An official website of the United States government
Abstract Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventingMycobacterium tuberculosisgrowth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.
more »
« less
Bacterial Influence on Pharmacokinetics of Tacrolimus and Sulfasalazine through Regulation of Host Metabolism
Abstract The unpredictable oral bioavailability of established drugs like tacrolimus and sulfasalazine presents a significant clinical challenge. This variability can lead to either toxicity or insufficient therapeutic effect. It is known that alterations in drug transporters and metabolic enzymes influence drug bioavailability. Recent evidence suggests that the indirect metabolism by gut microbes could influence transporters and enzymes which can affect the bioavailability of oral drugs. In this study, the pharmacokinetics of tacrolimus and sulfasalazine are modeled under varying host colonic conditions induced by the bacteriaE. coli Nissle 1917andBifidobacterium adolescentis. Insight is provided into the sensitivity of pharmacokinetics to the bacterial influence on expression of intestinal drug transporters and cytochrome p450 enzymes. Our findings demonstrate that bacterial modulation reduces tacrolimus peak blood concentration compared to healthy renal transplant patients. Conversely, bacterial presence leads to a two‐fold increase in sulfasalazine's peak plasma concentration compared to healthy subjects. These results suggest that incorporating the gut bacteria's influence on colonic transporters and enzymes can improve the explanation of pharmacokinetic variability. This approach has the potential to refine pharmacokinetic models and ultimately address the challenge of variable oral drug bioavailability.
more »
« less
- Award ID(s):
- 2240045
- PAR ID:
- 10517801
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Therapeutics
- Volume:
- 7
- Issue:
- 8
- ISSN:
- 2366-3987
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Long-term and high-dose prescription opioid use places individuals at risk for opioid misuse, opioid use disorder (OUD), and overdose. Existing methods for monitoring opioid use and detecting misuse rely on self-reports, which are prone to reporting bias, and toxicology testing, which may be infeasible in outpatient settings. Although wearable technologies for monitoring day-to-day health metrics have gained significant traction in recent years due to their ease of use, flexibility, and advancements in sensor technology, their application within the opioid use space remains underexplored. In the current work, we demonstrate that oral opioid administrations can be detected using physiological signals collected from a wrist sensor. More importantly, we show that models informed by opioid pharmacokinetics increase reliability in predicting the timing of opioid administrations. Forty-two individuals who were prescribed opioids as a part of their medical treatment in-hospital and after discharge were enrolled. Participants wore a wrist sensor throughout the study, while opioid administrations were tracked using electronic medical records and self-reports. We collected 1,983 hours of sensor data containing 187 opioid administrations from the inpatient setting and 927 hours of sensor data containing 40 opioid administrations from the outpatient setting. We demonstrate that a self-supervised pre-trained model, capable of learning the canonical time series of plasma concentration of the drug derived from opioid pharmacokinetics, can reliably detect opioid administration in both settings. Our work suggests the potential of pharmacokinetic-informed, data-driven models to objectively detect opioid use in daily life.more » « less
-
The oral route is the most common choice for drug administration because of several advantages, such as convenience, low cost, and high patient compliance, and the demand and investment in research and development for oral drugs continue to grow. The rate of dissolution and gastric emptying of the dissolved active pharmaceutical ingredient (API) into the duodenum is modulated by gastric motility, physical properties of the pill, and the contents of the stomach, but current in vitro procedures for assessing dissolution of oral drugs are limited in their ability to recapitulate this process. This is particularly relevant for disease conditions, such as gastroparesis, that alter the anatomy and/or physiology of the stomach. In silico models of gastric biomechanics offer the potential for overcoming these limitations of existing methods. In the current study, we employ a biomimetic in silico simulator based on the realistic anatomy and morphology of the stomach (referred to as “StomachSim”) to investigate and quantify the effect of body posture and stomach motility on drug bioavailability. The simulations show that changes in posture can potentially have a significant (up to 83%) effect on the emptying rate of the API into the duodenum. Similarly, a reduction in antral contractility associated with gastroparesis can also be found to significantly reduce the dissolution of the pill as well as emptying of the API into the duodenum. The simulations show that for an equivalent motility index, the reduction in gastric emptying due to neuropathic gastroparesis is larger by a factor of about five compared to myopathic gastroparesis.more » « less
-
null (Ed.)Drug delivery through the skin offers many advantages such as avoidance of hepatic first-pass metabolism, maintenance of steady plasma concentration, safety, and compliance over oral or parenteral pathways. However, the biggest challenge for transdermal delivery is that only a limited number of potent drugs with ideal physicochemical properties can passively diffuse and intercellularly permeate through skin barriers and achieve therapeutic concentration by this route. Significant efforts have been made toward the development of approaches to enhance transdermal permeation of the drugs. Among them, microneedles represent one of the microscale physical enhancement methods that greatly expand the spectrum of drugs for transdermal and intradermal delivery. Microneedles typically measure 0.1–1 mm in length. In this review, microneedle materials, fabrication routes, characterization techniques, and applications for transdermal delivery are discussed. A variety of materials such as silicon, stainless steel, and polymers have been used to fabricate solid, coated, hollow, or dissolvable microneedles. Their implications for transdermal drug delivery have been discussed extensively. However, there remain challenges with sustained delivery, efficacy, cost-effective fabrication, and large-scale manufacturing. This review discusses different modes of characterization and the gaps in manufacturing technologies associated with microneedles. This review also discusses their potential impact on drug delivery, vaccine delivery, disease diagnostic, and cosmetics applications.more » « less
-
Abstract Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulatorflhDCto drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion withflhDCincreases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors.more » « less
