Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles

Enright E.F., Griffin B.T., Gahan C.G., Joyce S.A.

Once regarded obscure and underappreciated, the gut microbiota (the microbial communities colonizing the gastrointestinal tract) is gaining recognition as an influencer of many aspects of human health. Also increasingly apparent is the breadth of interindividual variation in these co-evolved microbial-gut associations, presenting novel quests to explore implications for disease and therapeutic response. In this respect, the unearthing of the drug-metabolizing capacity of the microbiota has provided impetus for the integration of microbiological and pharmacological research. This review considers a potential mechanism, 'microbial bile acid metabolism', by which the intricate interplay between the host and gut bacteria may influence drug pharmacokinetics. Bile salts traditionally regarded as biological surfactants, synthesized by the host and biotransformed by gut bacteria, are now also recognized as signalling molecules that affect diverse physiological processes. Accumulating data indicate that bile salts are not equivalent with respect to their physicochemical properties, micellar solubilization capacities for poorly water-soluble drugs, crystallization inhibition tendencies nor potencies for bile acid receptor activation. Herein, the origin, physicochemical properties, physiological functions, plasticity and pharmaceutical significance of the human bile acid pool are discussed. Microbial dependant differences in the composition of the human bile acid pool, simulated intestinal media and commonly used preclinical species is highlighted to better understand in vivo performance predictiveness. While the precise impact of an altered gut microbiome, and consequently bile acid pool, in the biopharmaceutical setting remains largely elusive, the objective of this article is to aid knowledge acquisition through a detailed review of the literature.

Gaowa A., Horibe T., Kohno M., Kawakami K.

The aim of this study was to improve the oral absorption of epidermal growth factor receptor-targeted hybrid peptide using bile acid as an absorption enhancer. The oral formulation of this peptide was formed through electrostatic interactions between the cationic peptide and anionic bile acid. Comparative studies of in vitro cell permeability and in vivo antitumor effects of peptide and peptide/bile acid complex were performed in Caco-2 cells and in a xenograft mouse model of human gastric cancer. The in vitro permeability of peptide/bile acid complex across Caco-2 cell monolayers was significantly enhanced to about 5.0-fold over those of peptide alone. Furthermore, in vivo mouse xenograft model treated with peptide/bile acid complex showed a 1.6-fold reduction in the mean tumor volume as compared with the peptide alone. A preliminary safety evaluation of blood cells counts, liver enzyme levels, and histopathology of gastrointestinal tissues and main organs showed that the peptide/bile acid complex did not induce any acute toxicity. These results suggest that bile acid is an effective absorption enhancer for improving the oral bioavailability and bioactivity of epidermal growth factor receptor-targeted hybrid peptide.

Tan Q., Bie M., Wang Z., Chu Y., Tao S., Xu X., Liu Y.

Ahad A., Raish M., Ahmad A., Al-Jenoobi F.I., Al-Mohizea A.M.

The objective of the present study was to formulate eprosartan mesylate loaded nano-bilosomes and investigates its potential for controlling streptozotocin induced diabetes nephropathy in Wistar rats. The eprosartan mesylate loaded nano-bilosomes comprising of various ratios of soybean phosphatidylcholine/sodium deoxycholate were prepared by thin film hydration technique. The prepared formulations were evaluated for vesicles size, polydispersity index, zeta potential and entrapment efficiency. Further the optimized formulation was characterized for vesicles morphology, and its efficacy for the management of diabetic nephropathy in Wistar rats. The optimized eprosartan mesylate loaded nano-bilosomes exhibited vesicles size, polydispersity index, zeta potential and entrapment efficiency of 63.88±3.46nm, 0.172±0.026, -30.40±2.75mV and 61.19±0.88% respectively. In vivo activity demonstrated that the prepared eprosartan mesylate loaded nano-bilosomes formulation demonstrated a nephro-protecting outcome as shown by the substantial decrease in serum creatinine, urea, lactate dehydrogenase, total albumin, and malondialdehyde. Additionally, an oral administration of eprosartan mesylate loaded nano-bilosomes decreases the raised expressions of Angiotensin II type 1 receptor, inducible nitric oxide synthase, and transforming growth factor-β1 in Wistar rats. Further, histopathological examination established the nephro-protective effect of prepared formulation. In conclusion, the research work in the paper suggests that the prepared eprosartan mesylate loaded nano-bilosomes could serve as a practical oral formulation for diabetic nephropathy in future therapy and may offer potential benefits in cases with hypertension and renal disease.

