Publications

2019
Andres Da Silva-Candal, Tyler Brown, Vinu Krishnan, Iganacio Lopez-Loureiro I., Paulo Ávila-Gómez, Anusha Pusuluri, Amparo Pérez-Díaz, Clara Correa-Paz, Pablo Hervella, Jose Castillo J., Samir Mitragotri, and Francisco Campos F. 7/19/2019. “Shape effect in active targeting of nanoparticles to inflamed cerebral endothelium under static and flow conditions.” Journal of Controlled Release, 309, Pp. 94-105. Publisher's Version
Tanner EEL, Curreri AM, Balkaran JPR, Selig-Wober NC, Yang AB, Kendig C, Fluhr MP, Kim N, and Mitragotri S. 5/21/2019. “Design Principles of Ionic Liquids for Transdermal Drug Delivery.” Adv Mater. Publisher's VersionAbstract
Ionic liquids (ILs) and deep eutectic solvents have shown great promise in drug delivery applications. Choline-based ILs, in particular choline and geranic acid (CAGE), have been used to enhance the transdermal delivery of several small and large molecules. However, detailed studies outlining the design principles of ILs for transdermal drug delivery are still lacking. Using two model drugs of differing hydrophilicities, acarbose and ruxolitinib and 16 ILs, the dependence of skin penetration on the chemical properties of ILs is examined. First, the impact of ion stoichiometry on skin penetration of drugs is assessed using CAGE, which evidences that a molar ratio of 1:2 of choline to geranic acid yields the highest delivery. Subsequently, variants of CAGE are prepared using anions with structural similarity to geranic acid and cations with structural similarity to choline at a ratio of 1:2. Mechanistic studies reveal that the potency of ILs in enhancing transdermal drug delivery correlates inversely with the inter-ionic interactions as determined by 2D NMR spectroscopy. Using this understanding, a new IL is designed, and it provides the highest delivery of ruxolitinib of all ILs tested here. Overall, these studies provide a generalized framework for optimizing ILs for enhancing skin permeability.
Anusha Pusuluri, Vinu Krishnan, Debra Wu, Lily Li-Wen Wang, Charles Wyatt Shields IV, and Samir Mitragotri. 3/28/2019. “Role of Synergy and Immunostimulation in Design of Chemotherapy Combinations: An Analysis of Doxorubicin and Camptothecin.” Bioeng Transl Med. Publisher's VersionAbstract
Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near‐their maximum tolerated doses (MTDs), elevating the risk of dose‐related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low‐dose treatment option for breast cancer. DOX‐CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA‐MB‐231). This combination led to excellent long‐term survival of mice bearing MDA‐MB‐231 tumors at doses roughly 5‐fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX‐CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable anti‐tumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment.
Bhuvaneshwar Vaidya, Vineela Parvathaneni, Nishant S Kulkarni, Snehal K Shukla, Jenna K Damon, Apoorva Sarode, Dipti Kanabar, Jerome V Garcia, Samir Mitragotri, Aaron Muth, and Vivek Gupta. 2019. “Cyclodextrin modified erlotinib loaded PLGA nanoparticles for improved therapeutic efficacy against non-small cell lung cancer.” Int J Biol Macromol, 122, Pp. 338-347.Abstract
This study was aimed at developing a nanoparticle strategy to overcome acquired resistance against erlotinib in non-small cell lung cancer (NSCLC). To load erlotinib on biodegradable PLGA nanoparticles, erlotinib-cyclodextrin (Erlo-CD) complex was prepared using β-cyclodextrin sulfobutyl ether, which was in turn loaded in the core of PLGA nanoparticles using multiple emulsion solvent evaporation. Nanoparticles were characterized for size distribution, entrapment and loading efficiency, in-vitro release, and therapeutic efficacy against different lung cancer cells. Effect of formulation on cell cycle, apoptosis, and other markers was evaluated using flow cytometry and western blotting studies. The efficacy of optimized nanoformulation was evaluated using a clinically relevant in-vitro 3D-spheroid model. Results showed that Erlo-CD loaded nanoparticles (210 ± 8 nm in size) demonstrated 3-fold higher entrapment (61.5 ± 3.2% vs 21.9 ± 3.7% of plain erlotinib loaded nanoparticles) with ~5% loading efficiency and sustained release characteristics. Developed nanoparticles demonstrated significantly improved therapeutic efficacy against NSCLC cells in terms of low IC50 values and suppressed colony forming ability of cancer cells, increased apoptosis, and autophagy inhibition. Interestingly, 3D spheroid study demonstrated better anticancer activity of Erlo-CD nanoparticles compared to plain erlotinib. Present study has shown a premise to improve therapeutic efficacy against erlotinib-resistant lung cancer using modified nanoErlo formulations.
