Low Bioavailability Research Articles

Psoralidin: emerging biological activities of therapeutic benefits and its potential utility in cervical cancer

Cervical cancer (CaCx) is the fourth most prevalent cancer in women contributing to 341,831 annual deaths globally in 2020. Owing to its high mortality rate, the identification of novel inhibitors preventing CaCx progression is of utmost importance. Recent studies have emphasized the use of phytochemicals for cancer prevention due to their low toxicity. Psoralidin, a bioactive compound extracted from the seeds of the medicinal plant Psoralea corylifolia, showcases the potential for promoting health benefits. A range of studies showing anti-inflammatory, anti-oxidant, estrogenic, neuroprotective, anti-diabetic, anti-depressant, antimicrobial, and anti-tumor activities substantiate its promising biological effects. The anti-tumor potential of psoralidin has been well-documented. Its capacity to effectively target cancer stem cells (CSCs) in general adds to its therapeutic potential. Psoralidin carries out its anti-cancer activity by inducing oxidative stress, autophagy, and apoptosis. This unique characteristic suggests its potential to be used as an adjunct molecule in combination with existing treatment to enhance the efficacy of chemo/radiotherapy for treating CaCx. However, low bioavailability and intestinal efflux limit the use of psoralidin in clinical applications. Therefore, further investigation is needed in area of drug delivery and mechanism of action to fully harness the beneficial effects of psoralidin. The present study examines the current understanding of the molecular properties of this coumestan, as well as its various molecular targets with a particular emphasis on its anti-cancer activity. The study will help in designing effective and novel therapeutic interventions for targeting signaling pathways and other regulators involved in mediating CaCx progression, which will eventually help in effective management of CaCx.

Development and Characterization of Olaparib-Loaded Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Pharmaceutical Applications.

This study aims to enhance the solubility of Olaparib, classified as biopharmaceutical classification system (BCS) class IV due to its low solubility and bioavailability using a solid self-nanoemulsifying drug delivery system (S-SNEDDS). For this purpose, SNEDDS formulations were created using Capmul MCM as the oil, Tween 80 as the surfactant, and PEG 400 as the co-surfactant. The SNEDDS formulation containing olaparib (OLS-352), selected as the optimal formulation, showed a mean droplet size of 87.0 ± 0.4 nm and drug content of 5.53 ± 0.09%. OLS-352 also demonstrated anticancer activity against commonly studied ovarian (SK-OV-3) and breast (MCF-7) cancer cell lines. Aerosil® 200 and polyvinylpyrrolidone (PVP) K30 were selected as solid carriers, and S-SNEDDS formulations were prepared using the spray drying method. The drug concentration in S-SNEDDS showed no significant changes (98.4 ± 0.30%, 25℃) with temperature fluctuations during the 4-week period, demonstrating improved storage stability compared to liquid SNEDDS (L-SNEDDS). Dissolution tests under simulated gastric and intestinal conditions revealed enhanced drug release profiles compared to those of the raw drug. Additionally, the S-SNEDDS formulation showed a fourfold greater absorption in the Caco-2 assay than the raw drug, suggesting that S-SNEDDS could improve the oral bioavailability of poorly soluble drugs like olaparib, thus enhancing therapeutic outcomes. Furthermore, this study holds significance in crafting a potent and cost-effective pharmaceutical formulation tailored for the oral delivery of poorly soluble drugs.

Preparation of Baicalin Liposomes Using Microfluidic Technology and Evaluation of Their Antitumor Activity by a Zebrafish Model.

Baicalin (BCL), a well-known flavonoid molecule, has numerous therapeutic applications. However, its low water solubility and bioavailability limit its applicability. Microfluidics is a new method for liposome preparation that provides efficient and rapid control of the process, improving the stability and controllability. This study used microfluidic techniques to create baicalin liposomes (BCL-LPs), first screening for optimal total flow rates (TFR) and flow rate ratios (FRR), and then optimizing the phospholipid concentration, phospholipid-to-cholesterol ratio, and Tween-80 concentration using univariate and response surface methodology approaches. The study found that the ideal phospholipid content was 9.5%, the phospholipid-to-cholesterol ratio was 9:1 (w:w), and the Tween-80 concentration was 15%. BCL-LPs achieved 95.323% ± 0.481% encapsulation efficiency under the optimum circumstances. Characterization indicated that the BCL-LPs were spherical and uniform in size, with a mean diameter of 62.32 nm ± 0.42, a polydispersity index of 0.092 ± 0.009, and a zeta potential of -25.000 mV ± 0.216. In vitro experiments found that BCL-LPs had a better slow-release effect and stability than the BCL monomer. In zebrafish bioassays, BCL-LPs performed better than BCL monomer in terms of biological activity and bioavailability. The established method provided a feasible medicine delivery platform for BCL and could apply for the transport and encapsulation of more natural compounds, expanding the applications of drug delivery systems in healthcare and cancer therapies.

