35 results on '"Lo, Justin H."'
Search Results
2. Core polymer optimization of ternary siRNA nanoparticles enhances in vivo safety, pharmacokinetics, and tumor gene silencing
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Patel, Shrusti S., Hoogenboezem, Ella N., Yu, Fang, DeJulius, Carlisle R., Fletcher, R. Brock, Sorets, Alex G., Cherry, Fiona K., Lo, Justin H., Bezold, Mariah G., Francini, Nora, d’Arcy, Richard, Brasuell, Jordan E., Cook, Rebecca S., and Duvall, Craig L.
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- 2023
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3. Polymeric Micellar Nanoparticles Enable Image-guided Drug Delivery in Solid Tumors
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Uddin, Md. Jashim, primary, Oltman, Connor G, additional, Lo, Justin H, additional, Gupta, Mukesh K, additional, Werfel, Thomas A, additional, mohyuddin, mohammed T, additional, nazmin, farhana, additional, Rahman, Md. Saidur, additional, Crews, Brenda C, additional, kingsley, philip J, additional, Marnett, Lawrence J, additional, Duvall, Craig L, additional, and Cook, Rebecca S, additional
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- 2024
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4. Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies
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Lo, Justin H., primary, Agarwal, Rajiv, additional, Goff, Laura W., additional, and Heumann, Thatcher R., additional
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- 2023
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5. Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis
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Colazo, Juan M., primary, Hoogenboezem, Ella N., additional, Shah, Veeraj, additional, Yu, Fang, additional, Lo, Justin H., additional, Sorets, Alexander G., additional, Francini, Nora, additional, Cho, Hongsik, additional, Michell, Danielle L., additional, Vickers, Kasey C., additional, Gibson-Corley, Katherine N., additional, Hasty, Karen A., additional, Crofford, Leslie, additional, Cook, Rebecca S., additional, and Duvall, Craig L., additional
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- 2023
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6. Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis
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Colazo, Juan M., Hoogenboezem, Ella N., Shah, Veeraj, Yu, Fang, Lo, Justin H., Sorets, Alexander G., Francini, Nora, Cho, Hongsik, Michell, Danielle L., Vickers, Kasey C., Gibson-Corley, Katherine N., Hasty, Karen A., Crofford, Leslie, Cook, Rebecca S., and Duvall, Craig L.
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Article - Abstract
Osteoarthritis ( OA ) and rheumatoid arthritis ( RA ) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin ‘hitchhiking’ for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA. EDITORIAL SUMMARY: Lipophilic siRNA conjugates optimized for albumin binding and “hitchhiking” can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists.
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- 2023
7. Abstract 2706: Therapeutic silencing of Rictor using siRNA nanoparticles to selectively block mTORC2 signaling in triple negative breast cancer
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Patel, Shrusti S., primary, Hoogenboezem, Ella N., additional, Yu, Fang, additional, Sorets, Alex G., additional, Cherry, Fiona K., additional, Lo, Justin H., additional, Francini, Nora, additional, d'Arcy, Richard A., additional, Cook, Rebecca S., additional, and Duvall, Craig L., additional
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- 2023
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8. Supplemental Information and Figures S1-S7 from iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
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Lo, Justin H., primary, Hao, Liangliang, primary, Muzumdar, Mandar D., primary, Raghavan, Srivatsan, primary, Kwon, Ester J., primary, Pulver, Emilia M., primary, Hsu, Felicia, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Fuchs, Charles S., primary, Hahn, William C., primary, Jacks, Tyler, primary, and Bhatia, Sangeeta N., primary
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- 2023
- Full Text
- View/download PDF
9. Supplemental Video 1. Intravital imaging of iRGD TPNs in a xenograft model of pancreatic cancer from iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
