Free Drug Research Articles

Synergistic antifungal activity against Candida albicans between voriconazole and cyclosporine a loaded in polymeric nanoparticles

The goal of this work is to investigate if the synergistic antifungal activity between cyclosporine A, CsA, and voriconazole, VRZ, increases when both drugs are encapsulated in a nanocarrier as compared when they are free. The preparation and characterization of blank and VRZ and CsA loaded polymeric based PLGA nanoparticles (PLGA, PLGA-PEG, and PLGA+PEG) was a necessary previous step. Using the more suitable NPs, those of PLGA, the antifungal susceptibility tests performed with VRZ-loaded PLGA NPs, show no significant increase of the antifungal activity in comparison to that of free VRZ. However, the synergistic behavior found for the (VRZ+CsA)-loaded PLGA NPs was fourfold stronger than that observed for the two free drugs together. On the other hand, the investigation into the suppression of C. albicans biofilm formation showed that blank PLGA NPs inhibit the biofilm formation at high NPs concentrations. However, a minor effect or even a slight biofilm increase formation was observed at low and moderate NPs concentrations. Therefore, the enhancement of the biofilm inhibition found for the three tested treatments (CsA alone, VRZ alone, and VRZ+CsA) when comparing free and encapsulated drugs, within the therapeutic window, can be attributed to the drug encapsulation approach. Indeed, polymeric PLGA NPs loaded with CsA, VRZ, or VRZ+CsA are more effective at inhibiting the C. albicans biofilm growth than their free counterparts.

High‐Load Core@Shell Nanocarriers with Irinotecan and 5‐Fluorouracil for Combination Chemotherapy in Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer type and second leading cause of cancer‐related deaths worldwide, requiring novel drug‐delivery concepts. ITC@ZrO(TocP)/ZrO(FdUMP) core@shell nanocarriers (designated ITC‐FdUMP‐NC) with the clinically relevant chemotherapeutics irinotecan (ITC) and fluoro‐2′‐deoxyuridine‐5′‐phosphate (FdUMP) (active derivative of 5′‐fluorouracil/5‐FU) are a new type of nanocarrier with high drug payload (22 wt% of lipophilic ITC: particle core; 10 wt% of hydrophilic FdUMP: particle shell). The nanocarriers are tested in different CRC cell lines, a normal cell line, and rectal cancer patient‐derived organoids (PDOs). Fluorescence‐labeled nanocarriers show efficient uptake by all CRC cells and allow to distinctly track the intracellular trafficking toward endolysosomal compartments. Although free chemotherapeutic drugs exhibit a greater potency in 2D cell cultures, ITC‐FdUMP‐NC demonstrate equivalent cytotoxic efficacies as the freely dissolved drugs in the more complex 3D rectal cancer PDOs. The sustained drug‐release profile of the nanocarriers contrasts favorably with conventional free drugs, potentially enhancing the therapeutic outcome in vivo. With a chemotherapeutic cocktail comparable to the clinically applied FOLFIRI (ITC + 5‐FU), the ITC‐FdUMP‐NC represent a novel type of nanocarrier with high anti‐tumor effect and high drug payload, offering a promising strategy to circumvent chemoresistance and to improve therapy efficacy in vivo with less side effects.

Unlocking the Power of Human Ferritin: Enhanced Drug Delivery of Aurothiomalate in A2780 Ovarian Cancer Cells.

Aurothiomalate (AuTM) is an FDA-approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP-OES analysis, using three mutant ferritins and trypsinization experiments. The adduct contains ~3 gold atoms per ferritin subunit, arranged in a small cluster bound to Cys90 and Cys102. MD simulations provided a plausible structural model for the cluster. The adduct was evaluated for its pharmacological properties and was found to be significantly more cytotoxic than free AuTM against A2780 cancer cells mainly due to higher gold uptake. NMR-metabolomics showed that AuTM bound to HuHf and free AuTM induced qualitatively similar changes in treated cancer cells, indicating that the effects on cell metabolism are approximately the same, in agreement with independent biochemical experiments. In conclusion, we have demonstrated here that a molecularly precise bioconjugate formed between AuTM and HuHf exhibits anticancer properties far superior to the free drug, while retaining its key mechanistic features. Evidence is provided that human ferritin can serve as an excellent carrier for this metallodrug.

