Papers by Natnaree Siriwon
Nature Communications
Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset o... more Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we report on a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor. ARAC is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a feedforward manner. ARAC reduces effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model (LLC-JSP) and the effect is mainly mediated by CD8+ T cells. ARAC ...
Current Pharmaceutical Design, 2015
Adeno-associated virus (AAV) vectors are promising human gene delivery vehicles due to their abil... more Adeno-associated virus (AAV) vectors are promising human gene delivery vehicles due to their ability to establish long-term gene expression in a wide variety of target tissues; however, the broad native viral tropism raises concerns over the feasibility and safety of their systemic administration. To overcome this issue, much effort has been made to redirect AAVs toward specific tissues. This review presents several design strategies that have been applied to generate AAVs that target specific tissues and cells while inhibiting the transduction of non-target tissues. Multiple methods of vector capsid engineering have shown promise in vitro, including indirect targeting by adaptor systems and direct targeting by the insertion of antibodies or receptor-specific small peptide motifs. Other strategies, including creating mosaic or chimeric capsids and directed evolution, have also been used to successfully retarget AAV vectors. This research will further expand the clinical applications of AAV vectors by enhancing the control over tissue-specific gene delivery.
Molecular Therapy — Methods & Clinical Development, 2014
Adeno-associated virus type 2 (AAV2) is considered a promising gene delivery vector and has been ... more Adeno-associated virus type 2 (AAV2) is considered a promising gene delivery vector and has been extensively applied in several disease models; however, inefficient transduction in various cells and tissues has limited its widespread application in many areas of gene therapy. In this study, we have developed a general, but efficient, strategy to enhance viral transduction, both in vitro and in vivo, by incubating viral particles with cell-permeable peptides (CPPs). We show that CPPs increase internalization of viral particles into cells by facilitating both energy-independent and energy-dependent endocytosis. Moreover, CPPs can significantly enhance the endosomal escape process of viral particles, thus enhancing viral transduction to those cells that have exhibited very low permissiveness to AAV2 infection as a result of impaired intracellular viral processing. We also demonstrated that this approach could be applicable to other AAV serotypes. Thus, the membrane-penetrating ability of CPPs enables us to generate an efficient method for enhanced gene delivery of AAV vectors, potentially facilitating its applicability to human gene therapy.
Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset o... more Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we developed a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) to enhance the efficacy of PD-L1 inhibitor. ARAC is nanoparticle co-delivering PLK1 inhibitor, volasertib, and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a positive feedback manner. ARAC reduced effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model and the effect was mainly mediated by CD8 + T cells. We also observed a...
Cancer Letters
Radiation sensitizers that can selectively act on cancer cells hold great promise to patients who... more Radiation sensitizers that can selectively act on cancer cells hold great promise to patients who receive radiation therapy. We developed a novel targeted therapy and radiation sensitizer for non-small cell lung cancer (NSCLC) based on cetuximab conjugated nanoparticle that targets epidermal growth factor receptor (EGFR) and delivers small interfering RNA (siRNA) against polo-like kinase (PLK1). EGFR is overexpressed in 50% of lung cancer patients and a mediator of DNA repair, while PLK1 is a key mitotic regulator whose inhibition enhances radiation sensitivity. The nanoparticle construct (C-siPLK1-NP) effectively targets EGFR+ NSCLC cells and reduces PLK1 expression, leading to G2/M arrest and cell death. Furthermore, we show a synergistic combination between C-siPLK1-NP and radiation, which was confirmed in vivo in A549 flank tumors. We also demonstrate the translational potential of C-siPLK1-NP as a systemic therapeutic in orthotopic lung tumor model, where administration of C-siPLK1-NP reduced tumor growth and led to prolonged survival. Our findings demonstrate that C-siPLK1-NP is effective as a targeted therapy and as a potent radiation sensitizer for NSCLC. Potential application to other EGFR+ cancer types such as colorectal and breast cancer is also demonstrated.