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Lo, Justin H., primary, Hao, Liangliang, primary, Muzumdar, Mandar D., primary, Raghavan, Srivatsan, primary, Kwon, Ester J., primary, Pulver, Emilia M., primary, Hsu, Felicia, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Fuchs, Charles S., primary, Hahn, William C., primary, Jacks, Tyler, primary, and Bhatia, Sangeeta N., primary
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- 2023
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10. Data from iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
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Lo, Justin H., primary, Hao, Liangliang, primary, Muzumdar, Mandar D., primary, Raghavan, Srivatsan, primary, Kwon, Ester J., primary, Pulver, Emilia M., primary, Hsu, Felicia, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Fuchs, Charles S., primary, Hahn, William C., primary, Jacks, Tyler, primary, and Bhatia, Sangeeta N., primary
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- 2023
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11. Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy
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Hoogenboezem, Ella N., primary, Patel, Shrusti S., additional, Cavnar, Ashley B., additional, Lo, Justin H., additional, Babb, Lauren M., additional, Francini, Nora, additional, Patil, Prarthana, additional, Colazo, Juan M., additional, Michell, Danielle L., additional, Sanchez, Violeta M., additional, McCune, Joshua T., additional, Ma, Jinqi, additional, DeJulius, Carlisle R., additional, Lee, Linus H., additional, Rosch, Jonah C., additional, Allen, Ryan M., additional, Stokes, Larry D., additional, Hill, Jordan L., additional, Vickers, Kasey C., additional, Cook, Rebecca S., additional, and Duvall, Craig L., additional
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- 2023
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12. Smart nanosystems : Bio-inspired technologies that interact with the host environment
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Kwon, Ester J., Lo, Justin H., and Bhatia, Sangeeta N.
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- 2015
13. Drug-induced amplification of nanoparticle targeting to tumors
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Lin, Kevin Y., Kwon, Ester J., Lo, Justin H., and Bhatia, Sangeeta N.
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- 2014
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14. The Changing Demographics of Colorectal Cancer
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Lo, Justin H., primary and Ciombor, Kristen K., additional
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- 2022
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15. iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
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Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Koch Institute for Integrative Cancer Research at MIT, Lo, Justin H., Hao, Liangliang, Muzumdar, Mandar, Raghavan, Srivatsan, Kwon, Ester, Pulver, Emilia M, Hsu, Felicia, Aguirre, Andrew J., Wolpin, Brian M., Fuchs, Charles S., Hahn, William C., Jacks, Tyler E, Bhatia, Sangeeta N, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Koch Institute for Integrative Cancer Research at MIT, Lo, Justin H., Hao, Liangliang, Muzumdar, Mandar, Raghavan, Srivatsan, Kwon, Ester, Pulver, Emilia M, Hsu, Felicia, Aguirre, Andrew J., Wolpin, Brian M., Fuchs, Charles S., Hahn, William C., Jacks, Tyler E, and Bhatia, Sangeeta N
- Abstract
Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with a v b 3/5 integrins and neuropilin-1, we hypothesized that "tandem" peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer., NCI (Grants P30-CA14051 and U54CA151884), NIH/NIGMS (Grant MSTP T32GM007753)
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- 2020
16. Non-viral delivery of CRISPR/Cas9 complex using CRISPR-GPS nanocomplexes
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Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Broad Institute of MIT and Harvard, Jain, Piyush Kumar, Lo, Justin H., Rananaware, Santosh, Downing, Marco, Panda, Apekshya, Tai, Michelle, Raghavan, Srivatsan, Fleming, Heather, Bhatia, Sangeeta N, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Broad Institute of MIT and Harvard, Jain, Piyush Kumar, Lo, Justin H., Rananaware, Santosh, Downing, Marco, Panda, Apekshya, Tai, Michelle, Raghavan, Srivatsan, Fleming, Heather, and Bhatia, Sangeeta N