Wei He, Neha Kapate, C Wyatt Shields, and Samir Mitragotri. 2019. “Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases.” Adv Drug Deliv Rev.Abstract
Macrophages play a key role in defending against foreign pathogens, healing wounds, and regulating tissue homeostasis. Driving this versatility is their phenotypic plasticity, which enables macrophages to respond to subtle cues in tightly coordinated ways. However, when this coordination is disrupted, macrophages can aid the progression of numerous diseases, including cancer, cardiovascular disease, and autoimmune disease. The central link between these disorders is aberrant macrophage polarization, which misguides their functional programs, secretory products, and regulation of the surrounding tissue microenvironment. As a result of their important and deterministic roles in both health and disease, macrophages have gained considerable attention as targets for drug delivery. Here, we discuss the role of macrophages in the initiation and progression of various inflammatory diseases, summarize the leading drugs used to regulate macrophages, and review drug delivery systems designed to target macrophages. We emphasize strategies that are approved for clinical use or are poised for clinical investigation. Finally, we provide a prospectus of the future of macrophage-targeted drug delivery systems.
Rakesh Gupta, Balarama Sridhar Dwadasi, Beena Rai, and Samir Mitragotri. 2019. “Effect of Chemical Permeation Enhancers on Skin Permeability: In silico screening using Molecular Dynamics simulations.” Sci Rep, 9, 1, Pp. 1456.Abstract
Breaching of the skin barrier is essential for delivering active pharmaceutical ingredients (APIs) for pharmaceutical, dermatological and aesthetic applications. Chemical permeation enhancers (CPEs) are molecules that interact with the constituents of skin's outermost and rate limiting layer stratum corneum (SC), and increase its permeability. Designing and testing of new CPEs is a resource intensive task, thus limiting the rate of discovery of new CPEs. In-silico screening of CPEs in a rigorous skin model could speed up the design of CPEs. In this study, we performed coarse grained (CG) molecule dynamics (MD) simulations of a multilayer skin lipid matrix in the presence of CPEs. The CPEs are chosen from different chemical functionalities including fatty acids, esters, and alcohols. A multi-layer in-silico skin model was developed. The CG parameters of permeation enhancers were also developed. Interactions of CPEs with SC lipids was studied in silico at three different CPE concentrations namely, 1% w/v, 3% w/v and 5% w/v. The partitioning and diffusion coefficients of CPEs in the SC lipids were found to be highly size- and structure-dependent and these dependencies are explained in terms of structural properties such as radial distribution function, area per lipid and order parameter. Finally, experimentally reported effects of CPEs on skin from the literature are compared with the simulation results. The trends obtained using simulations are in good agreement with the experimental measurements. The studies presented here validate the utility of in-silico models for designing, screening and testing of novel and effective CPEs.
Zongmin Zhao, Anvay Ukidve, Yongsheng Gao, Jayoung Kim, and Samir Mitragotri. 2019. “Erythrocyte leveraged chemotherapy (ELeCt): Nanoparticle assembly on erythrocyte surface to combat lung metastasis.” Sci Adv, 5, 11, Pp. eaax9250.Abstract
Despite being the mainstay of cancer treatment, chemotherapy has shown limited efficacy for the treatment of lung metastasis due to ineffective targeting and poor tumor accumulation. Here, we report a highly effective erythrocyte leveraged chemotherapy (ELeCt) platform, consisting of biodegradable drug nanoparticles assembled onto the surface of erythrocytes, to enable chemotherapy for lung metastasis treatment. The ELeCt platform significantly extended the circulation time of the drug nanoparticles and delivered 10-fold higher drug content to the lung compared with the free nanoparticles. In both the early- and late-stage melanoma lung metastasis models, the ELeCt platform enabled substantial inhibition of tumor growth that resulted in significant improvement of survival. Further, the ELeCt platform can be used to deliver numerous approved chemotherapeutic drugs. Together, the findings suggest that the ELeCt platform offers a versatile strategy to enable chemotherapy for effective lung metastasis treatment.
