Author

Nan Zhang

Date of Award

8-2013

Degree Type

Dissertation

Embargo Date

4-7-2014

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering

Advisor(s)

Rebecca A. Bader

Keywords

Drug Delivery, Micelles, Nanoparticles, Polysaccharides, Rheumatoid Arthritis

Subject Categories

Biomedical Engineering and Bioengineering | Chemistry | Pharmacy and Pharmaceutical Sciences

Abstract

The field of drug delivery has provided a solution to the limited efficacy and high toxicity of many drugs. Nano-sized drug carriers are popular because their size allows for selective accumulation in the diseased area. Polysaccharides are non-toxic and biodegradable natural polymers that can serve as the basis for these nano-sized carriers. Polysialic acid (PSA) is such a polysaccharide with strong hydrophilicity that may reduce uptake by the reticuloendothelial system and prolong drug circulation. In this study, we developed PSA-based nanocarriers, specifically micelles and nanoparticles, for improved drug delivery with improved efficacy and minimized toxicity. PSA-based micelle systems were developed via conjugation with two hydrophobic groups, decylamine (DA) and polycaprolactone (PCL). Nanoparticles were fabricated via ionic complexation of the negatively charged PSA with positively charged N, N, N-trimethyl chitosan (TMC). All three nanocarriers possessed sizes close to 100 nm with low polydispersity (PDI) and high zeta potential values. Literature suggested that these characteristics would allow the nanocarriers to be physiologically stable and would facilitate passive accumulation within diseased areas. Rheumatoid arthritis (RA) was selected as the primary disease model for evaluation of our nanocarriers. PSA-PCL micelles and PSA-TMC nanoparticles showed low cytotoxicity, as demonstrated by high IC50 values (PSA-PCL: 10.5 ± 1.7 mg/ml; PSA-TMC: 7.65 ± 0.07 mg/ml) to synovial cells, the so-called conductors of joint destruction in rheumatoid arthritis. The synovial cells were also used to demonstrate effective uptake of fluorescently tagged nanocarriers. Three disease modifying anti-rheumatic drugs (DMARDs) were selected for loading into the nanocarriers. Cyclosporine A (CyA) was encapsulated within the PSA-PCL micelles, while methotrexate (MTX), and dexamethasone (DM) were entrapped within the PSA-TMC nanoparticles. PSA-PCL micelles were loaded with 0.09 ± 0.02 mg CyA per mg of PSA- PCL, while PSA-TMC nanoparticles were loaded with 0.10 ± 0.03 mg MTX and 0.10 ± 0.02 mg DM per mg of PSA-TMC. Controlled release of the DMARDs from the nanocarriers was demonstrated. An in vitro model of rheumatoid arthritis was used to demonstrate the anti-inflammatory nature of the MTX- and DM-loaded PSA-TMC nanoparticles. To the author's knowledge, this is the first time that PSA-based nanocarriers were successfully developed and evaluated for improved drug delivery.

Access

Open Access

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