Journal of Hazardous Materials
This work evaluated sorbent materials created from nanoporous silica self-assembled with monolaye... more This work evaluated sorbent materials created from nanoporous silica self-assembled with monolayer (SAMMS) of hydroxypyridinone derivatives (1,2-HOPO, 3,2-HOPO, 3,4-HOPO), acetamide phosphonate (Ac-Phos), glycine derivatives (IDAA, DE4A, ED3A), and thiol (SH) for capturing of actinides and transition metal cobalt. In filtered seawater doped with competing metals (Cr, Mn, Fe, Co, Cu, Zn, Se, Mo) at levels encountered in environmental or physiological samples, 3,4-HOPO-SAMMS was best at capturing uranium (U(VI)) from pH 2-8, Ac-Phos and 1,2-HOPO-SAMMS sorbents were best at pH < 2. 3,4-HOPO-SAMMS effectively captured thorium (Th(IV)) and plutonium (239Pu(IV)) from pH 2-8, and americium (241Am(III)) from pH 5-8. Capturing cobalt (Co(II)) from filtered river water doped with competing metals (Cu, As, Ag, Cd, Hg, Tl, and Pb) was most effective from pH 5-8 with binding affinity ranged from IDAA > DE4A > ED3A > Ac-Phos > SH on SAMMS. Iminodiacetic acid (IDAA)-SAMMS was also outstanding at capturing Co(II) in ground and seawater. Within 5 min, over 99% of U(VI) and Co(II) in seawater was captured by 3,4-HOPO-SAMMS and IDAA-SAMMS, respectively. These nanoporous materials outperformed the commercially available cation sorbents in binding affinity and adsorption rate. They have great potential for water treatment and recovery of actinides and cobalt from complex matrices.
Biotechnology and bioengineering, 2018
Blood vessel development is critical for the continued growth and progression of solid tumors and... more Blood vessel development is critical for the continued growth and progression of solid tumors and, therefore, makes an attractive target for improving cancer therapy. Indeed, vascular-targeted therapies have been extensively explored but they have shown minimal efficacy as monotherapies. Combretastatin A4 (CA-4) is a tubulin-binding vascular disrupting agent that selectively targets the established tumor endothelium, causing rapid vascular beak down. Despite its potent anticancer potential, the drug has dose-limiting side effects, particularly in the form of cardiovascular toxicity. Furthermore, its poor aqueous solubility and the resulting limited bioavailability hinder its antitumor activity in the clinic. To improve the therapeutic efficacy of CA-4, we investigated its application as a combination therapy with doxorubicin (Dox) in a tumor vasculature targeted delivery vehicle: peptide-modified cross-linked multilamellar liposomal vesicles (cMLVs). In vitro cell culture studies sh...
Cancer Immunology Research
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor... more One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4 þ and CD8 þ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CART cells within the TME. Cancer Immunol Res; 6(7); 812-24. Ó2018 AACR.
Molecular Therapy
The therapeutic limitations of conventional chemotherapeutic drugs include chemo-resistance, tumo... more The therapeutic limitations of conventional chemotherapeutic drugs include chemo-resistance, tumor recurrence, and metastasis. Numerous nanoparticle-based active targeting approaches have emerged to enhance the intracellular concentration of drugs in tumor cells; however, efficient delivery of these systems to the tumor site while sparing healthy tissue remains elusive. Recently, much attention has been given to human immune-cell-directed nanoparticle drug delivery, because immune cells can traffic to the tumor and inflammatory sites. Natural killer cells are a subset of cytotoxic lymphocytes that play critical roles in cancer immunosurveillance. Engineering of the human natural killer cell line, NK92, to express chimeric antigen receptors to redirect their antitumor specificity has shown significant promise. We demonstrate that the efficacy of chemotherapy can be enhanced in vitro and in vivo while reducing off-target toxicity by using chimeric antigen receptor-engineered NK92 cells as carriers to direct drug-loaded nanoparticles to the target site.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 14, 2017
Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic maligna... more Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. To evaluate the effector function and expansion capacity of CAR.αPD1-T cells in vitro, we measured the production of IFN-γ and T cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.αPD1-T cells, CAR-T cells, and CAR-T cells combined with anti-PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism was investigated by analyzing the expansion and functional capacity of TILs. Human anti-PD-1 CPIs secreted by CAR.αPD1-T cells efficiently bound t...
The World Scientific Encyclopedia of Nanomedicine and Bioengineering I, 2016
Therapeutic strategies for targeting cancer stem cells Yu Jeong Kim1#, Elizabeth L. Siegler2#, Na... more Therapeutic strategies for targeting cancer stem cells Yu Jeong Kim1#, Elizabeth L. Siegler2#, Natnaree Siriwon3, Pin Wang1,2,3 1Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA. 2Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA. 3Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA. #Authors contributed equally to this work Correspondence to: Dr. Pin Wang, Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, 3710 McClintock Ave, RTH509, Los Angeles, CA 90089, USA. E-mail: [email protected] The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy; these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies. Compelling eviden...
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Papers by Natnaree Siriwon