Publications

2017
Amrita Banerjee, Jessica Wong, Rohan Gogoi, Tyler Brown, and Samir Mitragotri. 2017. “Intestinal micropatches for oral insulin delivery.” J Drug Target, 25, 7, Pp. 608-615.Abstract
Diabetes mellitus has become a major public health issue that has almost reached epidemic proportions worldwide. Injectable insulin has been typically utilized for the management of this chronic disease. However, lack of patient compliance with injectable formulations has spurred the development of oral insulin formulations, which although appealing, face several delivery challenges. We have developed novel mucoadhesive intestinal patches, several hundred micrometers in dimension (micropatches) that address the challenges of oral insulin delivery. The micropatches adhere to the intestinal mucosa, release their drug load rapidly within 30 min and are effective in lowering blood glucose levels in vivo. When insulin-loaded micropatches were administered with a permeation enhancer and protease inhibitor, a peak efficacy of 34% drop in blood glucose levels was observed within 3 h. Efficacy further improved to 41% when micropatches were administered in multiple doses. Here, we describe the design of micropatches as an oral insulin formulation and report their in vivo efficacy.
Amrita Banerjee and Samir Mitragotri. 2017. “Intestinal patch systems for oral drug delivery.” Curr Opin Pharmacol, 36, Pp. 58-65.Abstract
Intestinal patches provide a unique platform for oral delivery of drugs which possess poor oral bioavailability, necessitating their administration by injections. Intestinal patch based devices prevent drug degradation in the gastrointestinal tract, facilitate their intestinal absorption through forming a localized drug depot at the delivery site and provide unidirectional, controlled drug release while preventing luminal drug loss. Consequently, intestinal patch-based devices are being developed for oral delivery of several drugs such as insulin, exenatide, calcitonin, interferon-α, erythropoietin and human granulocyte colony-stimulating factor for the treatment of diabetes, osteoporosis, hepatitis or for chemotherapy. This technology shows promise as a needle-free alternative to injectable drugs that would improve the quality of lives of millions of people requiring chronic administration of injectable drugs.
Kaushal Rege and Samir Mitragotri. 2017. “Introduction to Special Issue: 2016 Translational Medicine and Bioengineering Conference.” Bioeng Transl Med, 2, 2, Pp. 137-138.
Maria Jarvis, Michael Arnold, Jenna Ott, Kapil Pant, Balabhaskar Prabhakarpandian, and Samir Mitragotri. 2017. “Microfluidic co-culture devices to assess penetration of nanoparticles into cancer cell mass.” Bioeng Transl Med, 2, 3, Pp. 268-277.Abstract
In vitro and in vivo assessment of safety and efficacy are the essential first steps in developing nanoparticle-based therapeutic systems. However, it is often challenging to use the knowledge gained from in vitro studies to predict the outcome of in vivo studies since the complexity of the in vivo environment, including the existence of flow and a multicellular environment, is often lacking in traditional in vitro models. Here, we describe a microfluidic co-culture model comprising 4T1 breast cancer cells and EA.hy926 endothelial cells under physiological flow conditions and its utilization to assess the penetration of therapeutic nanoparticles from the vascular compartment into a cancerous cell mass. Camptothecin nanocrystals (∼310 nm in length), surface-functionalized with PEG or folic acid, were used as a test nanocarrier. Camptothecin nanocrystals exhibited only superficial penetration into the cancerous cell mass under fluidic conditions, but exhibited cytotoxicity throughout the cancerous cell mass. This likely suggests that superficially penetrated nanocrystals dissolve at the periphery and lead to diffusion of molecular camptothecin deep into the cancerous cell mass. The results indicate the potential of microfluidic co-culture devices to assess nanoparticle-cancerous cell interactions, which are otherwise difficult to study using standard in vitro cultures.
