Ameya Kirtane

In vitro systems that accurately model in vivo conditions in the gastrointestinal tract may aid the development of oral drugs with greater bioavailability. Here we show that the interaction profiles between drugs and intestinal drug transporters can be obtained by modulating transporter expression in intact porcine tissue explants via the ultrasound-mediated delivery of small interfering RNAs and that the interaction profiles can be classified via a random forest model trained on the drug–transporter relationships. For 24 drugs with well-characterized drug–transporter interactions, the model achieved 100% concordance. For 28 clinical drugs and 22 investigational drugs, the model identified 58 unknown drug–transporter interactions, 7 of which (out of 8 tested) corresponded to drug-pharmacokinetic measurements in mice. We also validated the model’s predictions for interactions between doxycycline and four drugs …

BackgroundDosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients.MethodsWe designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK).FindingsWe demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that …

Wound closure is critical for the care of wounds by preventing foreign matter entry and supporting healing. Failure of wound closure because of mechanical compromise or inflammation can lead to failure of effective apposition of tissues and manifest in delayed healing and even death, depending on the site of the wound. Therefore, a platform capable of identifying inflammation as well as delivery of therapeutics, including chemical, biological, and cellular therapies, could transform our capacity to effectively sense potential failure as well as maximize healing. Here, we report the development of a decellularized gut suture platform capable of sensing inflammation as well as delivering a broad array of therapeutics, including small molecules, monoclonal antibodies, and cell-based therapeutics. We demonstrate the mechanical and biological functionalities of our platform in rodents and pigs. We anticipate that this …

Recent advances in the understanding of the relationship between cancer and metabolism have highlighted the relevance of the serine synthetic pathway (SSP), which consists of three successive enzymatic reactions. Enzymes of the SSP, such as phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT-1), were recently highlighted because they are amplified in a significant subset of human tumors, and their suppression by RNAi caused a decrease in cancer cell survival and growth. Currently, the discovery of drugs that inhibit these enzymes is still in its infancy, and the identification of suitable inhibitors could serve to understand the emerging biology of these metabolic enzymes. In this review, we present the SSP as a significant and novel emerging area for medicinal chemistry and we provide an overview of one of the key enzymes of the pathway, PHGDH.

The present disclosure provides oleogel and oleopaste compositions, as well as methods, kits, preparations, and methods of using the same. The oleogels and oleopastes presented herein include compositions comprising azithromycin, albendazole, lumefantrine, praziquantel, moxifloxacin, and ivermectin.

Vaccination represents one of the oldest and most effective public health interventions. Vaccines are routinely administered via systemic injections. Due to the invasive nature of this technique, it introduces several challenges. Vaccine administration without the use of needles would be beneficial. However, vaccine uptake is significantly limited by the presence of tissue barriers. Here, we review physical methods that disrupt these tissue barriers and enable efficient vaccine delivery. Four methods, namely microneedles, needle-free jet injectors, electroporation, and ultrasound. We focus on how these methods compare to needle-based vaccination in preclinical and clinical studies, and discuss their use in mucosal vaccination. In sum, these methods offer an attractive alternative to conventional vaccine delivery strategies; however, much work needs to be done to further improve their efficacy.

A critical barrier to effective cancer therapy is the improvement of drug selectivity, toxicity, and reduced recurrence of tumors expanded from tumor‐initiating stem‐like cells (TICs). The aim is to identify circulating tumor cell (CTC)‐biomarkers and to identify an effective combination of TIC‐specific, repurposed federal drug administration (FDA)‐approved drugs. Three different types of high‐throughput screens targeting the TIC population are employed: these include a CD133 (+) cell viability screen, a NANOG expression screen, and a drug combination screen. When combined in a refined secondary screening approach that targets Nanog expression with the same FDA‐approved drug library, histone deacetylase (HDAC) inhibitor(s) combined with all‐trans retinoic acid (ATRA) demonstrate the highest efficacy for inhibition of TIC growth in vitro and in vivo. Addition of immune checkpoint inhibitor further decreases …

In article 2301033, Giovanni Traverso and co-workers develop an oral sandwiched pill with in situ gelling systems gelled based on enzyme catalyzed crosslinking reactions, which undergo mild conditions, tunable gelation rate, and tough mechanical properties by a simple mixing to deliver clinically-relevant doses of hydrophilic and hydrophobic drugs in a large animal model, with a sustained half life and T max compared to conventional pills. This work is seen as a transformative step in drug delivery research that ushers in a new era of oral sustained drug delivery: The invention can not only be used to orally deliver drugs to optimize drugs pharmacokinetics after oral administration, but also can be used in gastrointestinal (GI) diagnoses application to ensure the diagnostic device stays in the GI tract for enough time.