QBD approach for green synthesis of Rutin silver nanoparticles- screening for antioxidant, anticancer and anticlastogenic potential

Rutin is a flavonoid glycoside abundant in many plants exhibiting pharmacological activities like antioxidant, anticancer, anti-inflammatory and antimicrobial activities. Plant biomarkers suffer low bioavailability and solubility that lack clinical effectiveness. The smart nanoparticles conversion addresses this limitation with optimal particle size and targeted drug delivery. The present study involves QbD approach for formulation of Rutin silver nanoparticles and evaluation of antioxidant, anticancer and anticlastogenic potential. QbD experimentation involved particle size and drug release as dependent variables over the silver nitrate concentration, methanol and sonication time as independent variables devising 15 formulations (F1 –F15). F12 formulation was found to be optimized with 126.3 nm average size, stable and dispersible characterized by UV, FTIR, SEM and DLS studies. The calibration curve of Rutin was plotted at 352 nm with linearity (LOD = 0.061 μg/ml and LOQ = 0.187 μg/ml). The invitro drug release studies by USP dissolution apparatus I (Basket type) proved the sustained release characteristics with 97.3 % drug release when compared to the Rutin. The pharmacological screening for potential antioxidant and anticancer activity on G361 and MCF 7 cell line of F12 formulation have shown promising results and also enhanced solubility in water compared to Rutin. Anticalstogenic potential as a function of induced micronuclei frequency was evaluated as a characteristic feature in bone marrow cells obtained from mice. Results indicate pre-treatment with the F12 reduced frequency of micronuclei in mouse bone marrow cells caused by Cyclophosphamide (CP) significantly. The protective effect of F12 in suppression was demonstrated at both dosages of 100 and 200 mg/kg. Thus the findings suggest the novel Rutin silver nanoparticles as lead drug serving as antioxidant, anticancer and anticlastogenic agent.

Silybin: A Review of Its Targeted and Novel Agents for Treating Liver Diseases Based on Pathogenesis

ABSTRACTLiver disease represents a significant global public health concern. Silybin, derived from Silybum marianum, has been demonstrated to exhibit a range of beneficial properties, including anti‐inflammatory, antioxidative, antifibrotic, antiviral, and cytoprotective effects. These attributes render it a promising candidate for the treatment of liver fibrosis, cirrhosis, liver cancer, viral hepatitis, non‐alcoholic fatty liver disease, and other liver conditions. Nevertheless, its low solubility and low bioavailability have emerged as significant limitations in its clinical application. To address these limitations, researchers have developed a number of silybin formulations. This study presents a comprehensive review of the results of research on silybin for the treatment of liver diseases in recent decades, with a particular focus on novel formulations based on the pathogenesis of the disease. These include approaches targeting the liver via the CD44 receptor, folic acid, vitamin A, and others. Furthermore, the study presents the findings of studies that have employed nanotechnology to enhance the low bioavailability and low solubility of silybin. This includes the use of nanoparticles, liposomes, and nanosuspensions. This study reviews the application of silybin preparations in the treatment of global liver diseases. However, further high‐quality and more complete experimental studies are still required to gain a more comprehensive understanding of the efficacy and safety of these preparations. Finally, the study considers the issues that arise during the research of silybin formulations.

Oral administration of astilbin mitigates acetaminophen-induced acute liver injury in mice by modulating the gut microbiota.