A computer-aided, heterodimer-based “triadic” carrier-free drug delivery platform to mitigate multidrug resistance in lung cancer and enhance efficiency

Co-delivering multiple drugs or circumventing the drug efflux mechanism can significantly decrease multidrug resistance (MDR), a major cause of cancer treatment failure. In this study, we designed and fabricated a universal “three-in-one” self-delivery system for synergistic cancer therapy using a computer-aided strategy. First, we engineered two glutathione (GSH)-responsive heterodimers, ERL-SS-CPT (erlotinib [ERL] linked with camptothecin [CPT] via a disulfide bond [SS]) and CPT-SS-ERI (CPT conjugated with erianin [ERI]), which serve as both cargo and carrier material. Next, molecular dynamics simulations indicated that multiple noncovalent molecular forces, including π-π stacking, hydrogen bonds, hydrophobic interactions, and sulfur bonds, drive the self-assembly process of these heterodimers. We then explored the universality of the heterodimers and developed a “triadic” drug delivery platform comprising 40 variants. Subsequently, we conducted case studies on docetaxel (DTX)-loaded ERL-SS-CPT nanoparticles (denoted as DTX@ERL-SS-CPT NPs) and curcumin (CUR)-loaded ERL-SS-CPT NPs (identified as CUR@CPT-SS-ERI NPs) to comprehensively investigate their self-assembly mechanism, physicochemical properties, storage stability, GSH-responsive drug release, cellular uptake, apoptosis effects, biocompatibility, and cytotoxicity. Both NPs exhibited well-defined spherical structures, high drug loading rates, and excellent storage stability. DTX@ERL-SS-CPT NPs exhibited the strongest cytotoxicity in A549 cells, following the order of DTX@ERL-SS-CPT NPs > ERL-SS-CPT NPs > CPT > DTX > ERL. Conversely, DTX@ERL-SS-CPT NPs showed negligible cytotoxicity in normal human bronchial epithelium cell line (BEAS-2B), indicating good biocompatibility and safety. Similar observations were made for CUR@CPT-SS-ERI NPs regarding biocompatibility and cytotoxicity. Upon endocytosis and encountering intracellular overexpressed GSH, the disulfide-bond linker is cleaved, resulting in the release of the versatile NPs into three parts. The spherical NPs enhance water solubility, reduce the required dosage of free drugs, and increase cellular drug accumulation while suppressing P-glycoprotein (P-gp) expression, leading to apoptosis. This work provides a computer-aided universal strategy—a heterodimer-based “triadic” drug delivery platform—to enhance anticancer efficiency while reducing multidrug resistance.

Fabrication of ibuprofen/naringenin-coloaded into zein/sodium caseinate nanoparticles: evaluation of antiproliferative activity and apoptosis induction in liver cancer cells

Nowadays, liver cancer is one of the most disturbing types of cancer that can affect either sex. Nanoparticles (NPs) of zein/sodium caseinate incorporating ibuprofen (IBU) and naringenin (NAR) have improved bioavailability and a high encapsulation efficiency (EE%). These nanoparticles are uniformly spherical. In vitro, cytotoxicity analysis on HepG2 cell lines, which are used to study human liver cancer, shows that encapsulated drugs (86.49% ± 1.90, and 78.52% ± 1.98 for NAR and IBU, respectively) have significantly lower IC50 values than individual drugs or their combined free form. In addition, the combination indices of 0.623 and 0.155 for IBU and NAR, respectively, show that the two have joint beneficial effects. The scratch wound healing assay results also show that the free drugs and the engineered NPs have a more significant anti-migratory effect than the untreated cells. The designed nanoparticles also reduce angiogenesis and proliferation while inducing apoptosis, according to in vitro results. In conclusion, a new approach to treating liver cancer may lie in the nanoencapsulation of numerous drugs within nanoparticles.

