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Open Access Publications from the University of California

Scholarly Works (66 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2018)

As the “engines of life”, proteins play the most dynamic and diverse roles among all macromolecules in the body. Owing to their high specificity and potency, more than 130 proteins or peptides therapeutics have been developed for clinical use, and many more are being developed. Despite their tremendous promises, effective delivery of protein therapeutics to achieve the maximum efficacy needs to overcome three major barriers, which are associated with the delivery of therapeutics to the target organs, entrance of the therapeutics to the tissues, and entrance of the therapeutics to the cells. The inability to overcome such barriers may result in rapid loss of the activity, fast clearance and undesirable tissue biodistribution of the therapeutic proteins. Engineering nanocarriers for escorting therapeutic proteins into their specified destination has thus generated considerable interests.

In this dissertation, a delivery strategy employing polymeric nanocapsules for efficient extracellular and intracellular protein delivery is described. As an extension, zwitterionic polymer-based biosensors with effective protein immobilization and enhanced properties are also discussed. This dissertation work can be briefly outlined into three topics below:

1) Oxalate oxidase (OxO) was encapsulated within a thin layer of zwitterionic polymer shell via aqueous free-radical polymerization for the treatment of hyperoxaluria. As-synthesized OxO nanocapsules exhibited enhanced bioactivity, prolonged blood circulation half-life and reduced immunogenicity. This design enables systemic delivery of therapeutic enzymes for various applications.

2) The transcription activator-like effector nucleases (TALEN) were encapsulated. The shell properties were judiciously modulated to be cationic and acid-labile, which facilitates cellular uptake and subsequent cargo release. TALEN pairs recognizing the TAR region of HIV LTRs were delivered through this platform to induce robust excision of HIV-1 provirus in a variety of human cell lines, especially the primary T cell lines. This work provides useful suggestions for the research and development of anti-HIV therapies.

3) Zwitterionic polymers bearing amine groups were developed to facilitate the enzyme immobilization on chitosan-coated electrode for choline sensing. Such zwitterionic coating brought in sensors with improved enzyme loading, sensitivity and detection limit.

In summary, this research utilizes the nanocapsule platform to overcome different delivery barriers to realize specific delivery goals. The zwitterionic polymers can be used to prepare biosensors with enhanced properties.

    Cover page: Polymer-Protein Nanoparticles for Systemic Detoxification, Anti-HIV and Biosensor Applications
    • Article
    Earlier Faculty Research (1994)

    The purpose of this report is to evaluate the usefulness of the California Urban Futures (CUF) Model for analyzing realistic land use policy and planning alternatives at the sub-regional or county level. Following previous meetings of the ABAG Regional Planning Committee and consultations with local officials and planners, two Bay Area Counties were selected for further study: Solano and Sonoma.

    This report is organized into four sections. This section explains the logic and limitations of the CUF Model. Part II presents the results of four sets of land use policy simulations for Solano County. Part III presents CUF Model results for six Sonoma County Scenarios. Part IV builds on the experiences gained analyzing land use policy initiatives in Sonoma and Solano counties to evaluate the overall usefulness of the CUF Model for sub-regional planning.

      Cover page: Pilot Study of Solano and Sonoma Counties Land Use and Development Policy Alternatives
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2015)
      Liver metastasis is the most frequent cause of death from colon and other cancers. Generally, liver metastasis is recalcitrant to treatment. The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R on liver metastasis in orthotopic mouse models. HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used in the present study. S. typhimurium A1-R infected HT-29 cells in a time-dependent manner, inhibiting cancer-cell proliferation in vitro. S. typhimurium A1-R promoted tumor necrosis and inhibited tumor growth in a subcutaneous tumor mouse model of HT-29-RFP. In orthotopic mouse models, S. typhimurium A1-R targeted liver metastases and significantly reduced their growth. The results of this study demonstrate the future clinical potential of S. typhimurium A1-R targeting of liver metastasis.
        Cover page: Therapeutic efficacy of tumor-targeting Salmonella typhimurium A1-R on human colorectal cancer liver metastasis in orthotopic nude-mouse models
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2016)
        We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of "decoy, trap and shoot" chemotherapy.
          Cover page: Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2020)

          Background/aim

          Brain metastases are found in approximately 30% of patients with epidermal-growth-factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We compared the efficacy of two EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and osimertinib on a PC-9-GFP EGFR mutant NSCLC growing in the brain of nude mice.

          Materials and methods

          The brain metastasis models were randomized into five groups and treated for 15 days: Control; 5 mg/kg erlotinib; 50 mg/kg erlotinib; 0.5 mg/kg osimertinib; 5 mg/kg osimertinib. Tumor volume was evaluated by non-invasive fluorescence imaging.

          Results

          Only 5 mg/kg osimertinib, a low-dose compared to the clinically-equivalent dose, showed significant tumor regression compared to the control.