Acetaminophen (APAP) overdose-induced acute liver injury (ALI) is characterized by extensive oxidative stress, and the clinical interventions for this adverse effect remain limited. Astilbin is an active compound found in the rhizome of Smilax glabra Roxb. with anti-inflammatory and antioxidant activities. Due to its low oral bioavailability, astilbin can accumulate in the intestine, which provides a basis for the interaction between astilbin and gut microbiota (GM). In the present study we investigated the protective effects of astilbin against APAP-induced ALI by focusing on the interaction between astilbin and GM. Mice were treated with astilbin (50 mg·kg-1·d-1, i.g.) for 7 days. After the last administration of astilbin for 2 h, the mice received APAP (300 mg/kg, i.g.) to induce ALI. We showed that oral administration of astilbin significantly alleviated APAP-induced ALI by altering the composition of GM and enriching beneficial metabolites including hydroxytyrosol (HT). GM depletion using an "antibiotics cocktail" or paraoral administration of astilbin abolished the hepatoprotective effects of astilbin. On the other hand, administration of HT (10 mg/kg, i.g.) caused similar protective effects in APAP-induced ALI mice. Transcriptomic analysis of the liver tissue revealed that HT inhibited reactive oxygen species and inflammation-related signaling in APAP-induced ALI; HT promoted activation of the Nrf2 signaling pathway to combat oxidative stress following APAP challenge in a sirtuin-6-dependent manner. These results highlight that oral astilbin ameliorates APAP-induced ALI by manipulating the GM and metabolites towards a more favorable profile, and provide an alternative therapeutic strategy for alleviating APAP-induced ALI.

Intranasal Nanoemulsion: A Promising Approach for the Management of Parkinson’s Disease

Parkinson's Disease (PD) is a neurodegenerative syndrome defined by the deterioration of dopamine neurons, showing a loss of motor activity. The treatment of PD is still challenging despite the development of numerous management techniques. Blood-brain Barrier (BBB) provides limited access to drug transport, being a major limiting factor in the treatment of Central Nervous System (CNS) disorders. Further, the major challenges in neurodegenerative diseases are low bioavailability and side effects. Intranasal drug delivery has become increasingly accessible for the treatment of several CNS disorders, including PD. The nasal cavity has direct access to the brain and drugs may be delivered at the site of action by bypassing the blood-brain barrier. Therapeutic molecules could be directly delivered to the brain through the olfactory region in the nasal cavity; further, the first-pass effects of drugs could also be eliminated. Several novel and promising developments in non-invasive approaches have been revealed for brain targeting by the nasal route. Among them, Nanoemulsions (NEs)-based drug delivery has been most widely explored, which can assist in several significant issues, such as limited BBB permeability, limited solubility, poor bioavailability, limited onset of action, and less enzymatic degradation. Several research reports have indicated intranasal NEs to have potential brain-targeting abilities, which may be widely explored for the treatment of PD. Therefore, the present review article has focused on the current scenario of intranasal NEs for the management of PD, with recent outcomes outlined through various research studies.

Extended duration linagliptin nanoparticles: a novel, safe and effective future of diabetes treatment?

Dear Editor, Diabetes Mellitus (DM), a chronic disease characterised by hyperglycaemia caused by either underproduction of insulin or defective insulin action, has become more prevalent globally; affecting 1 in every 10 adults over the past years with type 2 diabetes being more common in the low- and middle-income countries and type 1 in high-income countries (1). Pakistan, being a lower-middle-income country, has a 26.7% prevalence of diabetes and age-adjusted comparative prevalence of 30.8% affecting 1 in approximately every 4th adult (2). The current guidelines for the management of diabetes include insulin, metformin, sulfonylureas, and sodium-glucose co-transporters type 2 (SGLT-2) inhibitors. However, hypoglycaemia, weight gain, gastrointestinal problems and contraindication of their use in patients with pre-existing renal diseases pose problems for clinicians. Poor patient compliance in following the regular antidiabetic regimen also make treatment plans ineffective. Thus, newer drugs are constantly being researched (3). Metformin has been an excellent treatment option with only a slight risk for some specific patients to develop lactic acidosis. It is the most commonly prescribed medication for DM. Another drug, Linagliptin (Lina) was approved by the FDA in 2011 as an effective dipeptidyl peptidase inhibitor for the treatment of DM. It has been used as monotherapy and in combination with dapagliflozin, an SGLT2 inhibitor, for the treatment of diabetes in patients with a history of metformin therapy. However, its use was limited due to its low bioavailability (4). Recent research suggests that the extended duration (ED) Lina via the use of poly d, l-lactic-co-glycolic acid (PLGA) polymers in nanoparticle form could be beneficial in the management of type 2 DM. It has an increased bioavailability, fewer reported side effects and a reduced need for regular dosage. Furthermore, the use of nanoparticles facilitates a targeted delivery of the drug which may omit the pain that is caused by the use of implants (5). Lina is also thought to be effective in Type 3 Diabetes which causes Alzheimer’s disease. As dementia can lead to forgetting to take medications regularly, the ED Lina, which is taken once weekly, may be a suitable option. This new formulation is being considered for its better safety profile compared to other antidiabetics and its effectiveness in controlling HbA1C both as monotherapy and in combination therapy (4,6) ---Continue