Bijay Singh and Samir Mitragotri. 2019. “Harnessing cells to deliver nanoparticle drugs to treat cancer.” Biotechnol Adv.Abstract
Clinical translation of nanoparticle drug (nanodrug) delivery systems for cancer therapy is primarily hindered by short half-life of nanodrugs in blood circulation and their poor ability of tumor targeting and penetration in vivo. Circulatory cells have garnered much attention in cancer therapy as drug delivery vehicles due to their biocompatibility, high mobility, biodegradability, tissue targeting capability, high drug loading capacity, ability to cross biological barriers and inherent ability to remain in blood circulation long enough to accumulate within the tumors. Here, we review the progress and potential of circulatory cells as nanodrug delivery vehicles, especially for cancer therapy.
Anusha Pusuluri, Debra Wu, and Samir Mitragotri. 2019. “Immunological consequences of chemotherapy: Single drugs, combination therapies and nanoparticle-based treatments.” J Control Release, 305, Pp. 130-154.Abstract
The tumor environment has been shown to employ several immunosuppressive mechanisms to evade cancer treatments. While immunotherapies actively reverse such mechanisms and polarize the immune system against malignant cells, combining immunotherapy with certain chemotherapeutics can lead to increased efficacy compared to either treatment alone. Low-dose chemotherapy demonstrates several immunogenic effects that can favorably potentiate immunotherapies. However, the clinical benefits of such therapies are confounded by treatment complexity and marginal improvements. The highly complex relationship between chemotherapeutic drug dosing and subsequent immunological consequences is often generalized, thus limiting their efficacy and potential. Also, continuous monitoring of the immunological impact is crucial for designing superior synergies while optimizing chemotherapeutic combinations or chemotherapeutics in novel delivery systems. In this review, we summarize the existing literature on the immunological outcomes of chemotherapies administered individually, in combination regimens, and in formulation with novel delivery agents. Further, we discuss the relevance of key parameters including dosage, schedule, and tumor models, and describe their clinical implications with an emphasis on approaches and evaluations that are crucial for developing effective immune-stimulating therapies.
Amrita Banerjee, Renwei Chen, Shamsul Arafin, and Samir Mitragotri. 2019. “Intestinal iontophoresis from mucoadhesive patches: a strategy for oral delivery.” J Control Release, 297, Pp. 71-78.Abstract
Biologics have limited permeability across the intestine and are prone to degradation in the acidic-proteolytic milieu of the gastrointestinal tract, leading to poor oral bioavailability. Iontophoresis is a promising technology that can substantially improve transport of drugs across biological barriers and has been particularly explored for skin. In this study, we investigated whether iontophoresis across the intestine can be utilized to improve oral insulin transport. Application of electric current to intestinal cells resulted in opening of the tight junctions in vitro and a consequent about 3-fold improvement in paracellular transport of insulin. When evaluated in vivo using insulin-loaded mucoadhesive patches, iontophoresis produced profound hypoglycemia (63% blood glucose drop in 3 h) without damaging the intestinal tissue and the efficacy depended on insulin dose and current density. This study presents a proof of principle for intestinal iontophoresis as a novel method for oral protein delivery.