Zhang X., Wu Y., Zhang M., Mao J., Wu Y., Zhang Y., Yao J., Xu C., Guo W., Yu B.

Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of paclitaxel (PTX). High antitumor efficacy and low toxicity require that PTX mainly accumulated in tumors with little drug exposure to normal tissues. However, many PTX-loaded micelle formulations suffer from low stability, fast drug release, and lack of tumor-targeting capability in the circulation. To overcome these challenges, we developed a micellar formulation that consists of sodium cholate (NaC) and monomethoxy poly (ethylene glycol)-block-poly (d,l-lactide) (mPEG-PDLLA).PTX-loaded NaC-mPEG-PDLLA micelles (PTX-CMs) and PTX-loaded mPEG-PDLLA micelles (PTX-Ms) were formulated, and their characteristics, particle size, surface morphology, release behavior in vitro, pharmacokinetics and in vivo biodistributions were researched. In vitro and in vivo tumor inhibition effects were systematically investigated. Furthermore, the hemolysis and acute toxicity of PTX-CMs were also evaluated.The size of PTX-CMs was 53.61±0.75 nm and the ζ-potential was -19.73±0.68 mV. PTX was released much slower from PTX-CMs than PTX-Ms in vitro. Compared with PTX-Ms, the cellular uptake of PTX-CMs was significantly reduced in macrophages and significantly increased in human cancer cells, and therefore, PTX-CMs showed strong growth inhibitory effects on human cancer cells. In vivo, the plasma AUC0-t of PTX-CMs was 1.8-fold higher than that of PTX-Ms, and 5.2-fold higher than that of Taxol. The biodistribution study indicated that more PTX-CMs were accumulated in tumor than PTX-Ms and Taxol. Furthermore, the significant antitumor efficacy of PTX-CMs was observed in mice bearing BEL-7402 hepatocellular carcinoma and A549 lung carcinoma. Results from drug safety assessment studies including acute toxicity and hemolysis test revealed that the PTX-CMs were safe for in vivo applications.These results strongly revealed that NaC-mPEG-PDLLA micelles can tumor-target delivery of PTX and enhance drug penetration in tumor, suggesting that NaC-mPEG-PDLLA micelles are promising nanocarrier systems for anticancer drugs delivery.

Sreekanth V., Medatwal N., Kumar S., Pal S., Vamshikrishna M., Kar A., Bhargava P., Naaz A., Kumar N., Sengupta S., Bajaj A.

Weakly basic drugs display poor solubility and tend to precipitate in the stomach's acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid-drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.

Mikov M., Đanić M., Pavlović N., Stanimirov B., Goločorbin-Kon S., Stankov K., Al-Salami H.

A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic β cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM. Results from in vivo experiments confirmed the positive effects of gliclazide in T1DM that are even more pronounced when combined with other hypoglycaemic agents such as probiotics and bile acids. Even though the exact mechanism of interaction at the molecular level is still unknown, there is a clear synergistic effect between gliclazide, bile acids and probiotics illustrated by the reduction of blood glucose levels and improvement of diabetic complications. Therefore, the manipulation of bile acid pool and intestinal microbiota composition in combination with old drug gliclazide could be a novel therapeutic approach for patients with T1DM.

Arafat M., Kirchhoefer C., Mikov M., Sarfraz M., Löbenberg R.

PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75- 30 mM) by rotary film evaporation followed by nano-size reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts.  Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nano-sized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Giovagnoli S., Pietrella D., Barberini L., Santi C., Carotti A., di Michele A., Ricci M.