In vitro and in vivo evaluation of Bombesin-MMAE conjugates for targeted tumour therapy

Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. The upregulation of the bombesin receptor 2 (BB2) in several malignancies and the advantages offered by peptide drug conjugates over antibody drug conjugates in terms of production and tumour targeting motivated us to synthesise and test bombesin conjugates armed with the tubulin binder monomethyl auristatin E. The widely used Val-Cit-PABC was initially included as cathepsin cleavable self-immolative linker for the release of the free drug. However, the poor stability of the Val-Cit-conjugates in mouse plasma encouraged us to consider the optimised alternatives Glu-Val-Cit-PABC and Glu-Gly-Cit-PABC. Conjugate BN-EVcM1, featuring Glu-Val-Cit-PABC, combined suitable stability (t(½) in mouse and human plasma: 8.4 h and 4.6 h, respectively), antiproliferative activity in vitro (IC50 = 29.6 nM on the human prostate cancer cell line PC-3) and the full release of the free payload within 24 h. Three conjugates, namely BN-EGcM1, BN-EVcM1 and BN-EVcM2, improved the accumulation of MMAE in PC-3 human prostate cancer xenograft mice models, compared to the administration of the free drug. Among them, BN-EVcM1 also stood out for the significantly extended survival of mice in in vivo acute efficacy studies and for the significant inhibition of the growth of a PC-3 tumour in mice in both acute and chronic efficacy studies.

Transungual Penetration and Antifungal Activity of Prescription and Over-the-Counter Topical Antifungals: Ex Vivo Comparison.

Topical antifungals for toenail onychomycosis must penetrate the nail to deliver an inhibitory concentration of free drug to the site of infection. In two ex vivo experiments, we tested the ability of topical antifungals to inhibit growth of Trichophyton rubrum and Trichophyton mentagrophytes, the most common causative fungi in toenail onychomycosis. Seven topical antifungals were tested: three U.S. Food and Drug Administration-approved products indicated for onychomycosis (ciclopirox 8% lacquer; efinaconazole 10% solution; tavaborole 5% solution) and four over-the-counter (OTC) products for fungal infections (tolnaftate 1% and/or undecylenic acid 25% solutions). The ability to inhibit fungal growth was tested in the presence and absence of keratin. Products were applied either to human cadaverous nails or keratin-free cellulose disks prior to placement on an agar plate (radius: 85mm) seeded with a clinical isolate of T. rubrum or T. mentagrophytes. After incubation, the zone of inhibition (ZI), defined as the radius of the area of no fungal growth, was recorded. In the nail penetration assay, average ZIs for efinaconazole (T. rubrum: 82.1mm; T. mentagrophytes: 63.8mm) were significantly greater than those for tavaborole (63.5mm; 39.1mm), ciclopirox (7.4mm; 3.6mm) and all OTC products (range: 10.5-34.2mm against both species; all P < 0.001). In the cellulose disk diffusion assay, efinaconazole and tavaborole demonstrated maximal antifungal activity against both species (ZIs = 85mm); average ZIs against T. rubrum and T. mentagrophytes were smaller for ciclopirox (59.0 and 55.7mm, respectively) and OTC products (range: 31.2-57.8mm and 25.7-47.7mm, respectively). Among all antifungals tested, the ability to penetrate human toenails to inhibit growth of both T. rubrum and T. mentagrophytes was greatest for efinaconazole, followed by tavaborole. These results indicate superior transungual penetration of efinaconazole compared to the other antifungals, suggesting lower keratin binding in the nail.

Continuous sampling of healthy and mastitic quarters of lactating cattle by ultrafiltration after intramammary ceftiofur hydrochloride administration.

Pharmacological activity of intramammary drugs depends on adequate drug concentrations within the cistern, but sampling is often limited. Insight into the active drug concentration within the mammary cistern may assist in determining effective and appropriate therapeutic decisions for cows being treated for mastitis. Evaluate the disposition of ceftiofur hydrochloride administered intramammary in diseased and nondiseased quarters. Whole milk and ultrafiltrate sampling techniques were compared. Ten mature, late lactation Holstein (n = 9) and Jersey (n = 1) dairy cows (422-670 kg) with naturally occurring clinical mastitis, producing between 1.4 and 15.9 kg/day of milk. Ultrafiltration probes were placed in both mastitic and healthy quarters. Each quarter was treated with 2 doses of 125 mg ceftiofur hydrochloride suspension, and whole milk and milk ultrafiltrate samples were collected. Ceftiofur concentrations in composite whole milk and milk ultrafiltrate were analyzed. The maximum concentration of ceftiofur was higher in ultrafiltrate samples, but no differences were identified in healthy or mastitic quarters. The use of ultrafiltration probes provides a novel technique for free drug concentrations within the mastitic and healthy bovine mammary gland. Significant inter- and intracow variability and lower daily milk weights may overestimate ceftiofur concentrations available within the cistern. The pharmacokinetic (PK) parameters reported in milk ultrafiltrate will help establish a link between the PK and the corresponding drug effect, potentially providing a meaningful rationale for the selection of a safe and effective dose in cows with mastitis.

Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease where standard-of-care chemotherapeutic drugs have limited efficacy due to the development of drug resistance and poor drug delivery caused by a highly desmoplastic tumor microenvironment. Combining multiple drugs in a tumor-targeting carrier would be a favorable approach to overcome these limitations. Hence, a tumor-targeted peptide (TTP) conjugated amphiphilic tri-block copolymer was developed to make targeted polymer nanoparticles (TTP-PNPs) serving as a vehicle for carrying gemcitabine (Gem), paclitaxel (PTX), and their combination (Gem + PTX). The TTP-PNPs in the form of empty polymer (P), single drug-loaded [P(Gem) and P(PTX)], and dual drug-loaded [P(Gem + PTX)] polymer nanoformulations exhibited stable and homogenous spherical shapes with 110–160 nm size. These nanoformulations demonstrated excellent stability under in vitro physiological conditions and led to an efficient release of the drugs in the presence of reduced glutathione (GSH). The efficacy of these nanoparticles was thoroughly evaluated in vitro and in vivo, demonstrating a notable capacity to selectively target and restrict PDAC cells (PANC-1 and KPC) growth. The cellular uptake and biodistribution study showed a significantly higher tumor-targeting ability of TTP-PNPs than PNPs without TTP. Notably, P(Gem + PTX) exhibited the lowest IC50 compared to all other controls and showed heightened synergistic effects in both cell lines. Furthermore, P(Gem + PTX) showed a significantly better tumor reduction and median overall survival in mouse models than single drug-loaded TTP-PNPs or a combination of free drugs (Gem + PTX). In summary, our TTP-PNP system shows great promise as a novel platform for delivering Gem + PTX specifically to pancreatic cancer (PC), maximizing the therapeutic benefits with lower concentrations of the drugs and potentially reducing toxic side effects.

Pharmacist intervention to improve controlled substance dispensing and use practices in Texas: A pilot study

BackgroundPharmacists play an important role in preventing and addressing opioid-related harm; as such, efforts to encourage and improve their participation are valuable. Face-to-face peer-pharmacist-delivered academic detailing targeted at community pharmacists may serve a role to support best practices in dispensing controlled substances (CS). ObjectivesThe objectives of the project were to (1) develop and pilot an academic detailing intervention, (2) determine the feasibility of delivering the intervention, and (3) determine which knowledge and practice should be emphasized during the education. This information would drive refinements to the project before it was expanded. MethodsEducational content and materials were developed based on previous research on dispensing practices and on delivering academic detailing. A pharmacist trainer visited community pharmacists to deliver education and to collect data about knowledge and practices surrounding CS dispensing. The community pharmacists were also offered drug disposal products for distribution to patients. ResultsA total of 53 community pharmacies in Fort Bend County, TX, were identified as potential targets for the intervention. Seven were determined to be ineligible and the pharmacists in 33 pharmacies consented to participation. Before the intervention, 60.6% of the participating pharmacists reported feeling uncomfortable filling CS and disposal of leftover CS was infrequently addressed with patients. Most pharmacies did not use drug disposal systems before intervention and most pharmacies were interested in receiving free drug disposal envelopes through the intervention. ConclusionAn educational intervention was developed and pilot tested. The pilot showed the intervention’s feasibility and suggested which educational content needed to be abridged to accommodate community pharmacists’ busy practices. Plans were made to scale up the intervention to include more peer pharmacists and community pharmacies.