Wyatt C Shields, Lily Li-Wen Wang, Michael A Evans, and Samir Mitragotri. 2019. “Materials for Immunotherapy.” Adv Mater, Pp. e1901633.Abstract
Breakthroughs in materials engineering have accelerated the progress of immunotherapy in preclinical studies. The interplay of chemistry and materials has resulted in improved loading, targeting, and release of immunomodulatory agents. An overview of the materials that are used to enable or improve the success of immunotherapies in preclinical studies is presented, from immunosuppressive to proinflammatory strategies, with particular emphasis on technologies poised for clinical translation. The materials are organized based on their characteristic length scale, whereby the enabling feature of each technology is organized by the structure of that material. For example, the mechanisms by which i) nanoscale materials can improve targeting and infiltration of immunomodulatory payloads into tissues and cells, ii) microscale materials can facilitate cell-mediated transport and serve as artificial antigen-presenting cells, and iii) macroscale materials can form the basis of artificial microenvironments to promote cell infiltration and reprogramming are discussed. As a step toward establishing a set of design rules for future immunotherapies, materials that intrinsically activate or suppress the immune system are reviewed. Finally, a brief outlook on the trajectory of these systems and how they may be improved to address unsolved challenges in cancer, infectious diseases, and autoimmunity is presented.
Qin M Qi and Samir Mitragotri. 2019. “Mechanistic study of transdermal delivery of macromolecules assisted by ionic liquids.” J Control Release, 311-312, Pp. 162-169.Abstract
Transdermal delivery of large hydrophilic molecules is a long-standing challenge owing to the strong diffusive barrier properties of the skin. Using choline and geranic acid (CAGE) based ionic liquid (IL) as a delivery technology, we report a significant improvement of transdermal transport of dextrans of various molecular weights up to 150 kDa. In addition, it is the first time that we show CAGE decreased the size-dependence of transport and thus can be applied to a broad range of solutes. At the molecular scale, we conducted Fourier Transform Infrared (FTIR) spectroscopy studies which showed lipid extraction in the skin due to CAGE. Based on these experimental observations, we built a novel theoretical model that elucidates how CAGE-induced skin structural changes result in faster macromolecular diffusion for enhanced permeability. The fundamental understanding gained from this study demonstrates the potential of ionic liquids as an effective and noninvasive transdermal drug delivery method.
Tyler D Brown, Maksymilian Nowak, Alexandra V Bayles, Balabhaskar Prabhakarpandian, Pankaj Karande, Joerg Lahann, Matthew E Helgeson, and Samir Mitragotri. 2019. “A microfluidic model of human brain (μHuB) for assessment of blood brain barrier.” Bioeng Transl Med, 4, 2, Pp. e10126.Abstract
Microfluidic cellular models, commonly referred to as "organs-on-chips," continue to advance the field of bioengineering via the development of accurate and higher throughput models, captivating the essence of living human organs. This class of models can mimic key in vivo features, including shear stresses and cellular architectures, in ways that cannot be realized by traditional two-dimensional in vitro models. Despite such progress, current organ-on-a-chip models are often overly complex, require highly specialized setups and equipment, and lack the ability to easily ascertain temporal and spatial differences in the transport kinetics of compounds translocating across cellular barriers. To address this challenge, we report the development of a three-dimensional human blood brain barrier (BBB) microfluidic model (μHuB) using human cerebral microvascular endothelial cells (hCMEC/D3) and primary human astrocytes within a commercially available microfluidic platform. Within μHuB, hCMEC/D3 monolayers withstood physiologically relevant shear stresses (2.73 dyn/cm) over a period of 24 hr and formed a complete inner lumen, resembling in vivo blood capillaries. Monolayers within μHuB expressed phenotypical tight junction markers (Claudin-5 and ZO-1), which increased expression after the presence of hemodynamic-like shear stress. Negligible cell injury was observed when the monolayers were cultured statically, conditioned to shear stress, and subjected to nonfluorescent dextran (70 kDa) transport studies. μHuB experienced size-selective permeability of 10 and 70 kDa dextrans similar to other BBB models. However, with the ability to probe temporal and spatial evolution of solute distribution, μHuBs possess the ability to capture the true variability in permeability across a cellular monolayer over time and allow for evaluation of the full breadth of permeabilities that would otherwise be lost using traditional end-point sampling techniques. Overall, the μHuB platform provides a simplified, easy-to-use model to further investigate the complexities of the human BBB in real-time and can be readily adapted to incorporate additional cell types of the neurovascular unit and beyond.
