Browsing by Subject "PLGA"

Now showing 1 - 4 of 4
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    Biodegradable, Liquid-Filled, Spherical Capsules With Pre-Determined Burst Times
    (2017-06) Harish Jain, Krutika
    A biodegradable poly(lactic acid-co-glycolic acid) (PLGA) capsule is presented in a spherical geometry, which exploits the principle of osmosis as an internal program to achieve a delayed-burst release of its load. The capsule burst lag-time is accurately predicted by modeling the rate of water uptake by the capsule core as a function of the capsule shell thickness, radius of the capsule, core osmotic pressure and the membrane tensile strength. Elastoplastic and failure characterization of PLGA was conducted as a function of hydration under uniaxial and biaxial stretch and by a novel “beach ball” inflation technique. The presence of small amounts of moisture leads to a decrease in yield stress and a decrease in elongation at break. The above presentation suggests reproducible preparation and evaluation of spherical rupturable osmotic capsules.
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    Effects of Freezing and Freeze-drying on Protein Conjugated Nanoparticles
    (2018-10) Su, Yafan
    Biodegradable poly(D,L-lactide-co-glycolide) PLGA nanoparticles (NPs) have been extensively investigated for drug delivery. Protein conjugated NPs provide the advantage of active targeting. To overcome the instability associated with storage of aqueous dispersions, NPs are usually lyophilized. However, the freezing and freeze-drying stress can lead to nanoparticle aggregation and protein denaturation. As such, sucrose is widely used as a cryoprotectant and minimal ‘cryoprotectant to particle ratio’ is required. In this study, we used trypsin as a model protein to conjugate on the PEGlyated NPs. The effects of the freezing and freeze-drying process on trypsin conjugated NPs was studied by comparing the size of the NPs, the morphology of the NPs under fluorescent images and the trypsin activity after of the fresh made, freeze-thawed and lyophilized NPs. A minimum sucrose to NPs ratio was founded to provide the complete protection of the trypsin conjugated NPs.
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    Examining and improving the chemopreventive efficacy of curcumin
    (2012-09) Grill, Alexander E.
    Curcumin, a polyphenol extracted from turmeric, has shown chemopreventive and chemotherapeutic effects against cancer. However, curcumin suffers from poor bioavailability, which limits its clinical use. We hypothesized that using novel microparticle and SMEDDS formulations will improve the pharmacokinetics and therapeutic efficacy of curcumin. Initial studies examined the anticancer efficacy of curcumin loaded poly(lactide-co-glycolic acid) (PLGA) microparticles in a transgenic mouse model of human epidermal growth factor receptor-2 (HER-2) cancer, Balb-neuT. HER-2 is overexpressed in 30% of breast cancer cases and is associated with poor prognosis and high incidence of metastasis. Curcumin microparticles delayed tumor appearance by 2-3 weeks and were associated with a decrease in VEGF protein levels and CD-31+ microvasculature compared to empty microparticles. However, when compared to saline controls, blank microparticles appeared to accelerate tumorigenesis. Blank PLGA microparticles were shown to activate NF-kB signaling, indicating systemic inflammation after injection. The delay in tumorigenesis with curcumin-loaded microparticles was likely attributed to the anti-inflammatory effects of curcumin. Future studies will examine the systemic effects of blank PLGA microparticles as well as explore other polymers for curcumin microparticle delivery. A self microemulsifying drug delivery system (SMEDDS) was examined for oral delivery of curcumin. The SMEDDS formulation solubilized curcumin at high concentrations (~45 mg/mL). However, administering curcumin in the SMEDDS formulation did not increase curcumin bioavailability but increased gut absorption, evident by increased plasma curcumin glucuronide levels. We hypothesized that oral bioavailability of curcumin could be enhanced by increasing its absorption and decreasing metabolic clearance simultaneously. Microsomal studies showed that silibinin and quercetin inhibited curcumin glucuronidation in vitro. Piperine, which was shown to improve curcumin bioavailability previously, silibinin and quercetin were administered with curcumin in vivo. Coadministration of curcumin and piperine showed high variability after dosing. Addition of silibinin significantly improved curcumin bioavailability (3.5 fold) compared to curcumin alone. Future studies should examine the chemopreventive potential of curcumin and silibinin for HER-2+ breast cancer.
