Person: Kamaly, Nazila
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Kamaly
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Nazila
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Kamaly, Nazila
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Publication Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice(American Association for the Advancement of Science (AAAS), 2015) Fredman, G.; Kamaly, Nazila; Spolitu, S.; Milton, J.; Ghorpade, D.; Chiasson, R.; Kuriakose, G.; Perretti, M.; Farokhzad, Omid; Tabas, I.Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26 (Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.Publication Targeted polymeric therapeutic nanoparticles: design, development and clinical translation(Royal Society of Chemistry (RSC), 2012) Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, OmidPolymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).Publication Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology(Elsevier BV, 2014) Bertrand, Nicolas; Wu, Jun; Xu, Xiaoyang; Kamaly, Nazila; Farokhzad, OmidCancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000’s. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential “retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.Publication A Solvent-Free Thermosponge Nanoparticle Platform for Efficient Delivery of Labile Proteins(American Chemical Society, 2014) Choi, Won Il; Kamaly, Nazila; Riol-Blanco, Lorena; Lee, In-Hyun; Wu, Jun; Swami, Archana; Vilos, Cristian; Yameen, Basit; Yu, Mikyung; Shi, Jinjun; Tabas, Ira; von Andrian-Werburg, Ulrich; Jon, Sangyong; Farokhzad, OmidProtein therapeutics have gained attention recently for treatment of a myriad of human diseases due to their high potency and unique mechanisms of action. We present the development of a novel polymeric thermosponge nanoparticle for efficient delivery of labile proteins using a solvent-free polymer thermo-expansion mechanism with clinical potential, capable of effectively delivering a range of therapeutic proteins in a sustained manner with no loss of bioactivity, with improved biological half-lives and efficacy in vivo.Publication Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair(American Society for Clinical Investigation, 2015) Leoni, Giovanna; Neumann, Philipp-Alexander; Kamaly, Nazila; Quiros, Miguel; Nishio, Hikaru; Jones, Hefin R.; Sumagin, Ronen; Hilgarth, Roland S.; Alam, Ashfaqul; Fredman, Gabrielle; Argyris, Ioannis; Rijcken, Emile; Kusters, Dennis; Reutelingsperger, Chris; Perretti, Mauro; Parkos, Charles A.; Farokhzad, Omid; Neish, Andrew S.; Nusrat, AsmaEpithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.Publication Development of Multinuclear Polymeric Nanoparticles as Robust Protein Nanocarriers(Wiley-Blackwell, 2014) Wu, Jun; Kamaly, Nazila; Shi, Jinjun; Zhao, Lili; Xiao, Zeyu; Hollett, Geoffrey; John, Rohit; Ray, Shaunak; Xu, Xiaoyang; Zhang, Xueqing; Kantoff, Philip; Farokhzad, OmidOne limitation of current biodegradable polymeric nanoparticles is their inability to effectively encapsulate and sustainably release proteins while maintaining protein bioactivity. Here we report the engineering of a PLGA-polycation nanoparticle platform with core-shell structure as a robust vector for the encapsulation and delivery of proteins and peptides. We demonstrate that the optimized nanoparticles can load high amounts of proteins (>20% of nanoparticles by weight) in aqueous solution by simple mixing via electrostatic interactions without organic solvents, forming nanospheres in seconds with diameter <200 nm. We also investigate the relationship between nanosphere size, surface charge, PLGA-polycation composition, and protein loading. The stable nanosphere complexes contain multiple PLGA-polycation nanoparticles, surrounded by large amounts of protein. This study highlights a novel nanoparticle platform and nanotechnology strategy for the delivery of proteins and other relevant molecules.