BACKGROUND:The use of automated injectors for the administration of radiopharmaceuticals limits staff exposure and optimises the dose administered to patients, but many of these devices are only validated for a limited number of radiopharmaceuticals. The objectives of this study were to investigate the physicochemical phenomena occurring during the manipulation of fluorinated radiopharmaceuticals when in contact with injector tubings and to quantify and qualify the interactions between the radiopharmaceuticals and the tubing materials. RESULTS:For six of the radiopharmaceuticals tested, the measured doses reached 97.64 ± 0.24% of the programmed dose. These results indicate an absence of sorption phenomena and validate their use on the injector. In contrast, the three most lipophilic molecules caused the injector to malfunction, resulting in significant residual activity in the tubing of up to 67%. These results were confirmed by activimeter measurements and positron emission tomography images. RESULTS:from electronic microscopy results showed an alteration of the inner surface of the tubings that came into contact with lipophilic radiopharmaceuticals; however, this modification did not drastically alter the surface Zeta potential. Infrared spectroscopy confirmed the composition of the tubings as being plasticized polyvinyl chloride (PVCp), and plasticizer identification and quantification showed the presence of di-(2-ethylhexyl) adipate (reaching 37.5%) and di-(2-ethylhexyl) phthalate (more than 20%). A clear improvement was observed when co-extruded polyethylene / PVPp tubings were used. CONCLUSIONS:Unlike lipophilic radiopharmaceuticals, which exhibit sorption behaviour dependent on the presence of plasticizers, the tested hydrophilic radiopharmaceuticals demonstrated minimal interaction with PVCp tubing and can be reliably administered using the automated injector.
Oxidative stress induced by inhaled oxidants, particularly cigarette smoke, contributes to the development of several acute and chronic respiratory diseases through oxidative damage and epigenetic alterations. Curcumin (CUR), a well-characterized natural polyphenol with potent antioxidant and anti-inflammatory properties, is considered a promising agent for modulating oxidative stress-related signaling pathways and epigenetic mechanisms; however, its poor aqueous solubility and bioavailability limit its clinical application. Therefore, in the present study, PEGylated curcumin (PEG-CUR) was investigated as a modified CUR formulation for subsequent incorporation into a dissolving microneedle-based intranasal delivery system. Exposure to cigarette smoke resulted in significant alterations in the expression of oxidative stress-related genes (SEPP1, NCF2, SFTPD, CCL5, and PTGS1) in nasal epithelial cells. However, pretreatment with curcumin (CUR) and polyethylene glycol-curcumin (PEG-CUR) mitigated these gene expression changes. Both treatments also reduced global DNA methylation, with PEG-CUR showing a more pronounced effect than CUR. Following the demonstration of the beneficial effects of PEG-CUR, we developed PEG-CUR-loaded dissolving microneedle patches (PEG-CUR-DMNPs) as a localized intranasal delivery platform designed to facilitate PEG-CUR delivery through rapid dissolution of the microneedle tips. The mechanical robustness and penetration capability of the patches were initially evaluated using Parafilm® and ex vivo rat dorsal skin models. To further confirm their appropriateness for intranasal use, PEG-CUR-DMNPs were subsequently tested on ex vivo sheep nasal mucosa to evaluate microneedle penetration and dissolution kinetics. Overall, these results indicate that PEG-CUR-DMNPs represent a promising approach for localized intranasal drug delivery targeting oxidative stress-related respiratory diseases.