The antibiotic era is on the verge of a profound change and facing a ground shaking crisis. The frequent failures of antibiotic treatments are often associated with biofilm formation, which is responsible for chronic infections, exacerbation as well as reinfection. So far, albeit the large number of valuable strategies employed to combat biofilm formation, little success has been recorded. In this work, we propose a simple approach, based on hydrophobic ionic complexation with the bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), to enhance anti-biofilm activity of well-known antibiotics, namely kanamycin (K), amikacin (A) and vancomycin (V). Activity was evaluated against Staphylococcus aureus ATCC 29213 and six methicillin-resistant clinical isolates. The formation of a 1:4 ADCA and KDCA and 1:1 VUDCA complexes was confirmed by 1HNMR, in silico molecular dynamics simulations, as well as thermal, spectrophotometric and HPLC analyses. The complexes showed higher inhibition of S. aureus growth compared to parent drugs and a concentration-independent biofilm inhibition and dispersion capacity in the order KDCA > ADCA >>VUDCA, even at concentrations ten-fold below the MIC. S. aureus growth inhibition evaluated upon treatment with bile acid-drug sequential addition and the complexes as well as the measured complex stability in solution suggest a bile acid carrier role. The complexes showed in vivo toxicity only at 10×MIC concentration on the chicken embryo chorioallantoic membrane model in the order KDCA < ADCA < VUDCA. KDCA was safe at all concentrations. Although several aspects to be addressed, this approach is promising due to its simplicity, the proved in vitro anti-biofilm activity enhancement and tolerability. A potential pulmonary drug delivery application is envisaged.

Pocuca M., Cvejic J., Vukmirovic S., Stilinovic N., Kuhajda K., Kevresan S., Mikov M.

Woodhams L., Al-Salami H.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the loss of glycemic control. Recent studies have shown significant inflammation and disturbed bile acid homeostasis, associated with T1DM. Bile acids are endogenously produced as a result of cholesterol catabolism in the liver and solely metabolized by gut microflora. This review investigates their potential oral delivery in T1DM using targeted delivery and encapsulation technologies. A sensitive and selective search was carried out using different search engines and databases. Keywords used included diabetes mellitus, bile acids and inflammation. To conclude, bile acids have a significant impact on diabetes symptoms and, when microencapsulated, may be used as an adjunct therapy to supplement T1DM treatment.

Priprem A., Johns J.R., Limsitthichaikoon S., Limphirat W., Mahakunakorn P., Johns N.P.

Aim: Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. Methodology: A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Results: Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. Conclusion: The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Leborgne C., Alimi-Guez D., El Shafey N., van Wittenberghe L., Bigey P., Scherman D., Kichler A.

Gene delivery to skeletal muscle is a promising strategy for the treatment of muscle disorders and for the systemic secretion of therapeutic proteins. In addition, muscle is an attractive target tissue because it is easily accessible. However, very few synthetic vectors proved capable of surpassing naked DNA mediated muscle gene transfer. In fact, only neutral copolymers, in particular poloxamers, demonstrated capacities to increase transgene expression in skeletal muscles. Here, we studied in vitro and in vivo behaviour of different bile salts. We report that sodium deoxycholate (DOC) and derivatives thereof increase after intramuscular injection by more than 100-fold the levels of the reporter gene luciferase compared to naked DNA. Using a LacZ expression cassette, we found that more than 20% of the muscle fibers expressed the reporter gene. Prolonged expression of a secreted reporter gene derived from a natural murine alkaline phosphatase enzyme could be documented. Altogether, our results demonstrate that bile salts belong to the most efficient chemicals identified so far for skeletal muscle gene transfer. Importantly, since these compounds are naturally found in the body, there is no risk of immune response against them and in addition several bile salts are already used in human medicine. Bile salt mediated muscle gene transfer may thus have broad applications in gene therapy.

Bharadwaj G., Nhan V., Yang S., Li X., Narayanan A., Macarenco A.C., Shi Y., Yang D., Vieira L.S., Xiao W., Li Y., Lam K.S.

