Hydrogels are three dimensional networks of hydrophilic homopolymers or copolymers generally covalently or ionically crosslinked. They interact with aqueous media by swelling to some equilibrium value by retaining the aqueous media in their structures. This study concerns the investigation of the swelling and the controlled drug release behaviour of hydrogels synthesized via the photopolymerisation process. The study of hydrogels in this project was oriented towards their biomedical applications as controlled drug delivery devices. It is a known fact that the complete conversion of monomers to polymers may not be achieved in the polymerisation process thus there is always a certain component of unreacted toxic monomers still remained in the polymer matrix. These monomers have the tendency to leach out of the polymer matrices when the polymers are in contact with an aqueous medium thus rendering the hydrogel to be nonbiocompatable. The polymers synthesized in this work were washed thoroughly in milli-Q-water and then evaluated in vitro for any possible toxic effect on human keratinocyte (HaCaT)v cells using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diaphenyl tetrazolium bromide (MTT) cell proliferation assay. The cytotoxicity results indicated that the hydrogels understudy sustained and allowed a positive growth of the HaCat cells in the duration of the cytotoxicity experiment, thus proving to be satisfactorily compatible. / Doctor of Philosophy (PhD)

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 86-92).

Nanomedicine, the medical application of nanotechnology, uses nanoscale objects that exist at the interface between small molecule and the macroscopic world for medical diagnosis and treatment. One of the healthcare applications of nanomedicine is drug delivery: the development of nanoscale objects to improve therapeutics' bioavailability and pharmacokinetics. Shell crosslinked knedel-like nanoparticles (SCKs), that are self assembled from amphiphilic block copolymers into polymeric micelles and then further stabilized with crosslinkers isolated throughout the peripheral shell layer, have been investigated for drug delivery applications that take advantage of their core-shell morphology and tunable surface chemistry. SCKs are attractive nanocarriers because the cores of the SCKs are used for sequestering and protecting guests. The readily adjustable shell crosslinking density allows for gating of the guest transport into and out of the core domain, while retaining the structural integrity of the SCKs. Moreover, the highly functionalizable shell surface provides opportunity for incorporation of targeting ligands for enhanced therapeutic delivery. The optimization of nanoparticle size, surface chemistry, composition, structure, and morphology has been pursued towards maximization of the SCKs' therapeutic efficacy. With distinctively different dimensions, compositions and structures of the core and shell domains of SCKs, and an ability to modify each independently, probing the effects of each is one of the major foci of this dissertation. Utilization of a living radical polymerization technique, reversible addition-fragmentation chain transfer (RAFT) polymerization, has allowed for facile manipulation of the block lengths of the polymer precursors and thus resulted in various dimensions of the nanoparticles. SCKs constructed from poly(acrylic acid)-b-polystyrene (PAA-b-PS) with various chain lengths, have been investigated on the loading and release of doxorubicin (DOX). The effect of PEGylation on paclitaxel (PTX) loaded SCKs on the cell internalization and killing was investigated. Apart from chemotherapies, the SCKs were explored as antimicrobial agents by incorporating silver species. Conjugation of the SCK surface with a protein adhesin through amidation chemistry to promote epithelial cell targeting and internalization was developed. Nanoscale assemblies with complex morphologies constructed from a linear triblock copolymer was investigated. Furthermore, a highly multifunctional nanodevice for imaging and drug delivery functionalized with a chelator for radio-labeling, polyethylene glycol (PEG) for improved biodistribution, targeting ligands, a chromophore and a therapeutic agent was evaluated in vivo as active-targeted delivery of therapeutics.