The present disclosure provides compositions, methods, and kits that enable the in situ growth of polymers on or within a subject. In some aspects, the tissue-active monomers, including monomers comprising macromolecules, provide abroad set of material choices for synthetic tissue barriers. In additional aspects, the compositions, methods, and kits are useful for treating or preventing a disease or disorder.

mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (− 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their distribution in rural areas and developing countries. Overcoming these challenges stands to transform future deployment of mRNA vaccines. In this study, we developed an mRNA vaccine that can trigger a systemic immune response through administration via the gastrointestinal (GI) tract and is stable at 4 °C. A library of cationic branched poly(β-amino ester) (PBAE) polymers was synthesized and characterized, from which a polymer with high intracellular mRNA delivery efficiency and immune stimulation capacity was down-selected. mRNA …

The disclosure describes poly (β-thioester) polymers and polymeric nanoparticles, pharmaceutical compositions comprising these materials, their use in the treatment of cancer and infectious disease, and machine learning methods for identifying and selecting them.

Administering medicines to 0- to 5-year-old children in a resource-limited environment requires dosage forms that circumvent swallowing solids, avoid on-field reconstitution, and are thermostable, cheap, versatile, and taste masking. We present a strategy that stands to solve this multifaceted problem. As many drugs lack adequate water solubility, our formulations used oils, whose textures could be modified with gelling agents to form “oleogels.” In a clinical study, we showed that the oleogels can be formulated to be as fluid as thickened beverages and as stiff as yogurt puddings. In swine, oleogels could deliver four drugs ranging three orders of magnitude in their water solubilities and two orders of magnitude in their partition coefficients. Oleogels could be stabilized at 40°C for prolonged durations and used without redispersion. Last, we developed a macrofluidic system enabling fixed and metered dosing. We …

Nucleic acids are enabling a new generation of therapeutics and vaccines to treat and prevent a range of diseases. While these therapies have typically been limited to parenteral dosing, patients and clinicians prefer oral dosage forms. Furthermore, oral delivery enables local transfection of cells in the gastrointestinal tract not easily targeted via parenteral administration. To address these challenges, we synthesized and screened a library of branched hybrid poly(β-amino ester) mRNA nanoparticles for transfection efficiency; then we combined the highest performing formulations with ingestible milli-injector capsules capable of delivering formulations directly into gastric tissue. We validated the performance of formulations and devices in rodents and pigs, demonstrating protein translation in the delta, gastric, and parietal cells of the gastric mucosa, in addition to systemic uptake. We anticipate oral delivery of mRNA …

HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C= C2C [C@@ H](O) CC [C@] 2 (C)[C@@ H] 2 [C@@ H] 1 [C@@ H] 1CC [C@ H]([C@ H](C) CCCC (C) C)[C@@] 1 (C) CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 27

The present disclosure provides compositions, methods, and kits that enable the in situ growth of polymers on or within a subject. In some aspects, the monomer, dopamine, polymerizes in vivo to form a polymer on a tissue. In additional aspects, the compositions, methods, and kits are useful for treating or preventing a disease or disorder.

Cancer patients undergoing therapeutic radiation routinely develop injury of the adjacent gastrointestinal (GI) tract mucosa due to treatment. To reduce radiation dose to critical GI structures including the rectum and oral mucosa, 3D‐printed GI radioprotective devices composed of high‐Z materials are generated from patient CT scans. In a radiation proctitis rat model, a significant reduction in crypt injury is demonstrated with the device compared to without (p < 0.0087). Optimal device placement for radiation attenuation is further confirmed in a swine model. Dosimetric modeling in oral cavity cancer patients demonstrates a 30% radiation dose reduction to the normal buccal mucosa and a 15.2% dose reduction in the rectum for prostate cancer patients with the radioprotectant material in place compared to without. Finally, it is found that the rectal radioprotectant device is more cost‐effective compared to a hydrogel …

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib–glycyrrhizin and terbinafine–taurocholic acid both ex vivo and in vivo …

Diurnal variation in enzymes, hormones, and other biological mediators has long been recognized in mammalian physiology. Developments in pharmacobiology over the past few decades have shown that timing drug delivery can enhance drug efficacy. Here, we report the development of a battery-free, refillable, subcutaneous, and trocar-compatible implantable system that facilitates chronotherapy by enabling tight control over the timing of drug administration in response to external mechanical actuation. The external wearable system is coupled to a mobile app to facilitate control over dosing time. Using this system, we show the efficacy of bromocriptine on glycemic control in a diabetic rat model. We also demonstrate that antihypertensives can be delivered through this device, which could have clinical applications given the recognized diurnal variation of hypertension-related complications. We anticipate that …

A61K 31/765 424/78.31 5,792,742 A 2004/0057947 A1* 8/1998 Gold et al. 3/2004 Duettmann

Provided herein are pharmaceutical compositions for local administration of metabolic inhibitors, methods of locally administering such compositions, and rapid diagnostic methods for identifying mutant allele during the course of a surgical procedure.