Saiman Zhang, Huilong Ou, Chunyun Liu, Yuan Zhang, Samir Mitragotri, Dexiang Wang, and Ming Chen. 2017. “Skin Delivery of Hydrophilic Biomacromolecules Using Marine Sponge Spicules.” Mol Pharm, 14, 9, Pp. 3188-3200.Abstract
We report the development of sponge Haliclona sp. spicules, referred to as SHS, and its topical application in skin delivery of hydrophilic biomacromolecules, a series of fluorescein isothiocyanate-dextrans (FDs). SHS are silicious oxeas which are sharp-edged and rod-shaped (∼120 μm in length and ∼7 μm in diameter). SHS can physically disrupt skin in a dose-dependent manner and retain within the skin over at least 72 h, which allows sustained skin penetration of hydrophilic biomacromolecules. The magnitude of enhancement of FD delivery into skin induced by SHS treatment was dependent on its molecular weight. Specifically, SHS topical application enhanced FD-10 (MW: 10 kDa) penetration into porcine skin in vitro by 33.09 ± 7.16-fold compared to control group (p < 0.01). SHS dramatically increased the accumulation of FD-10 into and across the dermis by 62.32 ± 13.48-fold compared to the control group (p < 0.01). In vivo experiments performed using BALB/c mice also confirmed the effectiveness of SHS topical application; the skin absorption of FD-10 with SHS topical application was 72.14 ± 48.75-fold (p < 0.05) and 15.39 ± 9.91-fold (p < 0.05) higher than those from the PBS and Dermaroller microneedling, respectively. Further, skin irritation study and transepidermal water loss (TEWL) measurement using guinea pig skin in vivo indicated that skin disruption induced by SHS treatment is self-limited and can be recovered with time and efficiently. SHS can offer a safe, effective, and sustained skin delivery of hydrophilic biomacromolecules and presents a promising platform technology for a wide range of cosmetic and medical applications.
Mengwen Zhang, Maksymilian Nowak, Paula Malo de Molina, Michael Abramovitch, Katherine Santizo, Samir Mitragotri, and Matthew E Helgeson. 2017. “Synthesis of Oil-Laden Poly(ethylene glycol) Diacrylate Hydrogel Nanocapsules from Double Nanoemulsions.” Langmuir, 33, 24, Pp. 6116-6126.Abstract
Multiple emulsions have received great interest due to their ability to be used as templates for the production of multicompartment particles for a variety of applications. However, scaling these complex droplets to nanoscale dimensions has been a challenge due to limitations on their fabrication methods. Here, we report the development of oil-in-water-in-oil (O/W/O) double nanoemulsions via a two-step high-energy method and their use as templates for complex nanogels comprised of inner oil droplets encapsulated within a hydrogel matrix. Using a combination of characterization methods, we determine how the properties of the nanogels are controlled by the size, stability, internal morphology, and chemical composition of the nanoemulsion templates from which they are formed. This allows for identification of compositional and emulsification parameters that can be used to optimize the size and oil encapsulation efficiency of the nanogels. Our templating method produces oil-laden nanogels with high oil encapsulation efficiencies and average diameters of 200-300 nm. In addition, we demonstrate the versatility of the system by varying the types of inner oil, the hydrogel chemistry, the amount of inner oil, and the hydrogel network cross-link density. These nontoxic oil-laden nanogels have potential applications in food, pharmaceutical, and cosmetic formulations.