Nanoemulsions are increasingly explored to enhance dermal drug delivery due to their nano-size. Microfluidic processing for nanoemulsion generation has attracted much attention but requires extensive optimisation. This study leverages 3D printed microfluidic chips for size reduction of a premixed emulsion as a scalable approach to fabricate cationic oil‑in‑water nanoemulsions loaded with ibuprofen (2%w/w) for dermal delivery. Phase inversion composition (PIC) and homogenisation were used as benchmark methods. Nanoemulsions comprising ethyl oleate, Tween® 80 and cetyltrimethylammonium bromide were optimised using the PIC (∼33 nm) and subsequently used to prepare premixed emulsions (∼84 nm). Microfluidisation effectively reduced the droplet size of premixed coarse emulsions (∼57-67 nm), achieving size reduction comparable to that obtained using conventional homogenisation (∼62 nm). Varying the microchannel geometry in microfluidic chips and flow rate did not significantly affect the nanoemulsion properties. Nanoemulsions prepared by homogenisation remained <200 nm for 3 months at 40°C and 12 months at 25°C, but they were less stable than those prepared via PIC and microfluidisation. Nanoemulsions produced via PIC exhibited higher skin permeation of ibuprofen (∼14 µg) as compared with microfluidisation (∼10 µg) and homogenisation (∼7 µg). Microchannel processing improved nanoemulsion stability and skin delivery over homogenisation, offering scalable, energy-efficient continuous manufacturing, although PIC remained superior overall.
Chronic wounds infected by Candida albicans impose a significant clinical burden, yet topical amphotericin B (AMB) delivery is constrained by low aqueous solubility. Wet-spun poly(vinyl alcohol) (PVA)/chitosan fibres loaded with an AMB/hydroxypropyl-γ-cyclodextrin (HP-γ-CD) inclusion complex were developed as a sustained-release antifungal wound dressing. Phase solubility analysis confirmed inclusion complex formation with an apparent stability constant of 36.1 × 103 M⁻1 in distilled water (AL-type profile, R2 = 0.9984), characterised by Fourier-transform infrared spectroscopy (FTIR), 1H NMR, and scanning electron microscopy (SEM). IC-SE-1 achieved ∼ 354-fold and ∼ 136-fold solubility enhancement in distilled water and phosphate-buffered saline (PBS, pH 7.4), respectively, while fully retaining antifungal activity (MIC = 1 µg/mL; p = 0.112 vs. pure AMB). The complex was incorporated into fibres at four PVA:chitosan ratios and crosslinked with tripolyphosphate and glutaraldehyde. Formulation P6C4 (PVA 60%:chitosan 40%) demonstrated the most favourable overall performance, with the highest water-holding capacity (346.51 ± 4.10%), swelling (463.40 ± 11.12%), tensile strength (18.47 ± 2.18 MPa), and elongation (431.57 ± 52.22%). Woven fibres maintained inhibition zones against C. albicans from day 2 to day 7, with AMB release exceeding the MIC throughout, while haemolysis remained below 5% (ASTM F756-08). HP-γ-CD complexation enables sustained above-MIC AMB delivery from a dual-crosslinked biopolymeric dressing, providing in vitro proof-of-concept for Candida-infected chronic wounds, pending cytotoxicity and in vivo validation.
Drug release and permeation play crucial roles in the therapeutic efficacy of cataplasms. However, due to the lack of research on the mechanisms underlying drug release and permeation, achieving optimal release and permeation characteristics through trial-and-error methods is inefficient. Therefore, we aimed to investigate the mechanisms of drug release and permeation in emulsion-type cataplasms from a structural perspective.Cataplasms with varied crosslinking densities, drug loadings, and drug types were prepared; drug release and permeation studies were performed using Franz diffusion cells, while the microstructural evolution of both the cataplasms and the skin was characterized via scanning electron microscopy, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and histology.It was revealed that drug release essentially occurred as the drug escaped from structural constraints through the swelling of the crosslinked network. Drug permeation was demonstrated to be governed by four synergistic mechanisms: (1) the physical contact established by the intimate adhesion between cataplasms and the skin; (2) the influence of drug release amount on drug permeation behavior; (3) stratum corneum hydration induced by water-mediated keratin swelling; (4) disruption of the stratum corneum lipid structure resulting from L-menthol. In addition, this study revealed that the acidity and basicity of the drug itself constituted a key determinant of drug permeation. Overall, the present work is expected to provide a scientific basis for the rational design of cataplasms, improve research and development efficiency, and further promote advances in this field.