          Conclusion

          This study strongly supports the high activity of osimertinib for intracranial lesions of EGFR-mutant NSCLC.
            Cover page: Comparison of the Efficacy of EGFR Tyrosine Kinase Inhibitors Erlotinib and Low-dose Osimertinib on a PC-9-GFP EGFR Mutant Non-small-cell Lung Cancer Growing in the Brain of Nude Mice
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2015)
            Colon cancer liver metastasis is often the lethal aspect of this disease. Well-isolated metastases are candidates for surgical resection, but recurrence is common. Better adjuvant treatment is therefore needed to reduce or prevent recurrence. In the present study, HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used to establish liver metastases in nude mice. Mice with a single liver metastasis were randomized into bright-light surgery (BLS) or the combination of BLS and adjuvant treatment with tumor-targeting S. typhimurium A1-R. Residual tumor fluorescence after BLS was clearly visualized at high magnification by fluorescence imaging. Adjuvant treatment with S. typhimurium A1-R was highly effective to increase survival and disease-free survival after BLS of liver metastasis. The results suggest the future clinical potential of adjuvant S. typhimurium A1-R treatment after liver metastasis resection.
              Cover page: Adjuvant treatment with tumor-targeting Salmonella typhimurium A1-R reduces recurrence and increases survival after liver metastasis resection in an orthotopic nude mouse model
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)

              Background/aim

              Pazopanib (PAZ) can inhibit tumor progression, but whether PAZ inhibits lymph node metastasis and lymphangiogenesis in colorectal cancer is still unknown. The aim of the present study was to determine the efficacy of PAZ on tumor growth, lymph node metastasis and lymphangiogenesis in an orthotopic nude mouse model in colorectal cancer.

              Materials and methods

              CT-26-green fluorescence protein (GFP)-expressing mouse colon cancer cells were injected into nude mice to establish a subcutaneous colorectal cancer model and were treated with saline and PAZ. Additionals subcutaneous tumors were harvested and cut into 5 mm3 fragments, then tumor fragments were implanted orthotopically in the cecum to establish an orthotopic colorectal-cancer nude mouse model. Orthotopic mice were randomized into two groups for the treatment with saline and PAZ, respectively. Tumor width, length and mouse body weight was measured twice a week. The Fluor Vivo imaging system was used to image the GFP. Hematoxylin & eosin staining and immunohistochemical staining was used for histological analysis.

              Results

              PAZ inhibited the growth of subcutaneous colorectal cancer, as wells as orthotopic transplanted colorectal cancer tumors. PAZ suppressed lymph node metastasis and lymphangiogenesis in the orthotopic colon cancer model. No significant changes were observed in the body weight between the control and the mice treated with PAZ.

              Conclusion

              PAZ can inhibit the growth of colorectal cancer and inhibit lymph node metastasis and lymphangiogenesis in orthotopic colon cancer nude mouse models.
                Cover page: Pazopanib Inhibits Tumor Growth, Lymph-node Metastasis and Lymphangiogenesis of an Orthotopic Mouse of Colorectal Cancer
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2020)
                The EphA2 tyrosine kinase receptor is highly expressed in several types of solid tumors. In our recent studies, we targeted EphA2 in pancreatic cancer with agonistic agents and demonstrated that suppression of EphA2 significantly reduced cancer-cell migration in cell-based assays. In the present study, we focused on targeting EphA2 in prostate cancer. While not all prostate cancers express EphA2, we showed that enzalutamide induced EphA2 expression in prostate cancer cells and in a patient-derived xenograft (PDX) animal model, which provides further impetus to target EphA2 in prostate cancer. Western blot studies showed that agonistic dimeric synthetic (135H12) and natural (ephrinA1-Fc) ligands effectively degraded EphA2 receptor in the prostate cancer cell line PC-3. The agents also delayed cell migration of prostate cancer (PC-3) cells, while an in vivo PC-3 orthotopic metastatic nude-mouse model also revealed that administration of ephrinA1-Fc or 135H12 strongly reduced metastases. The present study further validates EphA2 as an important target in metastatic prostate cancer treatment. Our results should incentivize further efforts aimed at developing potent and effective EphA2 synthetic agonistic agents for the treatment of EphA2-driven aggressive metastatic tumors including prostate, pancreatic, and breast cancer.
                  Cover page: Prostate Cancer Metastases Are Strongly Inhibited by Agonistic Epha2 Ligands in an Orthotopic Mouse Model
                  • Article
                  • Peer Reviewed
                  LBL Publications (2014)
                  Heavy rainfall and flooding associated with tropical cyclones (TCs) are responsible for a large number of fatalities and economic damage worldwide. Despite their large socioeconomic impacts, research into heavy rainfall and flooding associated with TCs has received limited attention to date and still represents a major challenge. The capability to adapt to future changes in heavy rainfall and flooding associated with TCs is inextricably linked to and informed by understanding of the sensitivity of TC rainfall to likely future forcing mechanisms. Here a set of idealized high-resolution atmospheric model experiments produced as part of the U.S. Climate Variability and Predictability (CLIVAR) Hurricane Working Group activity is used to examine TC response to idealized global-scale perturbations: the doubling of CO2, uniform 2-K increases in global sea surface temperature (SST), and their combined impact. As a preliminary but key step, daily rainfall patterns of composite TCs within climate model outputs are first compared and contrasted to the observational records. To assess similarities and differences across different regions in response to the warming scenarios, analyses are performed at the global and hemispheric scales and in six global TC ocean basins. The results indicate a reduction in TC daily precipitation rates in the doubling CO2 scenario (on the order of 5% globally) and an increase in TC rainfall rates associated with a uniform increase of 2K in SST (both alone and in combination with CO2 doubling; on the order of 10%-20% globally). © 2014 American Meteorological Society.
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2016)
                    Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer.
                      Cover page: Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model.
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