Nanostructured Hybrid Polymer‐Lipid Drug Delivery Platforms for Rapamycin Repositioning in Anticancer Therapy

AbstractHere, hybrid polymer‐lipid nanoparticles are designed as colloidal carriers for Rapamycin, to improve the aqueous drug stability and to support the drug repositioning for cancer treatment, that is, against rhabdomyosarcoma (RMS). With this aim, Rapamycin – loaded hybrid nanoparticles are produced by using as nanoparticle core a graft copolymer obtained from the functionalization of the α,β‐poly(N‐2‐hydroxyethyl)‐DL‐aspartamide (PHEA) with Rhodamine B (RhB), Polylactic acid (PLA), the PHEA‐g‐RhB‐g‐PLA, and different phospholipids, that is, 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine (DPPC) coated, pegylated and Mannose/PEG, for the surface coating. The drug loading of these samples allows for controlled release, and improves drug stability at pH 5.5 and 7.4 compared to the free drug. Chemical‐physical characterization confirms the nanostructure size below 200 nm, ideal for systemic administration, and easy re‐dispersibility in aqueous media. Moreover, biological characterization to test the potential use as antitumor agent shows induction of cytotoxicity in human rhabdomyosarcoma (RD) and macrophage (RAW) cell lines in a time‐ and concentration – dependent manner, and stimulated autophagy, comparable to the free drug. The uptake study following the fluorescence of the copolymer reveals that the hybrid nanoparticles are internalized by both tested cell lines, with a significantly higher amounts of internalized particles in the case of surface mannosylated and/or pegylated systems.

Polymeric Mixed Micelle-Loaded Hydrogel for the Ocular Delivery of Fexofenadine for Treating Allergic Conjunctivitis.

This study was designed to formulate a polymeric mixed micelle (PMM) formulation to sustainably release fexofenadine (FEX) to treat allergic conjunctivitis effectively. A 32 factorial design was employed where the studied factors were PL90G amount (X1) and Pluronic (F127 and P123) mixture ratio (X2), and the dependent variables were entrapment efficacy (EE, Y1, %), particle size (PS, Y2, nm), zeta potential (ZP, Y3, mV), and the percent of drug released after 6 h (Q6h, Y4, %). The optimized formula was blended with a hydrogel base to develop an FEX-PMM hydrogel, where the safety and efficiency of this hydrogel were evaluated using in vivo studies. The EE% of FEX-PMM ranged from 62.15 ± 2.75 to 90.25 ± 1.48%, the PS from 291.35 ± 6.43 to 467.95 ± 3.60 nm, the ZP from -5.41 ± 0.12 to -9.23 ± 0.23 mV, and the Q6h from 50.27 ± 1.11 to 95.38 ± 0.92%. The Draize test results confirmed the safety of the FEX-PMM hydrogel. Furthermore, the FEX-PMM hydrogel showed rapid recovery in animals with induced allergic conjunctivitis compared to the free drug hydrogel. These results assure PMM's capability to deliver FEX to the conjunctival surface in a sustained pattern, consequently achieving better therapeutic outcomes.

How vulnerable are people to victimisation of County Lines drug dealing?

The current study examined how willing a non-probability sample of adults were to engage in hypothetical activities typical of County Lines, and whether involvement could be predicted by perceived risk factors. Of the 101 participants; 48% were willing to engage in activities that could lead to cuckooing, 63% to a coffee meet up, 50% to transferring money, 32% would accept free drugs, 56% would pay off a friend’s debt, whereas only 1% were willing to engage in the control scenario (a phone scam). Actual occurrences of these scenarios were also documented and occurred in approximately 1% of the sample. Males and people with greater drug use scores were more likely to endorse engagement in a County Lines scenario involving drugs, whilst greater drug use scores were only associated with a lower risk of a County Lines scenario involving lending money to a friend. Our findings suggest that drug use may predict endorsement to engage in some County Lines scenarios. However, given a small non-probability sample was used in the current study, further development of methodologies to capture the likelihood to engage in County Lines activities are needed.

Drug Loading in Chitosan-Based Nanoparticles.