While pharmacodynamic and pharmacokinetic drug-drug interactions are well established, physicochemical interactions between co-administered oral drug products and their impact on drug absorption remain poorly understood. This study combined biorelevant in vitro testing and physiologically based pharmacokinetic (PBPK) modeling to investigate such interactions between three commercially available drug products SPORANOX (itraconazole), ACTOS (pioglitazone) and GEVILON (gemfibrozil). The in vitro experiments revealed contradictory effects. The apparent solubility of itraconazole was improved in the presence of gemfibrozil, and certain cellulose-based polymers present in ACTOS and GEVILON inhibited precipitation of itraconazole after release from the amorphous solid dispersion. However, in release experiments, Tween 80 present in the GEVILON formulation led to lower itraconazole concentrations due to destabilization of supersaturation. PBPK modeling suggested that this effect could be one of the main reasons for the decreased bioavailability of itraconazole in the presence of the other drug products, as observed in prior clinical studies. This work highlights the potential relevance of physicochemical interactions between different drug products for the efficacy and safety of oral pharmacotherapy. The staged approach presented herein enables early detection of such interactions so that formulation strategies can be applied to mitigate them.
Metastatic breast cancer remains a major therapeutic challenge due to the limited efficacy of current treatments against both primary tumors and distant metastases. Here, we developed an arginine-based click-crosslinked nanoplatform for the co-delivery of camptothecin (CPT) and STAT3 siRNA (siSTAT3). The nanoplatform was constructed using a dibenzocyclooctyne-functionalized arginine derivative, where guanidinium-phosphate interactions enabled efficient siRNA loading and copper-free click crosslinking improved structural stability. Hyaluronic acid modification further enhanced tumor cell uptake through CD44 recognition. HDCPT@siSTAT3 achieved efficient intracellular delivery, lysosomal escape, and intracellular release of CPT and siSTAT3. In 4T1 breast cancer cells, HDCPT@siSTAT3 reduced STAT3 expression by approximately 50%, promoted apoptosis, and inhibited migration. In 4T1 breast tumor models, HDCPT@siSTAT3 suppressed tumor growth with minimal systemic toxicity. Moreover, the treatment significantly decreased lung metastatic burden in a 4T1-Luc metastasis model. The integration of arginine-based interactions, covalent cross-linking, and active targeting may provide a useful strategy for combined chemo-gene therapy in metastatic breast cancer.
The Stimulator of Interferon Genes (STING) pathway is a promising target for vaccine adjuvants and cancer immunotherapy, but the clinical application of the endogenous STING agonist 2',3'-cGAMP is hindered by poor membrane permeability, enzymatic degradation, and rapid renal clearance. To address these barriers, we developed a liposome formulation of cGAMP (cGAMP-Lipo) for intramuscular administration. The optimized cGAMP-Lipo exhibited high encapsulation efficiency (≥90 %), a uniform size of 70-80 nm, and enhanced STING activation in THP-1 cells with a 37-fold lower EC50 (45.85 nM) compared to free cGAMP. In vivo, cGAMP-Lipo significantly boosted antigen-specific immune responses, increasing anti-RBD IgG titers by up to 18-fold relative to the aluminum adjuvant and promoting Th1-skewed immunity (IgG2c/IgG1 ratio = 29.6) with a high proportion of effector CD8⁺ T cells. In a B16-OVA melanoma model, cGAMP-Lipo achieved substantial tumor growth inhibition and enhanced CD8⁺ T cell infiltration. Pharmacokinetic studies revealed that cGAMP-Lipo formed a sustained depot at the injection site, extending the local half-life from 0.50 h to 7.09 h and increasing local exposure by 43-fold. Moreover, the manufacturing process was successfully scaled up to 1 L with consistent batch-to-batch reproducibility. Collectively, this work establishes cGAMP-Lipo as a potent, durable, and scalable STING agonist adjuvant platform with strong potential for clinical translation in both infectious disease vaccination and cancer immunotherapy.
