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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2018)

There is increased interest in porous silicon nanomaterials for biomedical applications due to their biodegradability, their biocompatibility, and their intrinsic photoluminescence. This thesis describes cargo loading chemistry, surface chemistry, molecularly targeted delivery and bioimaging applications using porous silicon nanomaterials.

After a brief introduction to porous silicon materials for biomedical applications, Chapter 2 describes a single-step procedure to simultaneously load and protect a model siRNA therapeutic in porous silicon nanoparticles (pSiNPs). Exogenous calcium ions precipitate with locally generated silicic acid to form calcium silicate, which serves to encapsulate the siRNA payload in pSiNPs. The target gene knockdown efficiency in vitro and target tissue accumulation of delivered siRNA in vivo are demonstrated.

Chapter 3 presents a facile chemical modification of the surface of the hydroxylated silicon nanostructure. The reaction, a ring-opening heterocyclic silane “click” reaction, is a rapid and efficient means to obtain high surface coverage while preserving the open pore structure and intrinsic photoluminescence of the original silicon nanostructure. This chemistry is sufficiently mild to maintain the activity of payload proteins.

Chapter 4 presents the example of pSiNPs as an imaging agent, which are targeted to tumor tissues in vivo using an iRGD peptide targeting probe, and the nanoparticles are imaged by two-photon microscopy. Superior photostability and low systemic toxicity are observed.

Chapter 5 discusses enhanced photoacoustic signals that can be obtained from indocyanine green (ICG) when it is encapsulated in pSiNPs. The photoacoustic response from ICG is enhanced 17-fold when it is sealed in pSiNPs. The substantially improved performance is attributed to the low thermal conductivity of pSiNPs and their ability to protect loaded ICG from photolytic degradation.

    Cover page: Porous Silicon Nanomaterials for Bioimaging and Nanomedicine
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2018)
    The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system's response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia.
      Cover page: Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2022)
      Traumatic brain injury (TBI) is a major cause of disability and death among children and young adults in the United States, yet there are currently no treatments that improve the long-term brain health of patients. One promising therapeutic for TBI is brain-derived neurotrophic factor (BDNF), a protein that promotes neurogenesis and neuron survival. However, outstanding challenges to the systemic delivery of BDNF are its instability in blood, poor transport into the brain, and short half-life in circulation and brain tissue. Here, BDNF is encapsulated into an engineered, biodegradable porous silicon nanoparticle (pSiNP) in order to deliver bioactive BDNF to injured brain tissue after TBI. The pSiNP carrier is modified with the targeting ligand CAQK, a peptide that binds to extracellular matrix components upregulated after TBI. The protein cargo retains bioactivity after release from the pSiNP carrier, and systemic administration of the CAQK-modified pSiNPs results in effective delivery of the protein cargo to injured brain regions in a mouse model of TBI. When administered after injury, the CAQK-targeted pSiNP delivery system for BDNF reduces lesion volumes compared to free BDNF, supporting the hypothesis that pSiNPs mediate therapeutic protein delivery after systemic administration to improve outcomes in TBI.
        Cover page: Porous Silicon Nanoparticles Targeted to the Extracellular Matrix for Therapeutic Protein Delivery in Traumatic Brain Injury
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2019)
        Silencing of aberrantly expressed microRNAs (miRNAs or miRs) has emerged as one of the strategies for molecular targeted cancer therapeutics. In particular, miR-21 is an oncogenic miRNA overexpressed in many tumors, including ovarian cancer. To achieve efficient administration of anti-miR therapeutics, delivery systems are needed that can ensure local accumulation in the tumor environment, low systemic toxicity, and reduced adverse side effects. In order to develop an improved anti-miR therapeutic agent for the treatment of ovarian cancer, a nanoformulation is engineered that leverages biodegradable porous silicon nanoparticles (pSiNPs) encapsulating an anti-miR-21 locked nucleic acid payload and displaying a tumor-homing peptide for targeted distribution. Targeting efficacy, miR-21 silencing, and anticancer activity are optimized in vitro on a panel of ovarian cancer cell lines, and a formulation of anti-miR-21 in a pSiNP displaying the targeting peptide CGKRK is identified for in vivo evaluation. When this nanoparticulate agent is delivered to mice bearing tumor xenografts, a substantial inhibition of tumor growth is achieved through silencing of miR-21. This study presents the first successful application of tumor-targeted anti-miR porous silicon nanoparticles for the treatment of ovarian cancer in a mouse xenograft model.
          Cover page: Tumor-Targeting, MicroRNA-Silencing Porous Silicon Nanoparticles for Ovarian Cancer Therapy
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