Madeleine Landry

All Publications

• Nanoscale Hafnium Metal-Organic Frameworks Enhance Radiotherapeutic Effects by Upregulation of Type I Interferon and TLR7 Expression ADVANCED HEALTHCARE MATERIALS Choi, E., Landry, M., Pennock, N., Neufeld, M., Weinfurter, K., Goforth, A., Walker, J., Sun, C. 2023; 12 (13): e2202830

  Abstract

  Recent preclinical and clinical studies have highlighted the improved outcomes of combination radiotherapy and immunotherapy. Concurrently, the development of high-Z metallic nanoparticles as radiation dose enhancers has been explored to widen the therapeutic window of radiotherapy and potentially enhance immune activation. In this study, folate-modified hafnium-based metal-organic frameworks (HfMOF-PEG-FA) are evaluated in combination with imiquimod, a TLR7 agonist, as a well-defined interferon regulatory factor (IRF) stimulator for local antitumor immunotherapy. The enhancement of radiation dose deposition by HfMOF-PEG-FA and subsequent generation of reactive oxygen species (ROS) deregulates cell proliferation and increases apoptosis. HfMOF-PEG-FA loaded with imiquimod (HfMOF-PEG-FA@IMQ) increases DNA double-strand breaks and cell death, including apoptosis, necrosis, and calreticulin exposure, in response to X-ray irradiation. Treatment with this multipronged therapy promotes IRF stimulation for subsequent interferon production within tumor cells themselves. The novel observation is reported that HfMOF itself increases TLR7 expression, unexpectedly pairing immune agonist and receptor upregulation in a tumor intrinsic manner, and supporting the synergistic effect observed with the γH2AX assay. T-cell analysis of CT26 tumors following intratumoral administration of HfMOF-PEG-FA@IMQ with radiotherapy reveals a promising antitumor response, characterized by an increase in CD8+ and proliferative T cells.

  View details for DOI 10.1002/adhm.202202830

  View details for Web of Science ID 000934555000001

  View details for PubMedID 36716704

• Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates SCIENCE ADVANCES Herrera-Barrera, M., Ryals, R. C., Gautam, M., Jozic, A., Landry, M., Korzun, T., Gupta, M., Acosta, C., Stoddard, J., Reynaga, R., Tschetter, W., Jacomino, N., Taratula, O., Sun, C., Lauer, A. K., Neuringer, M., Sahay, G. 2023; 9 (2): eadd4623

  Abstract

  Lipid nanoparticle (LNP)-based mRNA delivery holds promise for the treatment of inherited retinal degenerations. Currently, LNP-mediated mRNA delivery is restricted to the retinal pigment epithelium (RPE) and Müller glia. LNPs must overcome ocular barriers to transfect neuronal cells critical for visual phototransduction, the photoreceptors (PRs). We used a combinatorial M13 bacteriophage-based heptameric peptide phage display library for the mining of peptide ligands that target PRs. We identified the most promising peptide candidates resulting from in vivo biopanning. Dye-conjugated peptides showed rapid localization to the PRs. LNPs decorated with the top-performing peptide ligands delivered mRNA to the PRs, RPE, and Müller glia in mice. This distribution translated to the nonhuman primate eye, wherein robust protein expression was observed in the PRs, Müller glia, and RPE. Overall, we have developed peptide-conjugated LNPs that can enable mRNA delivery to the neural retina, expanding the utility of LNP-mRNA therapies for inherited blindness.

  View details for DOI 10.1126/sciadv.add4623

  View details for Web of Science ID 000911464300020

  View details for PubMedID 36630502

  View details for PubMedCentralID PMC9833661

• Development of a G2/M arrest high-throughput screening method identifies potent radiosensitizers TRANSLATIONAL ONCOLOGY Landry, M., Nelson, D., Choi, E., DuRoss, A., Sun, C. 2022; 16: 101336

  Abstract

  Radiation is a powerful tool used to control tumor growth and induce an immune response; however, it is limited by damage to surrounding tissue and adverse effects such skin irritation. Breast cancer patients in particular may endure radiation dermatitis, and potentially lymphedema, after a course of radiotherapy. Radio-sensitizing small molecule drugs may enable lower effective doses of both radiation and chemotherapy to minimize toxicity to healthy tissue. In this study, we identified a novel high-throughput method for screening radiosensitizers by image analysis of nuclear size and cell cycle. In vitro assays were performed on cancer cells lines to assess combined therapeutic and radiation effects. In vivo, radiation in combination with proflavine hemisulfate led to enhanced efficacy demonstrated by improved tumor volume control in mice bearing syngeneic breast tumors. This study provides a proof of concept for utilizing G2/M stall as a predictor of radiosensitization and is the first report of a flavin acting as an X-ray radiation enhancer in a breast cancer mouse model.

