Browsing by Subject "micelles"

Now showing 1 - 3 of 3
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    Amphiphilic And Random Copolymers: Self Assembly And Application In Drug Delivery Formulations
    (2019-03) Tale, Swapnil
    One of the biggest challenges in the field of drug delivery is the development of a system that can deliver cargo to a specific organ or cell and improve the aqueous solubility of poorly water soluble drugs. Recently, amphiphilic and random polymers have attracted considerable attention from researchers in order to elucidate these issues. Amphiphilic polymers consist of both hydrophilic and hydrophobic segments. Amphiphilic polymers are not only limited to drug delivery applications but also have utility in products such as food, detergents, paints, and cosmetics etc. Random copolymers consist of two or more monomers, the chain can add these monomers in any order. The incorporation on monomers into chain based on numerous factors such as conditions used for polymerization, reactivity of one monomer towards another etc. which can follow order depend on reactivity of one monomer towards another. Random polymers are continuously finding applications in the formulation industry due to their ability to improve aqueous solubility of poorly water soluble drugs. This thesis highlights my work on 1) the self-assembly of amphiphilic polymers to form micelles, 2) the application of micelles in pharmaceutical formulation, 3) the use of amphiphilic polymers as excipients, and 4) the use of random copolymers to enhance aqueous solubility of model drugs. Chapter 2 describes the synthesis of trehalose-containing amphiphilic diblock terpolymers with increasing trehalose content in the hydrophilic segment of the terpolymers. A poly(ethylene-alt-propylene)–poly[(N,N-dimethylacrylamide)-grad-poly(6-deoxy-6-methacrylamido trehalose)] (PEP-P(DMA-g-MAT)) polymer was chosen as a model system. The PEP content of the system was deliberately kept low to trigger formation of micelles in solution. PEP-P(DMA-g-MAT) successfully self-assembled into micelles in water. When incubated in various salt and serum-containing media, these micelles exhibited excellent stability from aggregation. Due to their excellent stability, these nanocarriers can be further optimized for potential systemic drug delivery applications. Chapter 3 demonstrates the effect of forming solution state polymer assemblies (prior to spray drying) on drug dissolution and supersaturation maintenance of poorly water soluble drugs. Herein, we synthesized four model polymer excipients (amphiphilic diblock ter- and copolymers): PEP-P(DMA-grad-MAG) and PEP-PDMA, and their respective hydrophilic analogues, P(DMA-grad-MAG) and PDMA. Our study clearly showed that formation of micelles prior to spray drying enhanced the dissolution of poorly water soluble drugs. Therefore, using micelle structures in excipient formulations is a simple and controlled platform for oral drug delivery. Chapter 4 describes a new synthetic platform with Trehalose-based diblock terpolymers to increase the solubility of poorly water soluble drug candidates. This study reveals that the solubility of polymer matrices in dissolution media and increase in hydrogen bonding sites in polymer matrices are critically important to decrease drug crystallinity & maintaining super saturation concentration in dissolution media. Chapter 5 presents the solubility enhancement of a highly lipophilic drug, phenytoin via interaction with poly(N-isopropylacrylamide-co-vinylpyrrolidone) (P(NIPAAm-co-VP)). Chapter 6 explains a systematic approach to understand structure-property relationships between drugs and excipients. This study illustrates that the first step to design a new excipient for a drug is to study the crystallization mechanism of that drug. When the drug crystallization mechanism is known, it is necessary to incorporate groups in the excipient formulation that can interact and interfere with the drug crystallization process to increase and maintain its aqueous solubility.