Amrita Banerjee, Kelly Ibsen, Yasunori Iwao, Michael Zakrewsky, and Samir Mitragotri. 2017. “Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent.” Adv Healthc Mater, 6, 15.Abstract
Transdermal delivery of peptides and other biological macromolecules is limited due to skin's inherent low permeability. Here, the authors report the use of a deep eutectic solvent, choline and geranate (CAGE), to enhance topical delivery of proteins such as bovine serum albumin (BSA, molecular weight: ≈66 kDa), ovalbumin (OVA, molecular weight: ≈45 kDa) and insulin (INS, molecular weight: 5.8 kDa). CAGE enhances permeation of BSA, OVA, and insulin into porcine skin ex vivo, penetrating deep into the epidermis and dermis. Studies using tritium-labeled BSA and fluorescein isothiocyanate labeled insulin show significantly enhanced delivery of proteins into and across porcine skin, penetrating the skin in a time-dependent manner. Fourier transform IR spectra of porcine stratum corneum (SC) samples before and after incubation in CAGE show a reduction in peak area attributed to SC lipid content, suggesting lipid extraction from the SC. Circular dichroism confirms that CAGE does not affect insulin's secondary conformation. In vivo studies in rats show that topical application of 10 U insulin dispersed in CAGE (25 U kg insulin dose) leads to a highly significant 40% drop in blood glucose levels in 4 h that is relatively sustained for 12 h. Taken together, these studies demonstrate that CAGE is a promising vehicle for transdermal delivery of therapeutic proteins; specifically, as a noninvasive delivery alternative to injectable insulin for the treatment of diabetes.
2016
AC Anselmo and S Mitragotri. 2016. “A Chemical Engineering Perspective of Nanoparticle-based Targeted Drug Delivery: A Unit Process Approach.” AIChE., 62, 4, Pp. 966-974.
M Zakrewsky, A Banerjee, S Apte, T Kern, MR Jones, RE Del Sesto, A Kopposch, DT Fox, and S Mitragotri. 2016. “Choline and geranate deep eutectic solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications.” Advanced Healthcare Materials, 5, 11, Pp. 1282-1289.
K Camacho, S Menegatti, D Vogus, A Pusluri, Z Fuchs, M Jarvis, M Zakrewsky, M Evans, and S Mitragotri. 2016. “DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy.” Journal of Controlled Release, 229, Pp. 154-162.
S Menegatti, M Zakrewsky, S Kumar, J Oliveira, JA Muraski, and S Mitragotri. 2016. “De novo Design of Skin-penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs.” Advanced Healthcare Materials, 5, 5, Pp. 602-609.
V Gupta, BH Hwang, N Doshi, A Banerjee, AC Anselmo, and S Mitragotri. 2016. “Delivery of Exenatide and Insulin Using Mucoadhesive Intestinal Devices.” Annals of Biomedical Eng., Annals of Biomedical Engineering, 44, 6, Pp. 1993-2007.
D Pan, B. Zern O Vargas-Morales, AC Anselmo, V Gupta, M Zakrewsky, S Mitragotri, and V Muzykantov. 2016. “The Effect of Polymeric Nanoparticles on Biocompatibility of Carrier Red Blood Cells.” PloS one, 11, 3, Pp. e0152074.
M Zakrewsky, JA Muraski, and S Mitragotri. 2016. “Energy-Dependent Internalization of SPACETM Peptide for Rapid Drug Delivery into the Cytoplasm of Human Epidermal Keratinocytes”.
AC Anselmo and S Mitragotri. 2016. “Impact of Particle Elasticity on Particle-Based Drug Delivery Systems.” Advanced Drug Delivery Reviews.
A Banerjee, JH Lee, and S Mitragotri. 2016. “Intestinal Mucoadhesive Devices for Oral Delivery of Insulin”.
K Camacho, S Menegatti, and S Mitragotri. 2016. “Low-molecular-weight-Polymer-drug Conjugates for Synergistic Anticancer Activity of Camptothecin and Doxorubicin Combinations.” Nanomedicine, 11, 9, Pp. 1139-1151.
M Zakrewsky, JA Muraski, and S Mitragotri. 2016. “Mechanistic Analysis of Cellular Internalization of a Cell-and Skin-Penetrating Peptide.” Regenerative Engineering and Translational Medicine, 2, 1, Pp. 23-26.
J Myserson, AC Anselmo, Y Liu, S Mitragotri, D Eckmann, and V Muzykantov. 2016. “Non-affinity factors modulating vascular targeting of nano- and microcarriers.” Advanced Drug Delivery Reviews, 99, PartA, Pp. 97-112.
C Villa, AC Anselmo, S Mitragotri, and V Muzykantov. 2016. “Red blood cells: Supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems”.

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