Borneol promotes berberine-induced cardioprotection in a rat model of myocardial ischemia/reperfusion injury via inhibiting P-glycoprotein expression

Berberine is reported to protect the heart against ischemia/reperfusion (I/R) injury, although efficacy is limited by low bioavailability. This study aims to determine whether borneol, a classic guiding drug, can enhance the cardioprotection induced by berberine and to clarify the underlying mechanisms involving P-glycoprotein (P-gp) in the heart. Adult male Sprague Dawley rats were gavaged with berberine (200 mg/kg) with or without borneol (100 mg/kg) for 7 consecutive days. A rat model of myocardial I/R injury was established by 30 min left coronary artery occlusion followed with 120 min reperfusion. The arrhythmia score, cardiac enzyme content, and myocardial infarct size were determined following reperfusion. Heart tissues were collected for Western blot and immunofluorescence analyses to measure the protein expression levels of Bcl-2, Bax, and P-gp. The results showed that administration of berberine protected the heart against I/R injury, as demonstrated by lower arrhythmia scores, serum cTnI contents, myocardial infarct size, and cardiomyocytes apoptosis. Moreover, borneol substantially enhanced the cardioprotective effects of berberine. Western blot and immunofluorescence analyses showed that both berberine and I/R injury did not alter P-gp expression in heart. In contrast, borneol combined with berberine significantly reduced P-gp levels by 43.4% (P = 0.0240). Interestingly, treatment with borneol alone decreased P-gp levels, but did not protect against myocardial I/R injury. These findings suggest that borneol, as an adjuvant drug, improved the cardioprotective effects of berberine by inhibiting P-gp expression in heart. Borneol combined with berberine administration provides a new strategy to protect the heart against I/R injury.

Soluplus-TPGS Mixed Micelles as a Delivery System for Brigatinib: Characterization and In Vitro Evaluation.

Lung cancer is a major public health concern, with a high incidence and fatality rate. Its treatment is very difficult, as it is mostly diagnosed in advanced stages. Non-small cell lung carcinoma (NSCLC) is the major form of lung carcinoma that persists. Brigatinib (BGT), a powerful small-molecule tyrosine kinase inhibitor, has demonstrated significant therapeutic potential in the treatment of NSCLC with anaplastic lymphoma kinase (ALK) mutations. However, the therapeutic applicability of BGT is hampered by its low solubility and bioavailability. In this study, we developed a mixed micelle system comprising Soluplus and TPGS loaded with BGT. BGT was encapsulated into the mixed micelles using various combinations of Soluplus and TPGS, with encapsulation efficiency (EE%) ranging from 52.43 ± 1.07 to 97.88 ± 2.25%. The dynamic light scattering data showed that the mixed micelles ranged in size from 75.7 ± 0.46 to 204.3 ± 5.40 nm. The selected mixed micelles (F6) showed approximately 38% BGT release in the first 2 h, and subsequently, within 72 h, the release was 94.50 ± 5.90%. The NMR experiment confirmed the formation of micelles. Additionally, the mixed micelles showed significantly higher cellular uptake (p < 0.05) and increased cytotoxicity (p < 0.05) as compared to the free BGT. Specifically, the obtained IC50 values for BGT-loaded Soluplus-TPGS mixed micelles and free BGT were 22.59 ± 6.07 and 61.45 ± 6.35 μg/mL, respectively. The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.