- Abstract
There is a critical need for the development of safe and efficient delivery technologies for CRISPR/Cas9 to advance translation of genome editing to the clinic. Non-viral methods that are simple, efficient, and completely based on biologically-derived materials could offer such potential. Here we report a simple and modular tandem peptide-based nanocomplex system with cell-targeting capacity that efficiently combines guide RNA (sgRNA) with Cas9 protein, and facilitates internalization of sgRNA/Cas9 ribonucleoprotein complexes to yield robust genome editing across multiple cell lines
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- 2020
17. Health-related quality of life outcomes from the POLO study: a commentary
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Lo, Justin H., primary and Das, Satya, additional
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- 2020
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18. Non-viral delivery of CRISPR/Cas9 complex using CRISPR-GPS nanocomplexes
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Jain, Piyush K., primary, Lo, Justin H., additional, Rananaware, Santosh, additional, Downing, Marco, additional, Panda, Apekshya, additional, Tai, Michelle, additional, Raghavan, Srivatsan, additional, Fleming, Heather E., additional, and Bhatia, Sangeeta N., additional
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- 2019
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19. iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
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Lo, Justin H., primary, Hao, Liangliang, additional, Muzumdar, Mandar D., additional, Raghavan, Srivatsan, additional, Kwon, Ester J., additional, Pulver, Emilia M., additional, Hsu, Felicia, additional, Aguirre, Andrew J., additional, Wolpin, Brian M., additional, Fuchs, Charles S., additional, Hahn, William C., additional, Jacks, Tyler, additional, and Bhatia, Sangeeta N., additional
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- 2018
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20. Smart nanosystems: Bio-inspired technologies that interact with the host environment
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Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Koch Institute for Integrative Cancer Research at MIT, Kwon, Ester, Lo, Justin H., Bhatia, Sangeeta N., Bhatia, Sangeeta N, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Koch Institute for Integrative Cancer Research at MIT, Kwon, Ester, Lo, Justin H., Bhatia, Sangeeta N., and Bhatia, Sangeeta N
- Abstract
Nanoparticle technologies intended for human administration must be designed to interact with, and ideally leverage, a living host environment. Here, we describe smart nanosystems classified in two categories: (i) those that sense the host environment and respond and (ii) those that first prime the host environment to interact with engineered nanoparticles. Smart nanosystems have the potential to produce personalized diagnostic and therapeutic schema by using the local environment to drive material behavior and ultimately improve human health., National Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051), National Institute of Environmental Health Sciences (Core Center Grant P30-ES002109), Amar G. Bose (research grant), United States. Defense Advanced Research Projects Agency (Cooperative Agreement HR0011-13-2-0017)
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- 2016
21. Comparison of Modular PEG Incorporation Strategies for Stabilization of Peptide–siRNA Nanocomplexes
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Lo, Justin H., primary, Kwon, Ester J., additional, Zhang, Angela Q., additional, Singhal, Preeti, additional, and Bhatia, Sangeeta N., additional
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- 2016
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22. Self-Titrating Anticoagulant Nanocomplexes That Restore Homeostatic Regulation of the Coagulation Cascade
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Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Lin, Kevin Yu-Ming, Lo, Justin H., Consul, Nikita, Kwong, Gabriel A., Bhatia, Sangeeta N., Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Lin, Kevin Yu-Ming, Lo, Justin H., Consul, Nikita, Kwong, Gabriel A., and Bhatia, Sangeeta N.
