Development and Evaluation of Nano‑scale Systems for Targeted Delivery to Treat Liver Fibrosis

<p>Excessive deposition of ECM is the common characteristic of liver fibrosis. During hepatic fibrosis, various inflammatory cytokines are released and trigger the activation of quiescent HSCs. The activated HSCs play the major role in producing extra amount collagen. It becomes very crucial to focus on HSCs to find out therapeutics, such as inhibiting collagen synthesis, inhibiting activation to myofibroblasts, or controlling inflammation.</p> <p>To control excessive collagen synthesis, one triplex forming oligonucleotides (TFO), was systemically administrated to prevent type I collagen mRNA transcription. To enhance circulation time and targeted delivery efficiency, TFO was conjugated to M6P‑HPMA and showed efficient targeted delivery to HSCs. Two week short term in vivo i.v. administration also showed the therapeutic effects on liver fibrosis by M6P‑HPMA‑TFO.</p> <p>Transforming growth factor β1 (TGF‑β1) acts as the initial factor for liver fibrosis. TGF‑β1 gene was demonstrated to be interfered by siRNA in a sequence and dose dependent mode in HSC‑T6 cell line. Later, GFAP promoter driven HSC‑specific pri‑miRNA mimic and pri‑miRNA cluster mimic showed HSC‑specific TGF‑β1 gene silencing to avoid nonspecific inhibition of TGF‑β1 expression in other cells and organs.</p> <p>The novel LPA antagonist, PTP, can interact with LPA receptor on the surface of cells to inhibit the proliferation, which is also one consequence of HSCs activation. However, the low aqueous solubility affects its in vivo application. Therefore, poly(ethylene glycol)‑b‑poly(carbonate‑co‑lactide) copolymers were used to make micellar formulation to enhance solubility. PEG‑PCcL micelles were applied to increase the aqueous solubility of PTP. In vivo administration of PTP loaded PEG‑PCcL showed therapeutic effects on fibrosis in common bile duct ligated mice.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2011

Author dc:creator

• Yang, Ningning

Contributors dc:contributor

• Ram I. Mahato, Ph.D.

• gene therapy
• HSC
• liver fibrosis
• nano
• targeted delivery
• Medicine and Health Sciences
• Pharmaceutics and Drug Design
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/310

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1308