Effective treatment of aggressive breast tumors remains challenging due to poor drug selectivity, systemic toxicity, and limited therapeutic synergy. Here, a thermo/pH‑responsive magnetic Janus nanogel was employed as a smart platform for on‑demand co‑delivery of 5‑fluorouracil (5‑Fu) and quercetin (Qu) combined with magnetic hyperthermia. Drug release behavior under acidic and hyperthermic conditions was investigated, followed by evaluation of cellular uptake and cytotoxicity in 4T1 breast cancer cells. Therapeutic efficacy was further assessed in BALB/c mice bearing orthotopic 4T1 tumors under alternating magnetic field (AMF)-induced hyperthermia. Tumor growth, histopathological alterations, hepatotoxicity, and the expression of apoptosis‑related genes (Bax, Bcl‑2, p53, caspase‑3, caspase‑8, and caspase‑9) were analyzed. The Janus nanogel exhibited dual-stimuli-responsive release of 5-Fu and Qu and showed enhanced in vitro cytotoxicity in the nanoformulated co-delivery system. In vivo, treatment with drug‑loaded nanogels combined with AMF produced pronounced tumor regression (p < 0.01) and extensive apoptotic cell death. Gene expression analysis indicated activation of both intrinsic and extrinsic apoptotic pathways, reflected by upregulation of Bax, p53, and caspases together with an increased Bax/Bcl‑2 ratio. No significant hepatotoxicity was observed. The integration of dual‑drug chemotherapy with magnetic hyperthermia using a thermo/pH‑responsive Janus nanogel provides a synergistic and safe therapeutic strategy for aggressive breast cancer. These findings highlight the potential of stimuli‑responsive nanocarriers for advanced combination cancer therapy.
We present a unified framework for dissolution profile modeling and formulation optimization to identify formulation settings that reproduce a target dissolution profile. In generic drug development, the reference formulation is often unavailable or proprietary, making the underlying release behavior difficult to verify in advance. The proposed framework integrates parametric dissolution models and functional data analysis using functional principal component analysis (FPCA) within a candidate-based formulation-space exploration workflow. Curve similarity is quantified using the integrated squared difference, with the regulatory similarity factor f2 used as an additional evaluation metric. The framework was evaluated using two extended-release dissolution datasets exhibiting different release behaviors. Results demonstrated that model performance depends on the relationship between the modeling approach and the underlying dissolution characteristics. The parametric approach achieved strong performance when the dissolution behavior was well represented by the assumed model structure, whereas FPCA provided a flexible alternative when the underlying release behavior was not adequately described by a predefined model. The proposed framework enables systematic identification of candidate formulations and provides a flexible strategy for dissolution-guided inverse formulation design under uncertain release behavior.
Inflammatory skin diseases, such as psoriasis, lead to significant humanistic and economic burdens, mainly psychosocial impacts due to the relapsing papulosquamous characteristic of the disease. Due to the extensive skin lesions, topical therapies remain the main form of treatment. However, their effectiveness is limited by poor skin penetration. In addition, single-target mechanisms limit the simultaneous modulation of inflammatory and oxidative pathways involved in the pathogenesis of psoriasis and other skin diseases. To overcome these limitations, we developed hybrid lipid-polymeric nanoparticles (HLPNs) for the co-delivery of coenzyme Q10 (CoQ10), an endogenous antioxidant with anti-inflammatory properties, and small interfering RNA (siRNA) targeting TNFα, a central pro-inflammatory cytokine. HLPNs exhibited particles of 150-250 nm with low polydispersity (0.08-0.16), and high CoQ10 encapsulation efficiency (>85%). The presence of poly(allylamine hydrochloride) reversed the zeta potential (-27 to + 20 mV), enabling high siRNA binding efficiency and RNase protection. Structural analysis (ATR-FTIR, DSC, PXRD) confirmed successful CoQ10 incorporation into the lipid matrix and its amorphous conversion. HLPNs enhanced CoQ10 penetration into the stratum corneum (2-4.5-fold) and viable epidermis/dermis (4.7-7.5-fold) compared to solution, while confocal microscopy demonstrated improved siRNA skin delivery. In cell culture, HLPN-siRNA complexes promoted robust siRNA uptake in keratinocytes and macrophages. Therapeutic efficacy was validated in LPS-stimulated RAW264.7 macrophages, where HLPN_CoQ10-siTNFα significantly suppressed TNFα (3-6.5-fold), IL-6 (2-2.7-fold), and IL-1β (1.3-3-fold) secretion, while preserving CoQ10's antioxidant capacity and reducing reactive oxygen species (1.3-1.5-fold). Collectively, these findings show that the dual lipid-polymeric nature of HLPNs enables combinatorial delivery of antioxidant and RNAi therapies, offering a promising strategy for complex inflammatory skin disorders.
