Date of Award

Summer 2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Yuri Lvov

Abstract

The significance of any drugs, therapeutic proteins, or any bioactive compounds, is based not only on their effects on diseases but also on how specifically, how readily, how controllable and how prolonged their effects on the disease without having any side effects. Thus the techniques involved in the drug encapsulation and its controlled release for a longer duration of time form one of the important processes of drug reformulation. In recent years nanoparticles have created overwhelming attention for delivering drugs by nanoencapsulation. The smaller size of nanoparticles has longer circulation time and higher cellular uptake when compared with larger size of microparticles. Thus, the field of nanotechnology through its subsections of nanomedicine and biomedical nanotechnology is revolutionizing the pharmaceutical industries. The purpose of this research work is to nanoengineer bioresponsive materials for its application as a template for making submicron or nanosized drug delivery systems.

The first half of this work deals with alginate template, a semi-synthetic polymer. Alginate has been reported as suitable for encapsulation of many bioactive agents like cells, enzymes, and drugs, owing to its relatively aqueous environment within the alginate matrix, the mild room condition encapsulation process, and high gel porosity. Recently biotechnological innovations have introduced some new forms of drugs with therapeutic proteins and oligonucleotides. Hence, submicron or nanoemulsions with narrow particle size ranges are becoming favored over larger particulate and/or polydisperse systems. This work deals in detail with the optimization of the size of calcium alginate nanoparticle preparation by the emulsification technique. By the optimized emulsion method calcium alginate nanoparticles of 300 nm in diameter can be prepared. These nanoparticles were later used for encapsulation and release of curcumin. Earlier, the smallest alginate particle produced had a minimum size of 1–5 μm; hence, this work remains as a frontrunner in the preparation of calcium alginate nanoparticles.

The second half of this work deals with a natural nanotubular template called halloysite. Halloysite is tubular alumina silicate clay of 15–200 nm inner lumen diameter and 0.5–5 microns long. It was used for loading poorly soluble drugs and sustaining their release. Loading was optimized by varying pH and alcohol/water ratio in the solvent with a maximum drug loading of 12% by volume. Near linear release of dexamethasone, furosemide, and nifedipine was demonstrated for 5–10 hours. The presence of silicates on halloysite outer surface provides a negatively charged exterior, and makes it possible to do Layer-by-Layer (LbL) assembly of positively charged polyelectrolytes and nanoparticles on halloysite. The LbL assembly was later extended to dexamethasone drug-loaded halloysite for its controlled release. A study of the effect of number of assembled layers and the effect of molecular weight of the assembled polymers on the release profile of the drug revealed that a high molecular weight of the assembled polymers and an optimum number of layers gave a very slow sustained release. Encapsulation of the drugs inside the lumen of the halloysite coupled with LbL assembly of clay-drug composite provides a novel formulation for controlled release of drugs.

Biocompatibility is a major problem for many materials to be used as a drug constituent. The cytotoxicity studies for halloysite were also done in this work to ensure the valid application of halloysite in drug reformulations.

Halloysite clay was also demonstrated as a nanoreactor for synthesizing silver nanoparticles. Synthesis was carried out by reducing the silver acetate which was loaded inside the halloysite. This in situ synthesis offers a novel way of fabricating surface modified clay materials, nano-rod metals, core-shell type ceramic nanocomposites, and potential application in antimicrobial coatings and wound healing.

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