Chitosan nanoparticles (CSNPs) are promising vehicles for targeted and controlled drug release. Recognized for their biodegradability, biocompatibility, low toxicity, and ease of production, CSNPs represent an effective approach to drug delivery. Encapsulating drugs within nanoparticles (NPs) provides numerous benefits compared to free drugs, such as increased bioavailability, minimized toxic side effects, improved delivery, and the incorporation of additional features like controlled release, imaging agents, targeted delivery, and combination therapies with multiple drugs. Keys parameters in nanomedicines are drug loading content and drug loading efficiency. Most current NP systems struggle with low drug loading, presenting a significant challenge to the field. This review summarizes recent research on developing CSNPs with high drug loading capacity, focusing on various synthesis strategies. It examines CSNP systems using different materials and drugs, providing details on their synthesis methods, drug loadings, encapsulation efficiencies, release profiles, stability, and applications in drug delivery. Additionally, the review discusses factors affecting drug loading, providing valuable guidelines for future CSNPs' development.

COMPARATIVE EVALUATION OF ARTIFICIAL INTELLIGENCE AND DRUG INTERACTION TOOLS: A PERSPECTIVE WITH THE EXAMPLE OF CLOPIDOGREL

Objective: The study aims to compare the ability of free artificial intelligence (AI) chatbots to detect drug interactions with freely available drug interaction tools, using clopidogrel as an example. Material and Method: The Lexicomp database was used as a reference to determine drug interactions with clopidogrel. ChatGPT-3.5 AI and Bing AI were selected as the free AI chatbots. Medscape Drug Interaction Checker, DrugBank Drug Interaction Checker and Epocrates Interaction Check were selected as free drug interaction tools. Accuracy score and comprehensiveness score were calculated for each drug interaction tool and AI chatbots. The kappa coefficient was calculated to assess inter-source agreement for interaction severity. Result and Discussion: The results most similar to those of Lexicomp were obtained from the DrugBank and the ChatGPT-3.5 AI chatbot. The ChatGPT-3.5 AI chatbot performed best, with 69 correct results and an accuracy score of 307. ChatGPT-3.5 AI has the highest overall score of 387 points for accuracy and comprehensiveness. In addition, the highest kappa coefficient with Lexicomp was found for ChatGPT-3.5 AI chatbot (0.201, fair agreement). However, some of the results obtained by ChatGPT-3.5 AI need to be improved as they are incorrect/inadequate. Therefore, information obtained using AI tools should not be used as a reference for clinical applications by healthcare professionals and patients should not change their treatment without consulting doctor.

Efficacy and mechanism of energy metabolism dual-regulated nanoparticles (atovaquone-albendazole nanoparticles) against cystic echinococcosis

BackgroundAlbendazole (ABZ) and atovaquone (ATO) achieve killing efficacy on Echinococcus granulosus (Egs) by inhibiting energy metabolism, but their utilization rate is low. This study aims to analyze the killing efficacy of ABZ-ATO loading nanoparticles (ABZ-ATO NPs) on Egs.MethodsPhysicochemical properties of NPs were evaluated by ultraviolet spectroscopy and nanoparticle size potentiometer. In vitro experiments exmianed the efficacy of ATO, ABZ, or ATO-ABZ NPs on protoscolex activity, drug toxicity on liver cell LO2, ROS production, and energy metabolism indexes (lactic dehydrogenase, lactic acid, pyruvic acid, and ATP). In vivo of Egs-infected mouse model exmianed the efficacy of ATO, ABZ, or ATO-ABZ NPs on vesicle growth and organ toxicity.ResultsDrug NPs are characterized by uniform particle size, stability, high drug loading, and − 21.6mV of zeta potential. ABZ or ATO NPs are more potent than free drugs in inhibiting protoscolex activity. The protoscolex-killing effect of ATO-ABZ NPs was stronger than that of free drugs. In vivo Egs-infected mice experiment showed that ATO-ABZ NPs reduced vesicle size and could protect various organs. The results of energy metabolism showed that ATO-ABZ NPs significantly increased the ROS level and pyruvic acid content, and decreased lactate dehydrogenase, lactic acid content, and ATP production in the larvae. In addition, ATO-ABZ NPs promoted a decrease in DHODH protein expression in protoscolexes.ConclusionATO-ABZ NPs exhibits anti-CE in vitro and in vivo, possibly by inhibiting energy production and promoting pyruvic acid aggregation.

