi.

• Harvard--MIT Program in Health Sciences and Technology.

Statement 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/104611

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/104611