Aim: To structurally modify our existing cholic acid (CA)-based telodendrimer (TD; PEG5K-CA8) for effective micellar nanoencapsulation and delivery of the US FDA-approved members of taxane family. Materials & methods: Generation of hybrid TDs was achieved by replacing four of the eight CAs with biocompatible organic moieties using solution-phase peptide synthesis. Drug loading was done using the standard evaporation method. Results: Hybrid TDs can generate micelles with narrow size distributions, low critical micelle concentration values (1–6 μM), better hematocompatibility and lack of in vitro cytotoxicity. Conclusion: Along with PEG5K-CA8, CA-based hybrid nanoplatform is the first of its kind that can stably encapsulate all three FDA-approved taxanes with nearly 100% efficiency up to 20% (w/w) loading.

Enright E.F., Joyce S.A., Gahan C.G., Griffin B.T.

In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p < 0.05). Subsequent investigations in biorelevant media containing either the trihydroxy bile salt sodium taurocholate (TCA) or the dihydroxy bile salt sodium taurodeoxycholate (TDCA) revealed altered drug solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs, providing impetus to consider the gut microbiota in the drug absorption process. In the clinical setting, disruption of the gut microbial ecosystem, through disease or antibiotic treatment, could transform the bile acid pool with potential implications for drug absorption and bioavailability.

Barahmand Z., Eikeland M.

Edo G.I., Mafe A.N., Akpoghelie P.O., Abiola O.T., Umelo E.C., Yousif E., Isoje E.F., Igbuku U.A., Opiti R.A., Madueke C.J., Essaghah A.E., Umar H., Alamiery A.A.

Santos G., Delgado E., Silva B., Braz B.S., Gonçalves L.

Topical ophthalmic drug delivery targeting the posterior segment of the eye has become a key area of interest due to its non-invasive nature, safety, ease of application, patient compliance, and cost-effectiveness. However, achievement of effective drug bioavailability in the posterior ocular segment is a significant challenge due to unique ocular barriers, including precorneal factors and anatomical barriers, like the cornea, the conjunctiva, and the sclera. Successful ocular drug delivery systems require increased precorneal residence time and improved corneal penetration to enhance intraocular bioavailability. A promising strategy to overcome these barriers is incorporating drug penetration enhancers (DPEs) into formulations. These compounds facilitate drug delivery by improving permeability across otherwise impermeable or poorly permeable membranes. At the ocular level, they act through three primary mechanisms: breaking tear film stability by interfering with the mucous layer; disrupting membrane components such as phospholipids and proteins; and loosening epithelial cellular junctions. DPEs offer significant potential to improve bioavailability and therapeutic outcomes, particularly for drugs targeting the posterior segment of the eye. This review is focused on analyzing the current literature regarding the use of penetration enhancers in topical ocular drug delivery, highlighting their mechanisms of action and potential to revolutionize ophthalmic treatments.

Borrego-Ruiz A., Borrego J.J.

Background/Objectives: This review examines the role of pharmacogenomics in individual responses to the pharmacotherapy of various drugs of abuse, including alcohol, cocaine, and opioids, to identify genetic variants that contribute to variability in substance use disorder treatment outcomes. In addition, it explores the pharmacomicrobiomic aspects of substance use, highlighting the impact of the gut microbiome on bioavailability, drug metabolism, pharmacodynamics, and pharmacokinetics. Results: Research on pharmacogenetics has identified several promising genetic variants that may contribute to the individual variability in responses to existing pharmacotherapies for substance addiction. However, the interpretation of these findings remains limited. It is estimated that genetic factors may account for 20–95% of the variability in individual drug responses. Therefore, genetic factors alone cannot fully explain the differences in drug responses, and factors such as gut microbiome diversity may also play a significant role. Drug microbial biotransformation is produced by microbial exoenzymes that convert low molecular weight organic compounds into analogous compounds by oxidation, reduction, hydrolysis, condensation, isomerization, unsaturation, or by the introduction of heteroatoms. Despite significant advances in pharmacomicrobiomics, challenges persist including the lack of standardized methodologies, inter-individual variability, limited understanding of drug biotransformation mechanisms, and the need for large-scale validation studies to develop microbiota-based biomarkers for clinical use. Conclusions: Progress in the pharmacogenomics of substance use disorders has provided biological insights into the pharmacological needs associated with common genetic variants in drug-metabolizing enzymes. The gut microbiome and its metabolites play a pivotal role in various stages of drug addiction including seeking, reward, and biotransformation. Therefore, integrating pharmacogenomics with pharmacomicrobiomics will form a crucial foundation for significant advances in precision and personalized medicine.