Nano-mupirocin as tumor-targeted antibiotic: Physicochemical, immunotoxicological and pharmacokinetic characterization, and effect on gut microbiome

Nano-mupirocin is a PEGylated nano-liposomal formulation of the antibiotic mupirocin, undergoing evaluation for treating infectious diseases and intratumor bacteria. Intratumoral microbiota play an important role in the regulation of tumor progression and therapeutic efficacy. However, antibiotic use to target intratumoral bacteria should be performed in a way that will not affect the gut microbiota, found to enable the efficacy of cancer treatments. Nano-mupirocin may offer such a selective treatment. Herein, we demonstrate the ability of Nano-mupirocin to successfully target tumor-residing Fusobacterium nucleatum without an immediate effect on the gut microbiome. In-depth characterization of this novel formulation was performed, and the main findings include: (i). the pharmacokinetic analysis of mupirocin administered as Nano-mupirocin vs mupirocin lithium (free drug) demonstrated that most of the Nano-mupirocin in plasma is liposome associated; (ii). microbiome analysis of rat feces showed no significant short-term difference between Nano-mupirocin, mupirocin lithium and controls; (iii). Nano-mupirocin was active against intratumoral F. nucleatum, a tumor promoting bacteria that accumulates in tumors of the AT3 mice model of breast cancer. These data suggest the ability of Nano-mupirocin to target tumor residing and promoting bacteria.

Industry's Perspective on Challenges Assessing the in Vivo Impact of Removing Titanium Dioxide (TiO2) from Drug Products

The European Commission (EC) has tasked the European Medicines Agency (EMA) to provide a recommendation towards the acceptability of titanium dioxide (TiO2) in pharmaceutical products by early 2024 to inform on final decision in early 2025[1]. Unlike the already implemented ban of TiO2 in foods, removing this excipient from pharmaceutical products will likely have significant impact on the pharmaceutical industry, regulatory agencies, and patients. This commentary explores the challenges facing the pharmaceutical industry tasked with supporting the development and registration of TiO2 free (TF) drug products. Specifically, justification of formulation changes and potential impact to in vitro and in vivo performance, as well as differences in global regulatory comparative dissolution requirements to justify changing to TF drug product are discussed. Particularly, the uncertainties around how a formulation change such as removal of TiO2 from immediate release solid oral dosage forms will be viewed in Europe compared to other regions is discussed. To respond to these challenges and avoid disruption to the medicines supply chain in case in vitro data such as dissolution is either too challenging or insufficient to justify changing to TF product, pharmaceutical companies may have to decide if the level of risk is worth the effort needed to reformulate, develop, and register a new TF product.

Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.

Fabrication of co-delivery liposomal formulation incorporating carmustine and cabazitaxel displays improved cytotoxic potential and induced apoptosis in ovarian cancer cells

Ovarian cancer is the primary cause of death from cancer in female patients. The existing treatments for ovarian cancer are restricted and ineffective in achieving a cure for the disease. To address this issue, we provide a novel approach to treating ovarian cancer by utilizing a liposomal carrier that effectively delivers the chemotherapeutic drugs carmustine (BCNU) and cabazitaxel (CTX). Initially, the combined impact of BCNU and CTX was confirmed, revealing that this impact reaches its maximum at a ratio of 1:2 mol/mol (BCNU/CTX). After that, the BC-Lipo co-delivery system was developed, which has a high capability for loading drugs (97.48% ± 1.14 for BCNU, 86.29% ± 3.03 for CTX). This system also has a sustained release profile and a beneficial long-circulating feature. The accumulation of BC-Lipo in tumors was dramatically enhanced compared to the accumulation of the free drug. Furthermore, BC-Lipo demonstrated similar levels of cytotoxicity to free BCNU and CTX (BCNU/CTX) when tested on HeLa cells in an in vitro model. Biochemical staining methods investigated the cancer cell’s morphological examination. The apoptosis was confirmed by FITC-Annexin-V/PI staining by flow cytometry analysis. In addition, the investigation of fluorescence and protein markers examined the apoptosis mechanistic pathway, and the results indicated that BC-Lipo induced apoptosis due to mitochondrial membrane potential variation. This proof-of-concept study has established the probability of these BCNU-CTX combined treatments as active drug delivery nanocarriers for poorly soluble BCNU and CTX.