Thermosensitive hydrogel as a sustained release carrier for mesenchymal stem cell-derived extracellular vesicles in the treatment of intrauterine adhesion

Intrauterine adhesion (IUA), a prevalent etiology of female infertility, is attributed to endometrial damage. However, conventional therapeutic interventions for IUA are plagued by high recurrence rates. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-EVs) demonstrate the promising therapeutic effects on IUA, but the current efficacy of extracellular vesicles (EVs) is hindered by lower retention and bioavailability. In this study, a thermosensitive hydrogel was utilized as a prolonged release carrier to improve the retention and bioavailability of hUCMSC-EVs in IUA treatment. The hydrogel-EVs complex effectively prolonged EVs retention in human endometrial stromal cells and an IUA mouse model. The complex exhibited superior protection against cellular injury, significantly alleviated endometrial damage, inhibited fibrosis, suppressed inflammation, and improved fertility compared to EVs alone. The results indicated that thermosensitive hydrogel enhanced the therapeutic capacity of EVs for IUA by prolonging their retention in the uterine environment. The hydrogel-EVs complex provides a novel strategy for the sustained release of hUCMSC-EVs in the treatment of IUA.Graphical

Multi-tracer evidence of hydrology and primary production controls on dissolved organic matter composition and stability in the semi-arid aquatic continuum

Autochthonous dissolved organic matter (Auto-DOM) produced by a biological carbon pump using dissolved inorganic carbon (DIC) from carbonate weathering plays an important role in carbon cycling within inland waters. However, little is known regarding how environmental conditions impact the composition and fate of organic matter, especially in surface waters of the semi-arid Loess Plateau, which is enriched in DIC by significant carbonate weathering. To obtain novel insight, we combined hydrochemistry, isotopic composition (δ2H, δ18O, and δ13CDIC), Rayleigh fractionation model, optical spectroscopy (absorbance and fluorescence), and Fourier transform ion cyclotron resonance mass spectrometry measurements to elucidate how primary production and hydrology impact the composition of DOM and the stability of the resulting Auto-DOM throughout the river–reservoir–wetland aquatic continuum of the Bahe River in the carbonate-mineral-rich semi-arid Loess Plateau where carbonate weathering is significant. The Rayleigh fractionation model results indicated that watershed DIC is primarily consumed through aquatic primary production rather than CO2 degassing. Further investigation revealed that primary production and evaporation co-occurred in this watershed. With the enrichment of the stable water isotope δ2H, the relative abundances of the allochthonous compounds decreased and the relative abundances of the autochthonous substances increased, suggesting that the terrestrial signal of riverine DOM decreased while autochthonous production increased along the flow pathway. In addition, associations between optical and molecular characteristics among DOM samples from different water bodies revealed that the stability ratio (Fmax(C2/(C2 + C4))) of Auto-DOM to the ratio of carboxylic-rich alicyclic molecules showed a consistent trend, suggesting that phytoplankton-derived and biomineralized C2 compounds are potentially recalcitrant DOM in inland waters. We conclude that hydrology and primary production affect the source, composition, and, potentially, the stability of DOM in DIC-enriched surface waters of the semi-arid Loess Plateau, which may lead to a more humic-like DOM composition in inland water and export this lower bioavailability DOC to the ocean in the long term.

Enhanced Therapeutic Potential of Liposome-Coated Bushen Jianpi Recipe for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) poses a major healthcare burden globally. Traditional Chinese medicine formula Bushen Jianpi (BSJP) recipe shows inhibitory effects on HCC but suffers from low bioavailability. This study aims to develop a BSJP-loaded liposome (BSJP@Lip) for targeted HCC treatment. BSJP@Lip was prepared using a microfluidic device. Particle characterization included size, morphology, drug loading, encapsulation efficiency, and release kinetics analysis. In vitro cytotoxicity, cellular uptake, apoptosis, and protein expression were evaluated in hepG2, Smmc-7721, and hepa 1-6 hepatic cancer cell lines treated with BSJP@Lip. BSJP@Lip nanoparticles showed a uniform spherical shape with an average size of 50 nm and zeta potential at around -2.24 mV. They significantly inhibited cell viability and induced apoptosis in a dose-dependent manner compared with traditional decoction formulations. Enhanced cellular uptake of BSJP@Lip increased the expression of proinflammatory factors IL-18 and NLRP3. BSJP@Lip nanoparticles were found to be efficiently internalized by hepatic cancer cell lines, resulting in a dose-dependent inhibition of cell viability and induction of apoptosis. This effect was accompanied by the upregulation of IL-18 and NLRP3.

