Stanford Advisors


All Publications


  • Targeting tumor-associated macrophage with mannosylated nanotherapeutics delivering TLR7/8 agonist enhances cancer immunotherapy. Journal of controlled release : official journal of the Controlled Release Society Dang, B. N., Duwa, R., Lee, S., Kwon, T. K., Chang, J. H., Jeong, J. H., Yook, S. 2024

    Abstract

    Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic-co-glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from "cold tumor" into "hot tumor", with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.

    View details for DOI 10.1016/j.jconrel.2024.06.062

    View details for PubMedID 38942083

  • Strengthened binding affinity of bispecific antibody nanoplatforms improved the anti-tumor efficacy Chemical Engineering Journal Duwa, R. 2024; 494: 153128
  • Dual receptor specific nanoparticles targeting EGFR and PD-L1 for enhanced delivery of docetaxel in cancer therapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Emami, F., Duwa, R., Banstola, A., Woo, S. M., Kwon, T. K., Yook, S. 2023; 165: 115023

    Abstract

    Dual-receptor targeted (DRT) nanoparticles which contain two distinct targeting agents may exhibit higher cell selectivity, cellular uptake, and cytotoxicity toward cancer cells than single-ligand targeted nanoparticle systems without additional functionality. The purpose of this study is to prepare DRT poly(lactic-co-glycolic acid) (PLGA) nanoparticles for targeting the delivery of docetaxel (DTX) to the EGFR and PD-L1 receptor positive cancer cells such as human glioblastoma multiform (U87-MG) and human non-small cell lung cancer (A549) cell lines. Anti-EGFR and anti-PD-L1 antibody were decorated on DTX loaded PLGA nanoparticles to prepare DRT-DTX-PLGA via. single emulsion solvent evaporation method. Physicochemical characterizations of DRT-DTX-PLGA, such as particle size, zeta-potential, morphology, and in vitro DTX release were also evaluated. The average particle size of DRT-DTX-PLGA was 124.2 ± 1.1 nm with spherical and smooth morphology. In the cellular uptake study, the DRT-DTX-PLGA endocytosed by the U87-MG and A549 cells was single ligand targeting nanoparticle. From the in vitro cell cytotoxicity, and apoptosis studies, we reported that DRT-DTX-PLGA exhibited high cytotoxicity and enhanced the apoptotic cell compared to the single ligand-targeted nanoparticle. The dual receptor mediated endocytosis of DRT-DTX-PLGA showed a high binding affinity effect that leads to high intracellular DTX concentration and exhibited high cytotoxic properties. Thus, DRT nanoparticles have the potential to improve cancer therapy by providing selectivity over single-ligand-targeted nanoparticles.

    View details for DOI 10.1016/j.biopha.2023.115023

    View details for PubMedID 37329708

  • T-cell engaging poly(lactic-co-glycolic acid) nanoparticles as a modular platform to induce a potent cytotoxic immunogenic response against PD-L1 overexpressing cancer. Biomaterials Duwa, R., Pokhrel, R. H., Banstola, A., Pandit, M., Shrestha, P., Jeong, J. H., Chang, J. H., Yook, S. 2022; 291: 121911

    Abstract

    Bispecific nanoparticles (NPs) are conjugated with two antibodies that enhance T cell cytotoxicity by sequentially targeting CD3 and tumor-specific proteins. This interaction redirects T cells to specific tumor antigens and activates them to lyse tumor cells by blocking two different signaling pathways simultaneously. This study developed NP-based bispecific T-cell engagers (nanoBiTEs), which are R848-loaded bispecific poly(lactic-co-glycolic acid) NPs decorated with anti-CD3 antibody targeting T cells and anti-PD-L1 antibody targeting PD-L1 ligands (bis-R848-PLGA-NPs). Bis-R848-PLGA-NPs enhance the immunogenic response in destroying cancer cells by restoring the T cell effector functions. These interactions allow T cells to come in close proximity to the tumor cells. Finally, the release of R848 from PLGA-NPs activates dendritic cells, enhancing T cell activation. In vitro results show maximum internalization of bis-R848-PLGA-NPs in SK-OV3 and B16F10 cell lines, attributed to high PD-L1 expression in both cells. Furthermore, bis-R848-PLGA-NPs-treated CD8+ T cells exhibit a significantly increased total amount of CD8+/CD25+, CD8+/CD69+, and cytokine expression that leads to the robust inhibition of PD-L1 expressed cancer cells. Additionally, tumor growth is significantly inhibited by bis-R848-PLGA-NPs in the B16F10 xenograft mouse model and significantly enhanced intratumoral infiltration of CD4+ and CD8+ T cells, as well as tumor-infiltrated cytokines.