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    Investigating The Interactions Of Polycations With Nucleic Acid And The Mechanisms Of Delivery
    (2015-05) Sprouse, Dustin
    Polymers - large macromolecules composed from many smaller subunits - have ever-growing uses and potentials in our lives. More specifically, cationically charged polymers have been widely explored as non-viral vectors to deliver nucleic acid to cells in an effort to regulate gene and protein expression. The polymeric vehicle must not only bind and complex with DNA to protect and deliver it to the targeted site, but also efficiently dissociate from the DNA and be non-toxic to the cell or host organism. Herein lies the wide array of polymers that must be rationally designed and synthesized in order for the delivery vehicle to perform its specific function. At the turn of the century, two monumental achievements paved way for gene therapy. First, the Human Genome Project was completed. This milestone continues to unravel important information about the genetic basis of human health, disease, hereditary, and genetic dispositions. Second, RNA interference was discovered, an innate cellular pathway to control gene expression within cells. These discoveries afforded scientists the information necessary to move forward with controlling gene and protein expression profiles. More recently, CRISPR-cas technology was discovered, which allows scientists to permanently edit the genetic code by either regulating genes or adding, disrupting, deleting, or altering the specific base-pairs within the DNA sequence. Herein, we investigate several classes of polymers and macromolecules for the complexation and delivery of nucleic acid, including: amino acids, dendrimers, micelles, and linear homo- and block polymers. Initially, it was shown that polymer type, length, charge, dispersity, and composition greatly affect the efficacy of these therapeutic delivery vehicles. With this in consideration we set out to explore some of the fundamental properties of polymeric vectors. Diblocks, triblocks, and statistical copolymers were designed and synthesized with varying amounts of primary and tertiary amines. These were complexed with pDNA to from polyplexes and probed for their toxicity, stability, gene expression profiles, and mechanisms of membrane permeability. Amphiphilic polymers were also synthesized, which in aqueous environments spontaneously self assembled into core-shell structured micelles. These were probed for their ability to change size in different buffers and form different sized aggregates with DNA.
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    Mechanisms of Chain Exchange in Block Copolymer Micelles
    (2015-11) Lu, Jie
    Mechanisms of equilibration in block copolymer micelles were investigated in detail using time resolved small angle neutron scattering (TR-SANS). The model polymers used in this study were polystyrene-b-polyethylenepropylene (PS-PEP) diblock copolymers and corresponding triblock copolymers (PS-PEP-PS, PEP-PS-PEP). When dissolved in squalane, the polymers self assembled into spherical micelles with the PEP blocks forming the solvated coronas, and undiluted PS blocks as the micelle cores. Normal and selectively deuterated equivalent polymers with controlled molecular weight, narrow molecular weight distribution and composition were synthesized by anionic polymerization of styrene and isoprene followed by the selective saturation of the polyisoprene blocks. The structure of polymer micelles were characterized using dynamic light scattering (DLS) and small angle X-ray scattering (SAXS). A contrast matching strategy was employed for the TR-SANS experiments, where separately prepared deuterated and protonated micelles were mixed at equal volume fractions in a solvent containing 42 vol% h-squalane and 58 vol% d-squalane. Chain exchange reduces the mean contrast of the micelle cores in the solvent mixture, thus reducing the SANS scattering intensity, providing a method to characterize the dynamics of the process as a function of time. In this thesis, several aspects of chain exchange mechanisms were investigated. The hypothesis of hypersensitivity of chain exchange rate to the core block length, and the single chain exchange mechanism, were first tested and confirmed in the PS-PEP model micelle system. The chain exchange mechanisms in PEP-PS-PEP and PS-PEP-PS micelles were then investigated, and a remarkable effect of molecular architecture on the chain exchange rate is documented. In addition, this study explores the facilitating role of the corona chains in molecular exchange. It was found that adding PEP homopolymers of size comparable to the PEP blocks into dilute PS-PEP micelle solutions can significantly retard the chain exchange rate. Decreasing the corona block fraction in the PS-PEP polymers also reduced the chain exchange rate, and the concentration dependence of the chain exchange relaxation time constant. Finally, we extended our scope to chain exchange between micelles away from equilibration, i.e., micelle hybridization of two populations of PS-PEP micelles of different sizes. The results of this work suggested quantitatively different mechanisms when the micelle systems are away from equilibration, and a concentration effect was found, even when the micelles are still dilute.