Browsing by Author "Talele, Surabhi"

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    Development of Antibody Conjugated Nanoparticles for Targeting Cerebrovascular Amyloid Deposits
    (2017-08) Talele, Surabhi
    Cerebral Amyloid Angiopathy (CAA) is characterized by the deposition of amyloid beta (Aβ) proteins in the cerebral vasculature. CAA could independently cause massive lobar hemorrhages and stroke. Moreover, CAA affects majority of Alzheimer’s Disease (AD) patients and is associated with a rapid decline in memory and cognition in AD1. Currently, there is no pre-mortem diagnosis available for CAA, the treatment options are ineffective, and just provide symptomatic relief. Also, the current diagnostic agents do not provide the required spatial resolution and contrast enhancement for the early detection of cerebrovascular amyloid deposits. To overcome these issues, our lab aims to design novel theranostic nanovehicles capable of targeting the cerebrovascular amyloid deposits. These nanovehicles are expected to facilitate the early diagnosis of CAA by enabling the detection of cerebrovascular amyloid with high specificity and sensitivity. The goal of the current study was to optimize the amyloid targeting and contrast enhancement for cerebrovascular amyloid detection by positron emission tomography (PET) and magnetic resonance imaging (MRI). Chitosan-polycarbophil nanoparticles (NPs) were functionalized with the anti-amyloid antibody IgG4.1 using carbodiimide chemistry. We characterized the particles for various physicochemical properties. The NPs were fluorescently labeled with Alexa Fluor 647 to evaluate amyloid protein targeting in vitro using human cerebral microvascular endothelial cell (hCMEC/D3) monolayers and in mouse models in vivo. We optimized the labeling of the NPs with PET isotope 89Zr followed by their serum stability studies prior to in vivo injections. The nanoprobe could also be employed for the early detection of other cerebrovascular diseases, by incorporating appropriate targeting moieties.
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    Distribution of DNA Damage Response Inhibitors to the Central Nervous System for Brain Tumor Therapy
    (2022-04) Talele, Surabhi
    Brain tumors are associated with a grim prognosis despite the aggressive treatment strategy of surgery, radiation, and chemotherapy. Therefore, there is a need to develop strategies to enhance efficacy of chemo-radiation treatments. DNA damage response (DDR) signaling pathways play a critical role of DNA repair in cancer cells and resistance to radiation and chemotherapy. Inhibition of these pathways can augment tumor kill. Berzosertib, peposertib and AZD1390 are potent small molecule inhibitors of three critical DDR pathways. We evaluated mechanisms limiting central nervous system (CNS) distribution of these molecules and identified their potential for chemo/radiosensitization in brain tumors. CNS distribution of all three molecules is restricted by active efflux mediated by P-gp and/or Bcrp. Moreover, high tissue binding to plasma, brain, and spinal cord, restricts partitioning of unbound drug across the blood-brain barrier (BBB). Additionally, peposertib concentrations in different anatomical regions of the brain were similar, however lower accumulation was observed in the spinal cord. Impact of efflux inhibition using elacridar demonstrated similar increase in peposertib concentrations within each of these regions, indicating that inhibition of efflux activity was functionally similar across these regions. Similarly, no differences were observed in AZD1390 distribution within different anatomical regions of the CNS, and the functional activity of P-gp and Bcrp also remained the same across brain regions. These molecules show heterogeneous tumor distribution in patient-derived xenograft models of brain tumors with drug accumulation maximum within tumor core, slightly lower in adjacent tumor rim, but significantly lower in surrounding normal brain. Berzosertib did not achieve effective chemosensitizing brain and tumor concentrations in vivo. Peposertib, despite its limited CNS delivery, showed potential as a safe yet effective radiosensitizer for brain metastases. Effective radiosensitizing concentrations of AZD1390 were achieved in brain and tumor despite its restricted CNS delivery. Combined, these CNS pharmacokinetic evaluations can guide dosing in pre-clinical efficacy studies and enable future clinical trial design to test these innovative chemo/radiosensitizers with the eventual goal of improving therapy for brain tumors. Integrating knowledge from these studies will aid in determining the potential of DDR inhibitors as effective chemo-radiosensitizing agents in brain tumors.