- Abstract
Antithrombotic therapy is a critical portion of the treatment regime for a number of life-threatening conditions, including cardiovascular disease, stroke, and cancer; yet, proper clinical management of anticoagulation remains a challenge because existing agents increase the propensity for bleeding in patients. Here, we describe the development of a bioresponsive peptide–polysaccharide nanocomplex that utilizes a negative feedback mechanism to self-titrate the release of anticoagulant in response to varying levels of coagulation activity. This nanoscale self-titrating activatable therapeutic, or nanoSTAT, consists of a cationic thrombin-cleavable peptide and heparin, an anionic polysaccharide and widely used clinical anticoagulant. Under nonthrombotic conditions, nanoSTATs circulate inactively, neither releasing anticoagulant nor significantly prolonging bleeding time. However, in response to life-threatening pulmonary embolism, nanoSTATs locally release their drug payload and prevent thrombosis. This autonomous negative feedback regulator may improve antithrombotic therapy by increasing the therapeutic window and decreasing the bleeding risk of anticoagulants., National Institutes of Health (U.S.) (R01CA124427-01), National Cancer Institute (U.S.) (U54CA119349), National Cancer Institute (U.S.) (U54CA119335), National Cancer Institute (U.S.) (Center of Cancer Nanotechnology Excellence at MIT-Harvard U54CA151884), David & Lucile Packard Foundation (Fellowship), David H. Koch Institute for Integrative Cancer Research at MIT (Marie D. and Pierre Casimir-Lambert Fund), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), MIT-Harvard Center of Cancer Nanotechnology Excellence (5 U54 CA151884-03), National Institutes of Health (U.S.). Medical Scientist Training Program (T32GM007753), National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award F32CA159496-02), Burroughs Wellcome Fund (Career Award at the Scientific Interface)
- Published
- 2015
23. Gas Transfer in Cellularized Collagen-Membrane Gas Exchange Devices
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Lo, Justin H., primary, Bassett, Erik K., additional, Penson, Elliot J. N., additional, Hoganson, David M., additional, and Vacanti, Joseph P., additional
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- 2015
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24. Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Target ID4
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Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Ren, Yin, von Maltzhan, Geoffrey, Agrawal, Amit, Mesirov, Jill P., Lo, Justin H., Bhatia, Sangeeta N., Cheung, Hiu Wing, Cowley, Glenn S., Weir, Barbara A., Boehm, Jesse S., Tamayo, Pablo, Karst, Alison M., Liu, Joyce F., Hirsch, Michelle S., Drapkin, Ronny, Root, David E., Fogal, Valentina, Ruoslahti, Erkki, Hahn, William C., Bhatia, Sangeeta N, Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Ren, Yin, von Maltzhan, Geoffrey, Agrawal, Amit, Mesirov, Jill P., Lo, Justin H., Bhatia, Sangeeta N., Cheung, Hiu Wing, Cowley, Glenn S., Weir, Barbara A., Boehm, Jesse S., Tamayo, Pablo, Karst, Alison M., Liu, Joyce F., Hirsch, Michelle S., Drapkin, Ronny, Root, David E., Fogal, Valentina, Ruoslahti, Erkki, Hahn, William C., and Bhatia, Sangeeta N
- Abstract
The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem. We describe a platform for the discovery and initial validation of cancer targets, composed of a systematic effort to identify amplified and essential genes in human cancer cell lines and tumors partnered with a novel modular delivery technology. We developed a tumor-penetrating nanocomplex (TPN) that comprised small interfering RNA (siRNA) complexed with a tandem tumor-penetrating and membrane-translocating peptide, which enabled the specific delivery of siRNA deep into the tumor parenchyma. We used TPN in vivo to evaluate inhibitor of DNA binding 4 (ID4) as a novel oncogene. Treatment of ovarian tumor–bearing mice with ID4-specific TPN suppressed growth of established tumors and significantly improved survival. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets., Howard Hughes Medical Institute, National Cancer Institute (U.S.) (Grant U54 CA119349), National Cancer Institute (U.S.) (Grant CA119335), National Cancer Institute (U.S.) (Grant R01 CA124427), Starr Cancer Consortium, Marie D. and Pierre Casimir-Lambert Fund, National Cancer Institute (U.S.) (Cancer Center Support Core Grant P30 CA14051)
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- 2014
25. Self-Titrating Anticoagulant Nanocomplexes That Restore Homeostatic Regulation of the Coagulation Cascade
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Lin, Kevin Y., primary, Lo, Justin H., additional, Consul, Nikita, additional, Kwong, Gabriel A., additional, and Bhatia, Sangeeta N., additional
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- 2014
- Full Text
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26. Nanoparticle amplification via photothermal unveiling of cryptic collagen binding sites