Curcumin-Loaded Liposomes in Gel Protect the Skin of Mice against Oxidative Stress from Photodamage Induced by UV Irradiation.

Prolonged exposure to ultraviolet (UV) irradiation can cause oxidative stress in the skin, accompanied by rapid immunosuppressive effects, resulting in a peroxidation reaction throughout the body. Curcumin (Cur), as the bioactive compound of turmeric, is a natural polyphenol with potent antioxidant properties but is often overlooked due to its poor solubility and low bioavailability. In this study, curcumin-loaded liposomes in a sodium alginate gel complex preparation were designed to improve the bioavailability of curcumin and to study its preventive effect on photodamage. Cur-loaded liposomes (Cur-L), Cur-loaded gel (Cur-G) based on an alginate matrix, and curcumin-loaded liposomes in gel (Cur-LG) were prepared, and their antioxidant effects and drug diffusion abilities were evaluated. The antioxidant capacity of Cur, Cur-L, Cur-G, and Cur-LG was also studied in a mouse model of photodamage. Cur had the highest antioxidant activity at about 4 mg/mL. Cur-LG at this concentration showed antioxidant effects during 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) and H2O2 experiments. During the UV light damage test, Cur-LG demonstrated the ability to effectively neutralize free radicals generated as a result of lipid peroxidation in the skin, serum, and liver, thereby enhancing the overall activity of superoxide dismutase (SOD). In conclusion, using Cur-LG may protect against epidermal and cellular abnormalities induced by UV irradiation.

Exosome Loaded Protein Hydrogel for Enhanced Gelation Kinetics and Wound Healing.

Exosomes are being increasingly explored in biomedical research for wound healing applications. Exosomes can improve blood circulation and endocrine signaling, resulting in enhanced cell regeneration. However, exosome treatments suffer from low retention and bioavailability of exosomes at the wound site. Hydrogels are a popular tool for drug delivery due to their ability to encapsulate drugs in their network and allow for targeted release. Recently, hydrogels have proven to be an effective method to provide increased rates of wound healing when combined with exosomes that can be applied noninvasively. We have designed a series of single-domain protein-based hydrogels capable of physical cross-linking and upper critical solution temperature (UCST) behavior. Hydrogel variant Q5, previously designed with improved UCST behavior and a significantly enhanced gelation rate, is selected as a candidate for encapsulation release of exosomes dubbed Q5Exo. Q5Exo exhibits low critical gelation times and significant decreases in wound healing times in a diabetic mouse wound model showing promise as an exosome-based drug delivery tool and for future hybrid, noninvasive protein-exosome design.

Variables Affecting the Preparation and Characterization of Axitinib as Oral Niosmoes

Axitinib is anticancer drug act on different solid tumors by inhibtion protein kinase enzyme which is responsible for support the tumors with blood demand. Due to its low solubility, it has low bioavailability when given orally also it is affected by liver metabolism. Axitinib formulated as non-ionic vesicles (niosomes) for the first time to study the effect of different variables on the in vitro behaviour of vesicles in a hope to improve drug oral bioavailability. Niosomal dispersion formulas were formulated by diverse techniques via multiple kinds of surface-active agent (tween also span), cholesterol and dicetyl phosphate then evaluated for visual appearance, efficiency of drug entrapment (EE%), size of the vesicles, poly dispersity index, zetapotential, viscosity, invitro drug release and study the vesicles morphology by FE-SEM. Many variables effect on EE% were studied such as effect of surfactant amount and type, effect of surfactant combination, impact of various ratios of cholesterol, impact of DCP in various amount , effect of preparation method and effect of sonication time. The results showed that the EE% between (50.97%-98.24%), the particle size was found within the range (64.5 nm - 530.79 nm), zeta potential which was between ( -16.6 to -31 mV), polydispersity index (PDI) &lt;1 and viscosity between (584 – 889.6) centipoise. The niosomal dispersion F1 which contained 1:1 weight ratio (span60: cholesterol) was found with high EE% (96.5±0.16%), smallest particle size (64.5±0.5 nm), highest drug release (100%) of drug released at the end of 4 hours and FE-SEM photograph showed that niosomes were spherical with no aggregation and had a smooth surface. The results showed that thin film hydration method with sonication for four minutes was the best method for preparation of axitinib niosomes, the type and amount of surfactants used, cholesterol ratio, stabilizer and the time of sonication had a substantial effect on EE%, the size of the vesicles as well as drug release; which were investigated so as to optimize the niosomal dispersion of anti-tumour drug reaching to an optimum formula that may improve drug bioavailability. Key words: Axitinib, Anticancer, Vesicles, Surfactants, Invitro behaviour, Entrapment efficiency.