  View details for DOI 10.1016/j.tranon.2021.101336

  View details for Web of Science ID 000820047200005

  View details for PubMedID 34986454

  View details for PubMedCentralID PMC8732089

• Fucoidan-coated nanoparticles target radiation-induced P-selectin to enhance chemoradiotherapy in murine colorectal cancer CANCER LETTERS DuRoss, A. N., Landry, M. R., Thomas, C. R., Neufeld, M. J., Sun, C. 2021; 500: 208-219

  Abstract

  Colorectal cancer (CRC) is a leading cause of cancer-related death for both men and women, highlighting the need for new treatment strategies. Advanced disease is often treated with a combination of radiation and cytotoxic agents, such as DNA damage repair inhibitors and DNA damaging agents. To optimize the therapeutic window of these multimodal therapies, advanced nanomaterials have been investigated to deliver sensitizing agents or enhance local radiation dose deposition. In this study, we demonstrate the feasibility of employing an inflammation targeting nanoscale metal-organic framework (nMOF) platform to enhance CRC treatment. This novel formulation incorporates a fucoidan surface coating to preferentially target P-selectin, which is over-expressed or translocated in irradiated tumors. Using this radiation stimulated delivery strategy, a combination PARP inhibitor (talazoparib) and chemotherapeutic (temozolomide) drug-loaded hafnium and 1,4-dicarboxybenzene (Hf-BDC) nMOF was evaluated both in vitro and in vivo. Significantly, these drug-loaded P-selectin targeted nMOFs (TT@Hf-BDC-Fuco) show improved tumoral accumulation over multiple controls and subsequently enhanced therapeutic effects. The integrated radiation and nanoformulation treatment demonstrated improved tumor control (reduced volume, density, and growth rate) and increased survival in a syngeneic CRC mouse model. Overall, the data from this study support the continued investigation of radiation-priming for targeted drug delivery and further consideration of nanomedicine strategies in the clinical management of advanced CRC.

  View details for DOI 10.1016/j.canlet.2020.11.021

  View details for Web of Science ID 000607200800020

  View details for PubMedID 33232787

  View details for PubMedCentralID PMC9392493

• Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy MATERIALS TODAY BIO Landry, M. R., DuRoss, A. N., Neufeld, M. J., Hahn, L., Sahay, G., Luxenhofer, R., Sun, C. 2020; 8: 100082

  Abstract

  Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.

  View details for DOI 10.1016/j.mtbio.2020.100082

  View details for Web of Science ID 000600569300009

  View details for PubMedID 33294836

  View details for PubMedCentralID PMC7689338

• Lanthanide Metal-Organic Frameworks for Multispectral Radioluminescent Imaging. ACS applied materials & interfaces Neufeld, M. J., Winter, H., Landry, M. R., Goforth, A. M., Khan, S., Pratx, G., Sun, C. 2020

  Abstract

  In this report, we describe the X-ray luminescent properties of two lanthanide-based nanoscale metal-frameworks (nMOFs) and their potential as novel platforms for optical molecular imaging techniques such as X-ray excited radioluminescence (RL) imaging. Upon X-ray irradiation, the nMOFs display sharp tunable emission peaks that span the visible to near-infrared spectral region (400-700 nm) based on the identity of the metal (Eu, Tb, or Eu/Tb). Surface modification of the nMOFs with polyethylene glycol (PEG) resulted in nanoparticles with enhanced aqueous stability that demonstrated both cyto- and hemo-compatibility important prerequisites for biological applications. Importantly, this is the first report to document and investigate the radioluminescent properties of lanthanide nMOFs. Taken together, the observed radioluminescent properties and low in vitro toxicity demonstrated by the nMOFs render them promising candidates for in vivo translation.

  View details for DOI 10.1021/acsami.0c06010

  View details for PubMedID 32442367

• Tb-Doped core-shell-shell nanophosphors for enhanced X-ray induced luminescence and sensitization of radiodynamic therapy. Biomaterials science Ren, Y. n., Rosch, J. G., Landry, M. R., Winter, H. n., Khan, S. n., Pratx, G. n., Sun, C. n. 2020

  Abstract

  The development of radiation responsive materials, such as nanoscintillators, enables a variety of exciting new theranostic applications. In particular, the ability of nanophosphors to serve as molecular imaging agents in novel modalities, such as X-ray luminescence computed tomography (XLCT), has gained significant interest recently. Here, we present a radioluminescent nanoplatform consisting of Tb-doped nanophosphors with an unique core/shell/shell (CSS) architecture for improved optical emission under X-ray excitation. Owing to the spatial confinement and separation of luminescent activators, these CSS nanophosphors exhibited bright optical luminescence upon irradiation. In addition to standard physiochemical characterization, these CSS nanophosphors were evaluated for their ability to serve as energy mediators in X-ray stimulated photodynamic therapy, also known as radiodynamic therapy (RDT), through attachment of a photosensitizer, rose bengal (RB). Furthermore, cRGD peptide was used as a model targeting agent against U87 MG glioblastoma cells. In vitro RDT efficacy studies suggested the RGD-CSS-RB in combination with X-ray irradiation could induce enhanced DNA damage and increased cell killing, while the nanoparticles alone are well tolerated. These studies support the utility of CSS nanophosphors and warrants their further development for theranostic applications.