Reshetnyak V.I., Maev I.V.

Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its treatment. Because the cause of primary biliary cholangitis (PBC), a chronic, slowly progressive cholestatic liver disease, is still unknown, treatment remains symptomatic. Knowledge of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the disease. Advances in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this disease. For 35 years, ursodeoxycholic acid (UDCA) has been the unique drug of choice for the treatment of patients with PBC. In recent years, the list of hydrophilic bile acids used to treat cholestatic liver diseases, including PBC, has expanded. In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC.

Paliwal H., Prajapati B.G., Parihar A., Khan M.R., Chauhan C.S.

Mitrović D., Zaklan D., Đanić M., Stanimirov B., Stankov K., Al-Salami H., Pavlović N.

Nano-drug delivery systems provide targeted solutions for addressing various drug delivery challenges, leveraging nanotechnology to enhance drug solubility and permeability. Liposomes, explored for several decades, face hurdles, especially in oral delivery. Bile-acid stabilized vesicles (bilosomes) are flexible lipid vesicles, composed of phospholipids or other surfactants, along with amphiphilic bile salts, and they show superior stability and pharmacokinetic behavior in comparison to conventional vesicular systems (liposomes and niosomes). Bilosomes enhance skin penetration, fluidize the stratum corneum, and improve drug stability. In oral applications, bilosomes overcome drawbacks, offering improved bioavailability, controlled release, and reduced side effects. Vaccines using bilosomes demonstrate efficacy, and bilosomes for intranasal, inhalation, ocular, and buccal applications enhance drug delivery, offering targeted, efficient, and controlled activities. Formulations vary based on active substances and optimization techniques, showcasing the versatility and potential of bilosomes across diverse drug delivery routes. Therefore, the aim of this comprehensive review was to critically explore the state-of-the-art of bilosomes in drug delivery and potential therapeutic applications.

Tavares E.B., Paiva M.C., Lobo G.D., Martins T.S., Segura W.D., Garcia M.T.

Sharma B., Pérez-García L., Chaudhary G.R., Kaur G.

Gao H., Chang K., Huang X., Hung P., Hsieh M., Tsai N.

Background: Esophageal cancer is a prevalent malignancy of the digestive tract with a high incidence rate in Asia. Esophageal squamous cell carcinoma (ESCC) is the most common histological type, accounting for more than 90% of cases. JIB is a plant extract of Juniperus indica Bertol that has been shown to have anti-proliferation effects in nasopharyngeal carcinoma, oral cancer, and melanoma. Objectives: The aim of this study was to investigate the anti-cancer effects and underlying mechanisms of action of JIB in combination with 5-FU in ESCC cells. Methods: The effects of the combination of JIB and 5-FU on cytotoxicity, cell cycle arrest, apoptosis and drug resistance development were explored using CE81T/VGH human ESCC cells. Results: The results showed that JIB synergized the inhibitory effects of 5-FU on cell proliferation via downregulating the AKT/mTOR pathway in CE81T/VGH cells harboring the TP53 exon 8 R273C mutation. The combination treatment of JIB and 5-FU induced cell cycle arrest at G0/G1 and S phases via mediating the levels of CDK4/cyclin D1 and CDK2/cyclin A. Furthermore, JIB combined with 5-FU was more effective in inducing apoptosis by activation of extrinsic (Fas/caspase-8) and intrinsic (Bax/caspase-9) pathways than the use of a single drug. Additionally, JIB attenuated the development of resistance to 5-FU in long-term culture and exhibited enhanced cytotoxicity in bile acid environments. Conclusion: JIB combined with 5-FU synergistically inhibited the ESCC growth and triggered cell cycle arrest and apoptosis. These findings suggest that the combination of JIB and 5-FU may be a potential strategy for the treatment of esophageal cancer.