Developing and applying a single strategy for improved intestinal permeability of diverse and complex phytomolecules: nanoformulations of rutin, quercetin, thymoquinone provide proof-of-concept

Purpose: The clinical use of phytomolecules is restricted due to low oral bioavailability that may be attributed to their poor intestinal permeability owing to their complex structure, poor aqueous solubility and low biological stability. Rutin (RT), quercetin (QU), thymoquinone (TQ) are such potent and therapeutically versatile phytomolecules that await maximal utilization. Here we report a single strategy for enhanced intestinal permeation of diverse phytomolecules. Method: A simple idea with easy-to-apply method was developed that involved preparing nanoparticles of the phytomolecules RT, QU, TQ using eudragit matrix (RT-PNP, QU-PNP, TQ-PNP) and encapsulated in HPMC grade capsule shell. The PNPs were evaluated for particle characteristics, encapsulation efficiency, in vitro release kinetics, and intestinal permeability. Result: The average particle sizes of RT-PNP, QU-PNP, TQ-PNP were 446 ± 0.152, 39.6 ± 0.006 and 186 ± 0.513 nm, polydispersity indices were &lt; 0.5 with negative zeta potential. The % release of respective phytomolecule from RT-PNP, QU-PNP, TQ-PNP was significantly higher (p&lt;0.05) at pH 6.8 than pH 1.2. PNPs followed higuchi kinetics with non-Fickian diffusion mechanisms. The apparent intestinal permeability (Papp) of RT-PNP, QU-PNP, TQ-PNP were 14.45 ± 4.85, 12.96 ± 1.73 and 30.87 ± 8.75 µg/cm2, respectively, significantly (P &lt;0.5) greater vs RT, QU, TQ, respectively. CLSM confirmed significantly higher (p&lt;0.05) intestinal permeation of RT-PNP, QU-PNP, TQ-PNP vs RT, QU, TQ, respectively. Conclusion: Developed PNPs appear to be a good approach to increase the permeability of hydrophobic phytomolecules.

Protective role of transforming growth factor-Β3 (TGF-Β3) in the formation of radiation-induced capsular contracture around a breast implant: In vivo experimental study