Aaron C Anselmo and Samir Mitragotri. 2019. “Nanoparticles in the clinic: An update.” Bioeng Transl Med, 4, 3, Pp. e10143.Abstract
Nanoparticle drug delivery systems have been used in the clinic since the early 1990's. Since that time, the field of nanomedicine has evolved alongside growing technological needs to improve the delivery of various therapeutics. Over these past decades, newer generations of nanoparticles have emerged that are capable of performing additional delivery functions that can enable treatment via new therapeutic modalities. In the current clinical landscape, many of these new generation nanoparticles have reached clinical trials and have been approved for various indications. In the first issue of in 2016, we reviewed the history, current clinical landscape, and clinical challenges of nanoparticle delivery systems. Here, we provide a 3 year update on the current clinical landscape of nanoparticle drug delivery systems and highlight newly approved nanomedicines, provide a status update on previous clinical trials, and highlight new technologies that have recently entered the clinic.
Md Nurunnabi, Kelly N Ibsen, Eden EL Tanner, and Samir Mitragotri. 2019. “Oral ionic liquid for the treatment of diet-induced obesity.” Proc Natl Acad Sci U S A, 116, 50, Pp. 25042-25047.Abstract
More than 70% of American adults are overweight or obese, a precondition leading to chronic diseases, including diabetes and hypertension. Among other factors, diets with high fat and carbohydrate content have been implicated in obesity. In this study, we hypothesize that the choline and geranate (CAGE) ionic liquid can reduce body weight by decreasing fat absorption through the intestine. In vitro studies performed using docosahexaenoic acid (DHA), a model fat molecule, show that CAGE forms particles 2 to 4 μm in diameter in the presence of fat molecules. Ex vivo permeation studies in rat intestine showed that formation of such large particles reduces intestinal fat absorption. In vivo, CAGE reduces DHA absorption by 60% to 70% compared with controls. DHA administered with CAGE was retained in the intestine even after 6 h. Rats fed with a high-fat diet (HFD) and 10 μL of daily oral CAGE exhibited 12% less body weight gain compared with rats fed with an HFD without CAGE for 30 d. Rats that were given CAGE also ate less food than the control groups. Serum biochemistry and histology results indicated that CAGE was well tolerated by the rats. Collectively, our data support the hypothesis that CAGE interacts with fat molecules to prevent their absorption through intestinal tissue and potentially providing a feeling of satiety. We conclude that CAGE offers an effective means to control body weight and a promising tool to tackle the obesity epidemic.
Peter L Mage, Andrew T Csordas, Tyler Brown, Daniel Klinger, Michael Eisenstein, Samir Mitragotri, Craig Hawker, and Tom H Soh. 2019. “Shape-based separation of synthetic microparticles.” Nat Mater, 18, 1, Pp. 82-89.Abstract
The functional properties of colloidal materials can be tailored by tuning the shape of their constituent particles. Unfortunately, a reliable, general methodology for purifying colloidal materials solely based on shape is still lacking. Here we exploit the single-particle analysis and sorting capabilities of the fluorescence-activated cell sorting (FACS) instrument, a commonly used tool in biomedical research, and demonstrate the ability to separate mixtures of synthetic microparticles based solely on their shape with high purity. We achieve this by simultaneously obtaining four independent optical scattering signals from the FACS instrument to create shape-specific 'scattering signatures' that can be used for particle classification and sorting. We demonstrate that these four-dimensional signatures can overcome the confounding effects of particle orientation on shape-based characterization. Using this strategy, robust discrimination of particles differing only slightly in shape and an efficient selection of desired shapes from mixtures comprising particles of diverse sizes and materials is demonstrated.
