Date of Award

12-1-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Anthony J. Di Pasqua

Second Advisor

Riyaz Basha

Third Advisor

Ignacy Grysczynski

Abstract

Nanomedicine is one of the fastest emerging fields in recent times. Small size, tunable surface properties and efficient drug loading capacity are some of the properties that make them a promising option for various applications in biological sciences. Using nanocarriers for drug delivery offers several advantages like delivery of poorly soluble drugs, better bioavailability, targeted delivery and extended release of drugs. In this work, we demonstrated the formulation and methods of use for three different nanocarriers.

1) 166Ho iron garnet nanoparticle-containing bandages for treatment of squamous cell carcinoma of skin: Squamous cell carcinoma (SCC) of skin is a type of non-melanoma skin cancer (NMSC) which constitutes 20% of all NMSCs. While surgery is the primary treatment option for SCC, radiation therapy also plays an irreplaceable role in the treatment of SCC. Our lab has previously reported an electrospun nanofibrous polyacrylonitrile (PAN) bandage containing holmium-165 iron garnet (165HoIG) nanoparticles, which can be neutron activated to 166Ho and used for radiotherapy of SCC. The synthesis, characterization and stability of the bandage were also reported. Here, we tested the in vivo efficacy of the 166HoIG-PAN bandage for the treatment of SCC. When treated with the radioactive bandage, tumor progression was significantly low in mice compared to those with non-radioactive bandage. The dose used was clinically relevant. Histological evaluation showed no damage to surrounding organelles.

2) Targeted chemotherapy for non-small cell lung cancer using antibody-coated gold nanoparticles: Non-small cell lung cancer (NSCLC) is a type of lung cancer which constitutes nearly 80% of all lung cancers. Being detected at later stages limits its treatment, thus resulting in a lower fiver year survival rates. Though limited by their dose related side effects, platinum drugs are the first line of treatment for NSCLC. Several Pt(IV) complexes, which are the prodrugs of Pt(II) compounds are shown to have potent anti-cancer activity and are capable of overcoming the limitations of Pt(II) compounds. Not many targeted therapies are available for NSCLC because of its complex molecular pathology. CD22 is an adhesion molecule that is shown to be broadly expressed on NSCLC cell lines. Hence, in this project, we developed CD22 targeted gold nanoparticles to deliver Pt(IV) complex for the treatment of NSCLC. Synthesis and characterization of polyethylene glycol (PEG) coated gold nanoparticles conjugated with Pt(IV) complex and an antibody against CD22 is reported. The expression of CD22 on various NSCLC and normal cell lines and the uptake of the synthesized nanoparticles in these cell lines was studied.

3) Tetracycline-Containing MCM-41 Mesoporous Silica Nanoparticles for the Treatment of Escherichia Coli: Tetracycline (TC) is a very well-known antibiotic whose use has been limited due to drug resistance. Nanoparticle formulations, can help overcome the resistance mechanisms to certain extent. Mesoporous silica nanomaterials (MSNs) are widely studied for drug delivery applications; Mobile Crystalline Material-41 (MCM-41), a type of MSN, that has a mesoporous structure with pores forming channels in a hexagonal fashion. We used MCM-41 mesoporous silica nanoparticles for the delivery of TC and tested its efficacy in E. coli. The TC containing nanoparticles showed a burst release of drug in PBS and in LB broth medium and most of the drug was released within 1 h. The TC loaded MSNs showed enhanced inhibition of E. coli compared to free TC and unloaded MSNs at a concentration of 0.5μg/mL and 1μg/mL. Further, the TC containing MSNs uptake by E. coli was demonstrated using transmission electron microscopy.

Comments

Bhuvaneswari Koneru, Inorganic nanoparticles for applications in biomedical sciences Doctor of Philosophy (Biomedical Sciences), November, 2016, 112 pp., 7 tables, 29 figures, bibliography, 225 titles.

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