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Whitaker College of Health Sciences and Technology, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Lo, Justin H., von Maltzahn, Geoffrey, Douglass, Jacqueline, Bhatia, Sangeeta N., Park, Ji-Ho, Sailor, Michael J., Ruoslahti, Erkki, Bhatia, Sangeeta N, von Maltzhan, Geoffrey, Whitaker College of Health Sciences and Technology, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Lo, Justin H., von Maltzahn, Geoffrey, Douglass, Jacqueline, Bhatia, Sangeeta N., Park, Ji-Ho, Sailor, Michael J., Ruoslahti, Erkki, Bhatia, Sangeeta N, and von Maltzhan, Geoffrey
- Abstract
The success of nanoparticle-based cancer therapies ultimately depends on their ability to selectively and efficiently accumulate in regions of disease. Outfitting nanoparticles to actively target tumor-specific markers has improved specificity, yet it remains a challenge to amass adequate therapy in a selective manner. To help address this challenge, we have developed a mechanism of nanoparticle amplification based on stigmergic (environment-modifying) signalling, in which a “Signalling” population of gold nanorods induces localized unveiling of cryptic collagen epitopes, which are in turn targeted by “Responding” nanoparticles bearing gelatin-binding fibronectin fragments. We demonstrate that this two-particle system results in significantly increased, selective recruitment of responding particles. Such amplification strategies have the potential to overcome limitations associated with single-particle targeting by leveraging the capacity of nanoparticles to interact with their environment to create abundant new binding motifs., National Institutes of Health (U.S.). Bioengineering Research Partnership (R01CA124427-01), National Institutes of Health (U.S.) (National Cancer Institute (U.S.) U54CA119349), National Institutes of Health (U.S.) (National Cancer Institute (U.S.) U54CA119335), National Institutes of Health (U.S.) (National Cancer Institute (U.S.) Alliance Challenge Project/MIT-Harvard Center of Cancer Nanotechnology Excellence U54CA151884), David & Lucile Packard Foundation (Fellowship 1999-1453), Marie D. and Pierre Casimir-Lambert Fund, National Institute of General Medical Sciences (U.S.) (Medical Scientist Training Program T32GM007753), Whitaker Foundation, National Science Foundation (U.S.)
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- 2013
27. In Vivo Gene Expression Dynamics of Tumor-Targeted Bacteria
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Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Danino, Tal, Lo, Justin H., Bhatia, Sangeeta N., Prindle, Arthur, Hasty, Jeff, Bhatia, Sangeeta N, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Danino, Tal, Lo, Justin H., Bhatia, Sangeeta N., Prindle, Arthur, Hasty, Jeff, and Bhatia, Sangeeta N
- Abstract
The engineering of bacteria to controllably deliver therapeutics is an attractive application for synthetic biology. While most synthetic gene networks have been explored within microbes, there is a need for further characterization of in vivo circuit behavior in the context of applications where the host microbes are actively being investigated for efficacy and safety, such as tumor drug delivery. One major hurdle is that culture-based selective pressures are absent in vivo, leading to strain-dependent instability of plasmid-based networks over time. Here, we experimentally characterize the dynamics of in vivo plasmid instability using attenuated strains of S. typhimurium and real-time monitoring of luminescent reporters. Computational modeling described the effects of growth rate and dosage on live-imaging signals generated by internal bacterial populations. This understanding will allow us to harness the transient nature of plasmid-based networks to create tunable temporal release profiles that reduce dosage requirements and increase the safety of bacterial therapies., Misrock Foundation (Postdoctoral Fellowship), National Institutes of Health (U.S.) (Medical Scientist Training Program), Massachusetts Institute of Technology. Ludwig Center for Molecular Oncology (Graduate Fellowship), Marie D. and Pierre Casimir-Lambert Fund, Howard Hughes Medical Institute (Investigator)
- Published
- 2012
28. Identification and characterization of receptor-specific peptides for siRNA delivery
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Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Ren, Yin, Hauert, Sabine, Lo, Justin H., Bhatia, Sangeeta N., Bhatia, Sangeeta N, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Ren, Yin, Hauert, Sabine, Lo, Justin H., Bhatia, Sangeeta N., and Bhatia, Sangeeta N
- Abstract