    View details for DOI 10.1016/j.biomaterials.2022.121911

    View details for PubMedID 36399833

  • Reactive oxygen species-responsive dual-targeted nanosystem promoted immunogenic cell death against breast cancer BIOENGINEERING & TRANSLATIONAL MEDICINE Banstola, A., Pandit, M., Duwa, R., Chang, J., Jeong, J., Yook, S. 2022

    View details for DOI 10.1002/btm2.10379

    View details for Web of Science ID 000835234800001

  • Enhancement of blood-brain barrier penetration and the neuroprotective effect of resveratrol. Journal of controlled release : official journal of the Controlled Release Society Katila, N., Duwa, R., Bhurtel, S., Khanal, S., Maharjan, S., Jeong, J. H., Lee, S., Choi, D. Y., Yook, S. 2022; 346: 1-19

    Abstract

    Parkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. The specific molecular mechanisms through which PD-associated neuronal loss occurs remain unclear, and there is no available effective treatment against PD-related neurodegeneration. Resveratrol (RSV) has exhibited promising neuroprotective effects via antioxidant and anti-inflammatory activity. However, its poor bioavailability in the brain represents a challenge for its application in PD treatment. In this study, we synthesized RSV-loaded PLGA nanoparticles (RSV-PLGA-NPs) conjugated with lactoferrin (Lf) to enhance RSV diffusion into the brain and assessed whether this formulation improved the neuroprotective effects of RSV in experimental PD models. The Lf-conjugated RSV-PLGA-NPs (Lf-RSV-PLGA-NPs) exhibited enhanced internalization into SH-SY5Y and human brain microvascular endothelial cells as compared to RSV-PLGA-NPs and free RSV. Further, Lf-RSV-PLGA-NPs were more effective than RSV-PLGA-NPs and free RSV in attenuating the MPP+-induced generation of reactive oxygen species, reduction of mitochondrial membrane potential, and cell death. Importantly, Lf conjugation specifically increased the accumulation of RSV-PLGA-NPs in the brain as determined via bioluminescent imaging analyses. Our formulation substantially enhanced the neuroprotective effects of RSV in the MPTP-induced PD model. Hence, Lf-RSV-PLGA-NPs represent a promising tool for improving RSV bioavailability and neuroprotection within the brain.

    View details for DOI 10.1016/j.jconrel.2022.04.003

    View details for PubMedID 35398173

  • Triple-negative breast cancer treatment meets nanoparticles: Current status and future direction JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY Shokooh, M., Emami, F., Duwa, R., Jeong, J., Yook, S. 2022; 71
  • Development of immunotherapy and nanoparticles-based strategies for the treatment of Parkinson's disease JOURNAL OF PHARMACEUTICAL INVESTIGATION Duwa, R., Jeong, J., Yook, S. 2021; 51 (4): 465-481
  • Immunotherapeutic strategies for the treatment of ovarian cancer: current status and future direction JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY Duwa, R., Jeong, J., Yook, S. 2021; 94: 62-77
  • Cetuximab conjugated temozolomide-loaded poly (lactic-co-glycolic acid) nanoparticles for targeted nanomedicine in EGFR overexpressing cancer cells JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY Duwa, R., Banstola, A., Emami, F., Jeong, J., Lee, S., Yook, S. 2020; 60
  • Enhanced Caspase-Mediated Abrogation of Autophagy by Temozolomide-Loaded and Panitumumab-Conjugated Poly(lactic-co-glycolic acid) Nanoparticles in Epidermal Growth Factor Receptor Overexpressing Glioblastoma Cells. Molecular pharmaceutics Banstola, A., Duwa, R., Emami, F., Jeong, J. H., Yook, S. 2020; 17 (11): 4386-4400

    Abstract

    The mechanism of cell death has attracted a great deal of research interest in the design of antitumor therapy in recent days. Several attempts have been carried out in this direction and in our study also, we studied this phenomenon with the design of panitumumab (PmAb)-conjugated and temozolomide (TMZ)-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs), termed PmAb-TMZ-PLGA-NPs. First, PmAb was functionalized on the surface of TMZ-PLGA-NPs using ethyl(dimethylaminopropyl)carbodiimide (EDC)-N-hydroxysuccinimide (NHS) chemistry. Targeted PLGA-NPs significantly enhanced the cellular uptake of nanoparticles in the U-87 MG cell line as a result of the high epidermal growth factor receptor (EGFR) expression, compared to the LN229 cell line. Our study demonstrated that following the treatment of PmAb-TMZ-PLGA-NPs, a more pronounced anticancer effect was noticed in comparison with free TMZ and TMZ-PLGA-NPs. Further, a more pronounced cytotoxic effect of PmAb-TMZ-PLGA-NPs was observed in the high EGFR-overexpressed glioblastoma multiforme (GBM) model (U-87 MG) cell line compared to the low EGFR GBM model (LN229). Our study demonstrated that the treatment of PmAb-TMZ-PLGA-NPs in GBM tried to adopt the autophagic pathway of the cell survival mechanism with the elevated level of autophagic marker (Beclin-1 and LC3B) at 24 h time point, thereby suppressing the expression of caspase-9 and PARP. However, at the 48 h time point, the elevated expression of caspase-9 and PARP with the downregulation of Beclin-1 and LC3B, following the treatment of PmAb-TMZ-PLGA-NPs in the GBM model, suggested that apoptotic cell death was superior over autophagic cell survival. It was also noteworthy the activation of caspase-9 was correlated with the continuous overproduction of reactive oxygen species up to a 48 h time point after the treatment of PmAb-TMZ-PLGA-NPs. This result sheds light on the biological effect of targeted chemotherapy and illustrates that PmAb-TMZ-PLGA-NPs could be applied for EGFR-overexpressed different cancer models.

    View details for DOI 10.1021/acs.molpharmaceut.0c00856

    View details for PubMedID 33079558

  • Polymeric and lipid-based drug delivery systems for treatment of glioblastoma multiforme Journal of Industrial and Engineering Chemistry Duwa, R., et al 2019; 79: 261-273