Postmastectomy radiotherapy causes capsular contracture due to fibroproliferation of the capsular tissue around the implant. In fibrosis, unlike normal wound healing, structural and functional disorders are observed in the tissues caused by excessive/irregular accumulation of extracellular matrix proteins. It has been reported that transforming growth factor-β3 (TGF-β3) prevents and reverses fibrosis in various tissues or provides scarless healing with its antifibrotic effect. Additionally, TGF-β3 has been shown to reduce fibrosis in radiotherapy-induced fibrosis syndrome. However, no study in the literature investigates the effects of exogenously applied TGF-β3 on capsular contracture in aesthetic or reconstructive breast implant application. TGF-β3, which has a very short half-life, has low bioavailability with parenteral administration. Within the scope of this study, free TGF-β3 was loaded into the nanoparticles to increase its low bioavailability and extend its duration of action by providing controlled release. The aim of this study is to investigate the preventive/improving effects of radiation induced capsular contracture using chitosan film formulations containing TGF-β3 loaded poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles in implant-based breast reconstruction. In the characterization studies of nanoparticles, the particle size and zeta potential of the TGF-β3-loaded PLGA-b-PEG nanoparticle formulation selected to be used in the treatment group were found to be 123.60 ± 2.09 nm and −34.87 ± 1.42 mV, respectively. The encapsulation efficiency of the formulation was calculated as 99.91 %. A controlled release profile was obtained in in vitro release studies. Chitosan film formulations containing free TGF-β3 or TGF-β3-loaded PLGA-b-PEG nanoparticles were used in in vivo studies. In animal studies, rats were randomly distributed into 6 groups (n = 8) as sham, implant, implant + radiotherapy, implant + radiotherapy + chitosan film containing unloaded nanoparticles, implant + radiotherapy + chitosan film containing free TGF-β3, implant + radiotherapy + chitosan film containing TGF-β3 loaded nanoparticle. In all study groups, a 2 cm incision was made along the posterior axillary line at the thoracic vertebral level in rats to reach the lateral edge of the latissimus dorsi. The fascial attachment to the chest wall was then bluntly dissected to create a pocket for the implants. In the treatment groups, the wound was closed after films were placed on the outer surface of the implants. After administering prophylactic antibiotics, rats were subjected to irradiation with 10 Gy photon beams targeted to each implant site. Each implant and the surrounding excised tissue were subjected to the necessary procedures for histological (capsule thickness, cell density), immunohistochemical, and biochemical (α-SMA, vimentin, collagen type I and type III, TGF-β1 and TGF-β3: expression level/protein level) examinations. It was determined that the levels of TGF-β1 and TGF-β3 collagen type III, which decreased as a result of radiotherapy, were brought to the control level with free TGF-β3 film and TGF-β3 nanoparticle film formulations. Histological analyses, consistent with biochemical analyses, showed that thick collagen and fibrosis, which increased with radiotherapy, were brought to the control level with free TGF-β3 film and TGF-β3 nanoparticle film treatments.In biochemical analyses, the decrease in thick collagen was compatible with the decrease in the collagen type I/type III ratio in the free TGF-β3 film and TGF-β3 nanoparticle film groups. Changes in protein expression show that TGF-β3 loaded nanoparticles are more successful than free TGF-β3 in wound healing. In line with these results and the literature, it is thought that the balance of TGF-β1 and TGF-β3 should be maintained to ensure scarless wound healing with no capsule contracture.

Amino polycarboxylic acids-modified abiraterone derivatives as potential injectable anti-prostate cancer agents

Abiraterone (Abi), an effective cytochrome oxidase P450 C17 (CYP17) inhibitor, inhibits androgen synthesis in testes, adrenal glands, and prostate tumors. However, their low bioavailability and dissolution rate due to their poor solubility and toxic side effects have hindered their clinical applications. In this study, water-soluble and injectable Abi derivatives were developed by introducing amino polycarboxylic acids into Abi, and their antiproliferation effects in vitro, mechanism of action, antitumor activities in vivo, pharmacokinetics, and toxicity were investigated. Compared to Abi, the water-soluble derivative Abi-DTPA exhibited excellent antitumor activity in vitro and in vivo. It decreased cell migration, invasion, and mitochondrial membrane potential. A mechanistic study revealed that it still targeted the CYP17 enzyme and increased the expression levels of apoptosis-related proteins, including cleaved caspase 9, cleaved PARP, and cleaved caspase 3. Abi-DTPA was the main form in the plasma and exhibited lower toxicity after intravenous administration. These findings suggest that Abi-DTPA can be used as a novel injectable anti-prostate cancer agent.

Two Novel Hydrate Salts of Norfloxacin with Phenolic Acids and Their Physicochemical Properties.

Norfloxacin (NORF) is a broad-spectrum quinolone that is widely utilized for the treatment of various bacterial infections and is considered one of the most commonly used fluoroquinolone antibiotics. However, NORF's clinical utility is limited by its poor water solubility and relatively low oral bioavailability. This study presents an optimization and synergistic enhancement approach through salt/co-crystal, aiming to maximize the biopharmaceutical properties of NORF with the use of phenolic acid. Following this strategy, two new hydrate salts of NORF with phenolic acid, namely, NORF-3,5-DBA hydrate (salt 1) and NORF-VA hydrate (salt 2), were prepared and systematically confirmed. Two hydrate salts were produced by means of the slow evaporation crystallization method, and the structures were determined through single-crystal X-ray diffraction (SCXRD). Additionally, powder X-ray diffraction (PXRD), Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high-performance liquid chromatography (HPLC) were applied to analyze the features of the two salts. The experimental results indicated that the formation of the two salts could enhance the solubility and improve the release behavior of NORF. Interestingly, the physicochemical properties of NORF were significantly improved as a result, leading to an enhancement in its antibacterial activity. This was demonstrated by the enhanced inhibition of bacterial strains and the lower minimum inhibitory concentration values.