Tumor-targeted delivery of siRNA remains a major barrier in fully realizing the therapeutic potential of RNA interference. While cell-penetrating peptides (CPP) are promising siRNA carrier candidates, they are universal internalizers that lack cell-type specificity. Herein, we design and screen a library of tandem tumor-targeting and cell-penetrating peptides that condense siRNA into stable nanocomplexes for cell type-specific siRNA delivery. Through physiochemical and biological characterization, we identify a subset of the nanocomplex library of that are taken up by cells via endocytosis, trigger endosomal escape and unpacking of the carrier, and ultimately deliver siRNA to the cytosol in a receptor-specific fashion. To better understand the structure–activity relationships that govern receptor-specific siRNA delivery, we employ computational regression analysis and identify a set of key convergent structural properties, namely the valence of the targeting ligand and the charge of the peptide, that help transform ubiquitously internalizing cell-penetrating peptides into cell type-specific siRNA delivery systems., Marie D. and Pierre Casimir-Lambert Fund, National Cancer Institute (U.S.) (U54 CA119349), National Cancer Institute (U.S.) (U54 CA119335), National Cancer Institute (U.S.) (1R01CA124427-01), Human Frontier Science Program (Strasbourg, France), National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051), Howard Hughes Medical Institute (Investigator)
- Published
- 2012
29. Nanoparticle amplification via photothermal unveiling of cryptic collagen binding sites
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Lo, Justin H., primary, von Maltzahn, Geoffrey, additional, Douglass, Jacqueline, additional, Park, Ji-Ho, additional, Sailor, Michael J., additional, Ruoslahti, Erkki, additional, and Bhatia, Sangeeta N., additional
- Published
- 2013
- Full Text
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30. Identification and Characterization of Receptor-Specific Peptides for siRNA Delivery
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Ren, Yin, primary, Hauert, Sabine, additional, Lo, Justin H., additional, and Bhatia, Sangeeta N., additional
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- 2012
- Full Text
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31. Influence of Vascular Network Design on Gas Transfer in Lung Assist Device Technology
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Bassett, Erik K., primary, Hoganson, David M., additional, Lo, Justin H., additional, Penson, Elliot J. N., additional, and Vacanti, Joseph P., additional
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- 2011
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32. Cellularized Collagen-Membrane Lung Assist Devices for Efficient Gas Transfer
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Lo, Justin H.
- Abstract
Chronic lower respiratory disease afflicts over 5% of the United States population, leading to over 145,000 deaths annually. There remains a need for safer and more durable alternatives to lung transplant for patients who progress to end-stage lung disease. Portable or implantable gas oxygenators based on microfluidic technologies can address this need, though harnessing their potential depends on efficient and biocompatible design. Incorporating biomimetic materials into such devices can help replicate efficient native gas exchange function and additionally support cellular components. In this work, we developed microfluidic devices that enable blood gas exchange across ultra-thin collagen membranes (as thin as 2 μm). Endothelial, stromal, and parenchymal cells readily adhere to these membranes, and long-term culture with cellular components results in membrane remodeling, reflected by reductions in membrane thickness. Functionally, these collagen-membrane lung devices in the acellular configuration mediated effective gas exchange up to rates of ~288 mL/min/m^2 O2 transfer and ~685 mL/min/m^2 CO2 transfer, approaching the gas exchange efficiency measured in the native lung. After testing several configurations of lung devices to explore various physical parameters of the device design, we concluded that thinner membranes and longer gas exchange distances result in improved hemoglobin saturation and increases in pO2. However, in the design space tested, these effects were relatively small compared to the improvement in overall oxygen and carbon dioxide transfer by increasing the blood flow rate – limited primarily by shear forces experienced by blood components. Finally, collagen-membrane devices cultured with endothelial and parenchymal cells achieved similar gas exchange rates compared with acellular devices. Biomimetic blood oxygenator design opens the possibility of creating portable or implantable microfluidic devices that achieve efficient gas transfer while also maintaining physiologic conditions.
- Published
- 2017
33. Nanoparticle amplification via photothermal unveiling of cryptic collagen binding sites
- Author
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Justin H. Lo, Erkki Ruoslahti, Ji-Ho Park, Michael J. Sailor, Geoffrey von Maltzahn, Sangeeta N. Bhatia, Jacqueline Douglass, Whitaker College of Health Sciences and Technology, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Lo, Justin H., von Maltzahn, Geoffrey, Douglass, Jacqueline, and Bhatia, Sangeeta N.