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    TLR7/8 Agonist Encapsulating Polymeric Nanoparticles for Cancer Immunotherapy
    (2018-10) Kim, Hyunjoon
    The immune system is important for the prevention of cancer and formed the basis of cancer immunotherapy. That is, enhancement of the immune response for the treatment of malignant cancer cells. The field has undergone significant progress to include the use of checkpoint inhibitors, monoclonal antibodies and cytokine therapies. In addition, a cancer vaccine, composed of tumor associated antigens (TAAs) and vaccine adjuvant, is particularly promising. Effective vaccines can mobilize tumor-specific CD8 T cells to kill selectively tumor cells with cytotoxic granules and secrete IFN-ɣ that sensitize tumors to be susceptible to effector immune cells. Additionally, activated CD8 T cells become memory cells and can respond to same TAA-epitopes, which can be effective for long-term protective immunity to inhibit cancer recurrence. Activation of dendritic cells (DCs), which are the main antigen-presenting cells (APCs), is critical for T cell immunity. To an elicit tumor-specific CD8 T cell response, DCs have to process and present TAAs to CD8 T cells through the major histocompatibility complex (MHC) I. Moreover, co-stimulatory signals and pro-inflammatory cytokines are required to stimulate CD 8 T cells. However, CD8 T cell anergy and exhaustion will occur if TAA treatment is not sufficiently immunogenic to trigger DC activation. Therefore, development of immunostimulatory adjuvant that can trigger DC activation can enhance therapeutic efficacy of cancer vaccines. Imidazoquinoline-structured synthetic toll-like receptor (TLR) 7/8 agonists are strong cytokine inducers that can be a potent vaccine adjuvant. TLR7/8 ligation can activate MyD88 signaling pathways and stimulate DCs to upregulate co-stimulatory molecules and secrete pro-inflammatory cytokines and type I interferons. However, TLR7/8 agonists lack prominent efficacy in vivo due to the rapid clearance from the injection site. Following subcutaneous (SC) injection, small molecules enter the systemic circulation via blood capillaries and only small portion can reach the draining lymph nodes. Therefore, our goal was to develop a SC injectable drug carrier that can more efficiently deliver as well as prolong duration of at the site of action of TLR7/8 agonists. In this study, we fabricated poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) containing TLR7/8 agonists. Nanoparticulate delivery of TLR7/8 agonist showed enhanced DC activation and antigen-presentation compared to the soluble form of TLR7/8 agonists. When combined with peptide/tumor cell lysate-based antigens, NPs potentiated the antigen-specific CD8 T cell expansion and increased cytotoxic functions, which resulted in enhanced efficacy in both prophylactic and therapeutic tumor models. To further enhance endo/lysosomal delivery of TLR7/8 agonists in PLGA NPs, we included a sodium bicarbonate-mediated gas-generating system that is acidic pH-responsive. This approach resulted in 33-fold greater amount of TLR7/8 agonists encapsulated within the NPs. More importantly, the PLGA NP immunization elicited a stronger CD8 T cell response compared to conventional PLGA NPs, which in turn, enhanced therapeutic efficacy. As tumor microenvironment is immune suppressive, we examined whether modulation of tumor microenvironment can enhance the therapeutic efficacy of cancer vaccine. We reduced the immune suppressive cells including myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) by daily oral dosing of a tyrosine kinase inhibitor (TKI), sunitinib. Additionally, we adapted an anti-PD-L1 antibody to block programmed death ligand 1 (PD-L1) expressed on tumor-associated (M2) macrophages and MDSCs that exhaust CD8 T cells, to augment the CD8 T cell activation at the tumor. In our study, combination of sunitinib and PD-L1 blockade significantly decreased the immune suppressive cell population and reduced PD-L1 expression on these cells. We also examined if nanoparticulate delivery of TLR7/8 agonist can potentiate NK cell-mediated cancer immunotherapy through its known effect on TH1 immunity. Antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies was found to be augmented in response to TLR7/8 agonist encapsulating NPs as a vaccine adjuvant. Overall, our studies demonstrate that PLGA NPs broaden the application of TLR7/8 agonists for improved cancer treatment. Moreover, this platform holds promise to enhance the efficacy of cancer vaccines composed of tumor associated antigens (TAAs) and vaccine adjuvant