The interest in microemulsions as transdermal delivery systems have been motivated by their large surface area for mass transfer, their high solubilization capacity of hydrophobic actives, and their ability to improve skin penetration. Lecithins (mixtures of phospholipids similar to those find in the skin) have been proposed as ideal surfactants in microemulsions due to their skin compatibility. Unfortunately, their incorporation into microemulsions used to require toxic medium-chain alcohols or viscous polymeric co-surfactants. Recently, microemulsion-base “green solvents” were formulated with lecithin and linker molecules. The main objective of this dissertation was to test this concept of linker-based lecithin microemulsions in transdermal delivery. In the first part of this study, linker-based lecithin formulations were developed using soybean lecithin as main surfactant, sorbitol monooleate as lipophilic linker, and caprylic acid/sodium caprylate as hydrophilic linkers. These additives, at the suggested concentration, are safe for cosmetic and pharmaceutical applications. The low toxicity of these formulations was confirmed in cultured human skin tissues. The solubilization and permeation of a common anaesthetic, lidocaine, was evaluated. The concept of “skin” permeability was introduced to account for the differences in solvent-skin partition when comparing different delivery systems. The linker-based lecithin microemulsion produced a substantial absorption of lidocaine into the skin, when compared to a conventional pentanol-lecithin microemulsion. The second part of this study takes advantage of the lidocaine adsorbed in the skin with the linker-based lecithin microemulsion as reservoir for in situ skin patches. The in situ patches were able to release 90% of the lidocaine over 24 hours, which is comparable to the release profile obtained from conventional polymer or gel-based patches. In the third part of this work, the role of surfactant droplets on the transport of lidocaine was studied. A mass balance model that accounted for mass transfer and partition coefficients was introduced. The parameters generated from the model confirm that in most cases the transport through the skin limits the overall penetration of lidocaine. Besides the conventional diffusion mechanism, the results suggest that surfactant droplets, carrying lidocaine, also penetrate into the skin and contribute to the accumulation of the lidocaine in the skin.

Polymeric nanoparticles have gained increased popularity for drug delivery as they not only overcome the problem of limited aqueous solubility of many hydrophobic drug molecules, but also have the potential to improve the pharmacologic properties of anticancer drugs by increasing their in vivo half-life. A series of biodegradable poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate), P(LA-co-TMCC), was first synthesized by Sn(Oct)2 catalyzed bulk polymerization. In order to obtain the polymer product with a better-defined composition, the polymer synthesis was improved by using organo-catalytic ring-opening copolymerization. The copolymer molar mass and composition were controlled by varying the monomer to initiator ratio and the monomer feed ratio. By grafting amine-terminated polyethylene glycol (PEG-NH2) to the carboxylate groups on the copolymer backbone, amphiphilic copolymers were formed and self-assembled to form nanoparticles with narrow size distribution. The nanoparticle size was observed to be influenced by the polymer composition and the self-assembly conditions. To gain greater insight into the stability of these nanoparticles in blood, they were tested in both fetal bovine serum and individual serum protein solutions. By encapsulating Förster resonance energy transfer (FRET) pairs and following their release by fluorescence, these micelles demonstrated strong thermodynamic and kinetic stability in the presence of serum. By incorporating functional groups (azide or furan) on the PEG chains, either cell adhesive peptides (i.e. alkyne-functionalized GRGDS) or targeting antibodies (i.e. maleimide-modified trastuzumab) were coupled to the surface of the nanoparticles through Huisgen 1,3-dipolar cycloaddition reaction or Diels-Alder chemistry, respectively. The GRGDS modified nanoparticles showed specific binding affinity to rabbit corneal epithelial cells that express αvβ1 integrin receptors.

Polymeric nanoparticles have gained increased popularity for drug delivery as they not only overcome the problem of limited aqueous solubility of many hydrophobic drug molecules, but also have the potential to improve the pharmacologic properties of anticancer drugs by increasing their in vivo half-life. A series of biodegradable poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate), P(LA-co-TMCC), was first synthesized by Sn(Oct)2 catalyzed bulk polymerization. In order to obtain the polymer product with a better-defined composition, the polymer synthesis was improved by using organo-catalytic ring-opening copolymerization. The copolymer molar mass and composition were controlled by varying the monomer to initiator ratio and the monomer feed ratio. By grafting amine-terminated polyethylene glycol (PEG-NH2) to the carboxylate groups on the copolymer backbone, amphiphilic copolymers were formed and self-assembled to form nanoparticles with narrow size distribution. The nanoparticle size was observed to be influenced by the polymer composition and the self-assembly conditions. To gain greater insight into the stability of these nanoparticles in blood, they were tested in both fetal bovine serum and individual serum protein solutions. By encapsulating Förster resonance energy transfer (FRET) pairs and following their release by fluorescence, these micelles demonstrated strong thermodynamic and kinetic stability in the presence of serum. By incorporating functional groups (azide or furan) on the PEG chains, either cell adhesive peptides (i.e. alkyne-functionalized GRGDS) or targeting antibodies (i.e. maleimide-modified trastuzumab) were coupled to the surface of the nanoparticles through Huisgen 1,3-dipolar cycloaddition reaction or Diels-Alder chemistry, respectively. The GRGDS modified nanoparticles showed specific binding affinity to rabbit corneal epithelial cells that express αvβ1 integrin receptors.