- Subjects
education.field_of_study ,Population ,Biomedical Engineering ,Nanoparticle ,Nanotechnology ,General Chemistry ,General Medicine ,Biology ,Photothermal therapy ,Epitope ,Cell biology ,Fibronectin ,Chemistry ,Signalling ,biology.protein ,General Materials Science ,Binding site ,education - Abstract
The success of nanoparticle-based cancer therapies ultimately depends on their ability to selectively and efficiently accumulate in regions of disease. Outfitting nanoparticles to actively target tumor-specific markers has improved specificity, yet it remains a challenge to amass adequate therapy in a selective manner. To help address this challenge, we have developed a mechanism of nanoparticle amplification based on stigmergic (environment-modifying) signalling, in which a “Signalling” population of gold nanorods induces localized unveiling of cryptic collagen epitopes, which are in turn targeted by “Responding” nanoparticles bearing gelatin-binding fibronectin fragments. We demonstrate that this two-particle system results in significantly increased, selective recruitment of responding particles. Such amplification strategies have the potential to overcome limitations associated with single-particle targeting by leveraging the capacity of nanoparticles to interact with their environment to create abundant new binding motifs., National Institutes of Health (U.S.). Bioengineering Research Partnership (R01CA124427-01), National Institutes of Health (U.S.) (National Cancer Institute (U.S.) U54CA119349), National Institutes of Health (U.S.) (National Cancer Institute (U.S.) U54CA119335), National Institutes of Health (U.S.) (National Cancer Institute (U.S.) Alliance Challenge Project/MIT-Harvard Center of Cancer Nanotechnology Excellence U54CA151884), David & Lucile Packard Foundation (Fellowship 1999-1453), Marie D. and Pierre Casimir-Lambert Fund, National Institute of General Medical Sciences (U.S.) (Medical Scientist Training Program T32GM007753), Whitaker Foundation, National Science Foundation (U.S.)
- Published
- 2013
34. Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis.
- Author
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Colazo JM, Hoogenboezem EN, Keech MC, Francini N, Shah V, Yu F, Lo JH, Sorets AG, McCune JT, Cho H, DeJulius CR, Michell DL, Maerz T, Vickers KC, Gibson-Corley KN, Hasty KA, Crofford L, Cook RS, and Duvall CL
- Abstract
Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin 'hitchhiking' for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA., Editorial Summary: Lipophilic siRNA conjugates optimized for albumin binding and "hitchhiking" can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists.
- Published
- 2023
- Full Text
- View/download PDF
35. Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy.
- Author
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Hoogenboezem EN, Patel SS, Cavnar AB, Lo JH, Babb LM, Francini N, Patil P, Colazo JM, Michell DL, Sanchez VM, McCune JT, Ma J, DeJulius CR, Lee LH, Rosch JC, Allen RM, Stokes LD, Hill JL, Vickers KC, Cook RS, and Duvall CL
- Abstract
The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C
18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association. Comparison to higher albumin affinity (diacid) lipid variants and siRNA directly conjugated to albumin underscored the importance of conjugate hydrophobicity and reversibility of albumin binding for siRNA delivery and bioactivity in tumors. The lead conjugate increased tumor siRNA accumulation 12-fold in orthotopic mouse models of triple negative breast cancer over the parent siRNA. When applied for silencing of the anti-apoptotic oncogene MCL-1, this structure achieved approximately 80% MCL1 silencing in orthotopic breast tumors. Furthermore, application of the lead conjugate structure to target MCL1 yielded better survival outcomes in three independent, orthotopic, triple negative breast cancer models than an MCL1 small molecule inhibitor. These studies provide new structure-function insights on optimally leveraging siRNA-lipid conjugate structures that associate in situ with plasma albumin for molecular-targeted cancer therapy., Competing Interests: Competing Interests Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.- Published
- 2023
- Full Text
- View/download PDF
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