  View details for DOI 10.1039/d0bm00897d

  View details for PubMedID 33006335

• Length and Charge of Water-Soluble Peptoids Impact Binding to Phospholipid Membranes JOURNAL OF PHYSICAL CHEMISTRY B Landry, M. R., Rangel, J. L., Dao, V. P., MacKenzie, M. A., Gutierrez, F. L., Dowell, K. M., Calkins, A. L., Fuller, A. A., Stokes, G. Y. 2019; 123 (27): 5822-5831

  Abstract

  In this study, we provide a quantitative description of the adsorption of water-soluble N-substituted glycine oligomers (peptoids) to supported lipid bilayers that mimic mammalian plasma membranes. We prepared a small array of systematically varied peptoid sequences ranging in length from 3 to 15 residues. Using the nonlinear optical method second harmonic generation (SHG), we directly monitored adsorption of aqueous solutions of 3- and 15-residue peptoids to phospholipid membranes of varying physical phase, cholesterol content, and head group charge in physiologically relevant pH buffer conditions without the use of extrinsic labels. Equilibrium binding constants and relative surface coverages of adsorbed peptoids were determined from fits to the Langmuir model. Three- and 15-residue peptoids did not interact with cholesterol-containing lipids or charged lipids in the same manner, suggesting that a peptoid's adsorption mechanism changes with sequence length. In a comparison of four three-residue peptoids, we observed a correlation between equilibrium binding constants and calculated log D7.4 values. Cationic charge modulated surface coverage. Principles governing how peptoid sequence and membrane composition alter peptoid-lipid interactions may be extended to predict physiological effects of peptoids used as therapeutics or as coatings in medical devices.

  View details for DOI 10.1021/acs.jpcb.9b04641

  View details for Web of Science ID 000475540400015

  View details for PubMedID 31251622

• PEGylated beta-NaGdF4/Tb@CaF2 Core/Shell Nanophosphors for Enhanced Radioluminescence and Folate Receptor Targeting ACS APPLIED NANO MATERIALS Ren, Y., Winter, H., Rosch, J. G., Jung, K., Duross, A. N., Landry, M. R., Pratx, G., Sun, C. 2019; 2 (6): 3718–27

  View details for DOI 10.1021/acsanm.9b00629

  View details for Web of Science ID 000473827600044

• Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy ACS APPLIED MATERIALS & INTERFACES DuRoss, A. N., Neufeld, M. J., Landry, M. R., Rosch, J. G., Eaton, C. T., Sahay, G., Thomas, C. R., Sun, C. 2019; 11 (13): 12342-12356

  Abstract

  Chemoradiation is an effective combined modality therapeutic approach that utilizes principles of spatial cooperation to combat the adaptability associated with cancer and to potentially expand the therapeutic window. Optimal therapeutic efficacy requires intelligent selection and refinement of radiosynergistic pharmaceutical agents, enhanced delivery methods, and temporal consideration. Here, a monodisperse sub-20 nm mixed poloxamer micelle (MPM) system was developed to deliver hydrophobic drugs intravenously, in tandem with ionizing radiation. This report demonstrates in vitro synergy and enhanced radiosensitivity when two molecularly targeted DNA repair inhibitors, talazoparib and buparlisib, are encapsulated and combined with radiation in a 4T1 murine breast cancer model. Evaluation of in vivo biodistribution and toxicity exhibited no reduction in particle accumulation upon radiation and a lack of both acute and chronic toxicities. In vivo efficacy studies suggested the promise of combining talazoparib, buparlisib, and radiation to enhance survival and control tumor growth. Tissue analysis suggests enhanced DNA damage leading to apoptosis, thus increasing efficacy. These findings highlight the challenges associated with utilizing clinically relevant inclusion criteria and treatment protocols because complete tumor regression and extended survival were masked by an aggressively metastasizing model. As with clinical treatment regimens, the findings here establish a need for further optimization of this multimodal platform.

  View details for DOI 10.1021/acsami.9b02408

  View details for Web of Science ID 000463843900020

  View details for PubMedID 30860347