The interest in microemulsions as transdermal delivery systems have been motivated by their large surface area for mass transfer, their high solubilization capacity of hydrophobic actives, and their ability to improve skin penetration. Lecithins (mixtures of phospholipids similar to those find in the skin) have been proposed as ideal surfactants in microemulsions due to their skin compatibility. Unfortunately, their incorporation into microemulsions used to require toxic medium-chain alcohols or viscous polymeric co-surfactants. Recently, microemulsion-base “green solvents” were formulated with lecithin and linker molecules. The main objective of this dissertation was to test this concept of linker-based lecithin microemulsions in transdermal delivery. In the first part of this study, linker-based lecithin formulations were developed using soybean lecithin as main surfactant, sorbitol monooleate as lipophilic linker, and caprylic acid/sodium caprylate as hydrophilic linkers. These additives, at the suggested concentration, are safe for cosmetic and pharmaceutical applications. The low toxicity of these formulations was confirmed in cultured human skin tissues. The solubilization and permeation of a common anaesthetic, lidocaine, was evaluated. The concept of “skin” permeability was introduced to account for the differences in solvent-skin partition when comparing different delivery systems. The linker-based lecithin microemulsion produced a substantial absorption of lidocaine into the skin, when compared to a conventional pentanol-lecithin microemulsion. The second part of this study takes advantage of the lidocaine adsorbed in the skin with the linker-based lecithin microemulsion as reservoir for in situ skin patches. The in situ patches were able to release 90% of the lidocaine over 24 hours, which is comparable to the release profile obtained from conventional polymer or gel-based patches. In the third part of this work, the role of surfactant droplets on the transport of lidocaine was studied. A mass balance model that accounted for mass transfer and partition coefficients was introduced. The parameters generated from the model confirm that in most cases the transport through the skin limits the overall penetration of lidocaine. Besides the conventional diffusion mechanism, the results suggest that surfactant droplets, carrying lidocaine, also penetrate into the skin and contribute to the accumulation of the lidocaine in the skin.

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Chemistry." Includes bibliographical references.

Immunotherapy as a means for cancer treatment has been investigated for over a century. While studies have been completed using different immunological strategies, development of a clinical therapeutic cancer vaccine has proven elusive. Recently, success has been seen with prophylactic vaccines for cancers with known viral origins (Gardasil® and Cervarix for Human Papiloma Virus). However, such strategies do not address the challenge in generating effective immune response against other tumor antigens, most of which are weakly immunogenic self-antigens. Tolerance to these self-antigens could ultimately limit the patient’s ability to mount an effective anti-tumor immune response. The US Food and Drug Administration recently approved the first DC cell-based cancer vaccine, Provenge®, for use in prostate cancer. This vaccine requires cell isolations from the patient as well as in vitro DC modifications, which ultimately leads to high cost as well as multiple procedures. However, results indicate that, on average, patients live only four months longer than those receiving a placebo. While this work remains important, and offers proof that priming DCs can improve the lifespan of a patient, it ultimately does not offer a long-term cure. Direct and highly efficient in vivo delivery of antigens to DCs could overcome the challenges associated with ex vivo DC manipulation and may offer a more scalable method for generating anti-tumor immunity. This research focuses on the development of novel formulations that allow simultaneous delivery of protein/peptide-based tumor antigens and immune-modulatory nucleic acids (siRNA and immune stimulatory CpG) to the same dendritic cells (DCs) in-vivo. Such formulations allow a synthetic immune-priming center to be created at the site of immunization and simultaneously deliver the tumor antigen to DCs and modulate their immune response through IL-10 silencing. Our hypothesis is that using such a DC-targeted dual delivery system we will be able to illicit strong T helper 1 (TH1) and Cytotxic T Lymphocyte (CTL) response in vivo against a wide array of tumor antigens. This can become a platform technology where the biomolecules (antigen and immunomodulatory agents) can be easily varied based on particular cancers. / text

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