Chi Zhang, Keda Zhang, Jialiang Zhang, Huilong Ou, Jiwen Duan, Saiman Zhang, Dexiang Wang, Samir Mitragotri, and Ming Chen. 2019. “Skin delivery of hyaluronic acid by the combined use of sponge spicules and flexible liposomes.” Biomater Sci, 7, 4, Pp. 1299-1310.Abstract
We demonstrated that the topical combined use of sponge Haliclona sp. spicules (SHS) and flexible liposomes (FL), referred to as SFLS (SHS-Flexible Liposomes combined System), can result in synergy to improve the skin absorption and deposition of hyaluronic acid (HA), especially in deep skin layers, both in vitro and in vivo. SHS treatment can result in skin micro-channels which are continuous, deep enough (48.6 ± 13.5 μm) and available in large quantities (850 ± 125 micro-channels per mm2). These micro-channels gradually closed up in 120 h and also allowed the intact vesicles of flexible liposomes and vesicle-bound or vesicle-encapsulated HA to penetrate into the skin-deep layers under the driving force of transdermal osmotic gradients. Specifically, SFLS topical application enhanced the penetration of FITC-HA (MW: 250 kDa) into porcine skin in vitro up to 23.2 ± 3.7%, which is 19.4 ± 3.1-fold (p < 0.001) that of a Phosphate Buffered Saline (PBS) group, 3.4 ± 0.5-fold (p < 0.01) that of an SHS group and 3.6 ± 0.6-fold (p < 0.01) that from the combined use of a Dermaroller and flexible liposomes. Moreover, SFLS can lead to significantly enhanced skin deposition of HA in all skin layers, especially in deep skin layers: up to 86.8 ± 4.1% of HA absorbed by skin was accumulated in deep skin layers. The effectiveness of SFLS topical application was also confirmed in vivo by using BALB/c mice. In addition, a skin irritation and toxicity study showed that the SFLS treatment may cause very minimal redness and the skin can recover in a short time. In sum, the combined use of SHS and FL (SFLS) offers a promising strategy to safely and effectively improve the skin delivery of hydrophilic biomacromolecules such as HA.
Anusha Pusuluri, Vinu Krishnan, Valerie Lensch, Apoorva Sarode, Elaine Bunyan, Douglas R Vogus, Stefano Menegatti, Tom H Soh, and Samir Mitragotri. 2019. “Treating Tumors at Low Drug Doses Using an Aptamer-Peptide Synergistic Drug Conjugate.” Angew Chem Int Ed Engl, 58, 5, Pp. 1437-1441.Abstract
Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non-optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor-targeting aptamers for effective low-dose treatment. A nucleolin-recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC (31.9 nm) against MDA-MB-231 breast cancer cells in vitro, and exhibited in vivo efficacy at micro-dose injections (500 and 350 μg kg  dose of DOX and CPT, respectively) that are 20-30-fold lower than their previously-reported MTDs. This approach represents a generalizable strategy for the safe and consistent delivery of combination drugs in oncology.
Zongmin Zhao*, Anvay Ukidve*, Vinu Krishnan*, and Samir Mitragotri. 2019. “Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers.” Adv Drug Deliv Rev.Abstract
Over the years, a plethora of materials - natural and synthetic - have been engineered at a nanoscopic level and explored for drug delivery. Nanocarriers based on such materials could improve the payload's pharmacokinetics and achieve the desired pharmacological response at the target tissue. Despite the development of rationally designed drug nanocarriers, only a handful of such formulations have been successfully translated into the clinic. The physicochemical properties (size, shape, surface chemistry, porosity, elasticity, and many others) of these nanocarriers influence its biological identity, which in presence of biological barriers in vivo, could significantly modulate the therapeutic index of its cargo and alter the desired outcome. Further, complexities associated with developing effective drug nanocarriers have led to conflicting views of its safety, permeation of biological barriers and cellular uptake. Here, in this review, we emphasize the effect of physicochemical properties of nanocarriers on their interactions with the biological milieu. The review will discuss in depth, how modulating the physicochemical properties would influence a drug nanocarrier's behavior in vivo and the mechanisms underlying these effects. The goal of this review is to summarize the design considerations based on these properties and to provide a conceptual template for achieving improved therapeutic efficacy with enhanced patient compliance.
Maria Jarvis*, Vinu Krishnan*, and Samir Mitragotri. 2019. “Nanocrystals: A perspective on translational research and clinical studies.” Bioeng Transl Med, 4, 1, Pp. 5-16.Abstract
Poorly soluble small molecules typically pose translational hurdles owing to their low solubility, low bioavailability, and formulation challenges. Nanocrystallization is a versatile method for salvaging poorly soluble drugs with the added benefit of a carrier-free delivery system. In this review, we provide a comprehensive analysis of nanocrystals with emphasis on their clinical translation. Additionally, the review sheds light on clinically approved nanocrystal drug products as well as those in development.

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