Samir Mitragotri

Intestinal patch systems for oral drug delivery

HIGHLIGHTSOral delivery of many drugs especially biologicals is quite challenging.Intestinal patch based devices can greatly improve oral bioavailability of drugs.The devices protect drug from degradation in gut and enhance intestinal absorption. &NA; 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‐&agr;, 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.

Transdermal immunomodulation: Principles, advances and perspectives

&NA; Immunomodulation, manipulation of the immune responses towards an antigen, is a promising strategy to treat cancer, infectious diseases, allergies, and autoimmune diseases, among others. Unique features of the skin including the presence of tissue‐resident immune cells, ease of access and connectivity to other organs makes it a unique target organ for immunomodulation. In this review, we summarize advances in transdermal delivery of agents for modulating the immune responses for vaccination as well as tolerization. The biological foundation of skin‐based immunomodulation and challenges in its implementation are described. Technological approaches aimed at enhancing the delivery of immunomodulatory therapeutics into skin are also discussed in this review. Progress made in the treatment of several specific diseases including cancer, infections and allergy are discussed. Finally, this review discusses some practical considerations and offers some recommendations for future studies in the field of transdermal immunomodulation. Graphical abstract Figure. No caption available.

Nanoparticle Properties Modulate Their Attachment and Effect on Carrier Red Blood Cells

Attachment of nanoparticles (NPs) to the surface of carrier red blood cells (RBCs) profoundly alters their interactions with the host organism, decelerating NP clearance from the bloodstream while enabling NP transfer from the RBC surface to the vascular cells. These changes in pharmacokinetics of NPs imposed by carrier RBCs are favorable for many drug delivery purposes. On the other hand, understanding effects of NPs on the carrier RBCs is vital for successful translation of this novel drug delivery paradigm. Here, using two types of distinct nanoparticles (polystyrene (PSNP) and lysozyme-dextran nanogels (LDNG)) we assessed potential adverse and sensitizing effects of surface adsorption of NPs on mouse and human RBCs. At similar NP loadings (approx. 50 particles per RBC), adsorption of PSNPs, but not LDNGs, induces RBCs agglutination and sensitizes RBCs to damage by osmotic, mechanical and oxidative stress. PSNPs, but not LDNGs, increase RBC stiffening and surface exposure of phosphatidylserine, both known to accelerate RBC clearance in vivo. Therefore, NP properties and loading amounts have a profound impact on RBCs. Furthermore, LDNGs appear conducive to nanoparticle drug delivery using carrier RBCs.

Ionic liquids for addressing unmet needs in healthcare

Abstract Advances in the field of ionic liquids have opened new applications beyond their traditional use as solvents into other fields especially healthcare. The broad chemical space, rich with structurally diverse ions, and coupled with the flexibility to form complementary ion pairs enables task‐specific optimization at the molecular level to design ionic liquids for envisioned functions. Consequently, ionic liquids now are tailored as innovative solutions to address many problems in medicine. To date, ionic liquids have been designed to promote dissolution of poorly soluble drugs and disrupt physiological barriers to transport drugs to targeted sites. Also, their antimicrobial activity has been demonstrated and could be exploited to prevent and treat infectious diseases. Metal‐containing ionic liquids have also been designed and offer unique features due to incorporation of metals. Here, we review application‐driven investigations of ionic liquids in medicine with respect to current status and future potential.

Ionic liquids for oral insulin delivery

Significance Insulin is currently available as an injectable formulation, but an oral product would enjoy higher patient compliance and would significantly improve the quality of life of diabetic patients worldwide. However, oral delivery of proteins such as insulin is challenging due to various gastrointestinal barriers to oral absorption of macromolecules. We have developed a safe and highly effective ionic liquid-based oral insulin formulation that significantly enhanced oral insulin absorption by efficiently circumventing the gastrointestinal barriers. Besides, the formulation demonstrated good stability at room temperature and under refrigeration. Evidence from cell and animal studies supports a promising prospect of development of the formulation into a clinical product. With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude

Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.Unwanted uptake in the liver and limited accumulation in target organs is a major obstacle to targeted drug delivery. Here, the authors report on the hitchhiking of nanocarriers on red blood cells and the targeted upstream delivery to different target organs in mice, pigs and ex vivo human lungs.

Surface-Functionalized Carrier-Free Drug Nanorods for Leukemia

Pure drug nanoparticles have emerged as an alternate method for formulating extremely hydrophobic drugs. Herein, a simple and efficient process for synthesizing PEGylated and antibody‐conjugated, carrier‐free nanomedicine is reported as a promising strategy to deliver the drug, Camptothecin (CPT) for aggressive circulating tumors such as Acute Myeloid Leukemia (AML). Size, shape, and surface morphology of pure drug nanorods (NRs) are examined and characterized by a variety of techniques. Incorporation of polyethylene glycol (PEG) onto the particle changed its surface charge and topography while affecting its drug‐dissolution kinetics. Furthermore, the toxicity of PEGylated versus non‐PEGylated forms of humanized anti‐CD33 antibody (Hu195Ab)–coated CPT NRs are compared. Hu195Ab drug‐linked NRs increased cell killing in leukemic cells and surface PEGylation show reduced non‐specific uptake in cells. The results demonstrate that surface‐modified carrier‐free nanodrugs could have significant implications in cancer drug delivery for treating AML. This would be the first instance of studying the potential of surface‐functionalized carrier‐free drug NRs in the treatment of leukemia.

Cyclodextrin modified erlotinib loaded PLGA nanoparticles for improved therapeutic efficacy against non-small cell lung cancer

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.

Detachment of ligands from nanoparticle surface under flow and endothelial cell contact: Assessment using microfluidic devices

Abstract Surface modification of nanoparticles is a well‐established methodology to alter their properties to enhance circulation half‐life. While literature studies using conventional, in vitro characterization are routinely used to evaluate the biocompatibility of such modifications, relatively little attention has been paid to assess the stability of such surface modifications in physiologically relevant conditions. Here, microfluidic devices were used to study the effect of factors that adversely impact surface modifications including vascular flow and endothelial cell interactions. Camptothecin nanoparticles coated with polyethylene glycol (PEG) and/or folic acid were analyzed using linear channels and microvascular networks. Detachment of PEG was observed in cell‐free conditions and was attributed to interplay between the flow and method of PEG attachment. The flow and cells also impacted the surface charge of nanoparticles. Presence of endothelial cells further increased PEG shedding. The results demonstrate that endothelial cell contact, and vascular flow parameters modify surface ligands on nanoparticle surfaces.

Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro‐in vivo correlation

Abstract Combination chemotherapy is commonly used to treat late stage cancer; however, treatment is often limited by systemic toxicity. Optimizing drug ratio and schedule can improve drug combination activity and reduce dose to lower toxicity. Here, we identify gemcitabine (GEM) and doxorubicin (DOX) as a synergistic drug pair in vitro for the triple negative breast cancer cell line MDA‐MB‐231. Drug synergy and caspase activity were increased the most by exposing cells to GEM prior to DOX in vitro. While the combination was more effective than the single drugs at inhibiting MDA‐MB‐231 growth in vivo, the clear schedule dependence observed in vitro was not observed in vivo. Differences in drug exposure and cellular behavior in vivo compared to in vitro are likely responsible. This study emphasizes the importance in understanding how schedule impacts drug synergy and the need to develop more advanced strategies to translate synergy to the clinic.