Chadwick S.R., Stack-Couture S., Berg M.D., Gregorio S.D., Lung B., Genereaux J., Moir R.D., Brandl C.J., Willis I.M., Snapp E.L., Lajoie P.

Cells counter accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) through activation of the Unfolded Protein Response (UPR). Small molecules termed chemical chaperones can promote protein folding to alleviate ER stress. The bile acid tauroursodeoxycholic acid (TUDCA), has been described as a chemical chaperone. While promising in models of protein folding diseases, TUDCA's mechanism of action remains unclear. Here, we found TUDCA can rescue growth of yeast treated with the ER stressor tunicamycin (Tm), even in the absence of a functional UPR. In contrast, TUDCA failed to rescue growth on other ER stressors. Nor could TUDCA attenuate chronic UPR associated with specific gene deletions or over-expression of a misfolded mutant secretory protein. Neither pretreatment with or delayed addition of TUDCA conferred protection against Tm. Importantly, attenuation of Tm-induced toxicity required TUDCA's critical micelle forming concentration, suggesting a mechanism where TUDCA directly sequesters drugs. Indeed, in several assays, TUDCA treated cells closely resembled cells treated with lower doses of Tm. In addition, we found TUDCA can inhibit dyes from labeling intracellular compartments. Thus, our study challenges the model of TUDCA as a chemical chaperone and suggests that TUDCA decreases drug bioavailability, allowing cells to adapt to ER stress.

Alruwaili N.K., Alsaidan O.A., Zafar A., Alhassan H.H., Alburaykan E.A., Alsaidan A.A., Yasir M., Singh L., Khalid M.

Santos L.G., Musther H., Bala N., Deferm N., Patel G., Brouwers J., Turner D.B.

Abstract Bile salts are biosurfactants released into the intestinal lumen which play an important role in the solubilisation of fats and certain drugs. Their concentrations vary along the gastrointestinal tract (GIT). This is significant for implementation in physiologically based pharmacokinetic (PBPK) modelling to mechanistically capture drug absorption. The aims of this meta-analysis were to collate all appropriate data on intestinal bile salt concentrations in healthy adults across all GIT segments in fasted and fed states for the purpose of PBPK modelling. Terms relating to bile composition were searched in PubMed and Google Scholar from inception to May 2024. Selected studies included aspirated intestinal fluid collected via gastric tubes or colonoscopy. Results showed high variability across studies and a time-dependency for the fed state. Data were rich for the duodenum, which showed a two-fold increase for the fed state versus the fasted state within multiple studies. Peaks and troughs in bile salt concentrations along the GIT were observed for both fasted and fed states, likely due to segmental water absorption differences. The highest between subject variability was observed for the duodenum in the fasted and fed state and the fed proximal jejunum, distal ileum, and colon. The findings from this meta-analysis can be used for the purpose of PBPK modelling to capture segmental drug solubilisation and absorption in fasted and fed states. However, data are lacking under different fed conditions, especially following low-fat meals, so the impact of different fat content associated with different meals on bile salt concentrations cannot be discerned. Graphical Abstract Gastrointestinal bile salt concentrations in healthy subjects A meta-analysis has been conducted to collate fasted and fed gastrointestinal bile salt concentrations in healthy subjects for the purpose of physiologically-based pharmacokinetic (PBPK) modelling within the Simcyp and other PBPK simulators. Values are presented as weighted means with coefficient of variability for each segment. These data will help improve mechanistic models of oral drug absorption.

Foster T., Lim P., Wagle S.R., Ionescu C.M., Kovacevic B., McLenachan S., Carvalho L., Brunet A., Mooranian A., Al-Salami H.

Kuldeep, Jena S.R., Samanta L., Subuddhi U.