Despite the fact that acetylsalicylic acid (ASA) remains clinically important for inflammatory conditions, conventional oral administration is hampered by gastrointestinal adverse effects and variable systemic exposure. Whilst polymeric microneedles (MNs) enable transdermal delivery as an alternative to oral delivery through bypassing the stratum corneum; how drug solid-state behaviour affects the release kinetics of sustained-release MN systems has yet to be thoroughly elucidated. Herein, ASA-loaded poly (lactic-co-glycolic acid) (PLGA) MNs were developed to examine how retained but altered ASA crystallinity within the PLGA matrices contributes to release across in vitro, ex vivo and in silico models. 10*10 arrays of pyramidal PLGA MNs with a needle length of 600 µm were produced via micromoulding. Parent ASA stability studies showed near-quantitative recovery following fabrication-like exposure (98.0 ± 3.11%). Because the MNs were not only able to penetrate Parafilm M® and dermatomed porcine skin under a 32 N application force, but also withstand whole-patch compression at the exact same insertion force, the fabricated MN patches were deemed mechanically robust enough for application-relevant insertion into the skin under tested conditions. Whilst PXRD showed that ASA loaded into PLGA MNs retained crystalline features, albeit attenuated, DSC demonstrated that ASA-PLGA MNs exhibited a broadened, lower-temperature ASA-associated endotherm. As such, it was inferred that ASA solid-state behaviour had been altered within the polymer matrix. In contrast to apparent ex vivo release, which reached near completion by 168 h, in vitro ASA release was slower and incomplete, with drug release plateauing at approximately 60% by 504 h. These differences suggest that retained but altered ASA crystallinity may contribute to sustained release by limiting the rate at which ASA dissolves and diffuses from the PLGA matrix under static in vitro conditions. However, when MNs are in constant contact ex vivo, hydration of the PLGA matrix, in consort with tissue-associated diffusion and partitioning may promote continued removal of dissolved ASA from the polymer-skin interface, thereby accelerating apparent release. Taken together, this work identifies ASA solid-state behaviour as one formulation variable that interacts with the release environment to shape release from PLGA MNs. Furthermore, an exploratory in silico model simulating a potential ASA pharmacokinetic profile based on empirically obtained release profiles sets the foundation for future in vivo investigation.
Reduced brain cholesterol synthesis is an early dysfunction that plays a major role in Huntington's disease (HD) pathogenesis. Because the blood-brain barrier (BBB) prevents cholesterol uptake from the circulation, surface-modified, biodegradable, and biocompatible nanoparticles (NPs) that enhance BBB crossing have emerged as promising tools for delivering cholesterol to the brain in HD mouse models. In these models, such NPs have been shown to rescue cognitive, motor, and neuropathological defects. Here, we describe a new formulation of nanoparticles primarily composed of cholesterol and surface-engineered with a short carbon chain fatty acid (BUT) or its variant glucose (Glu) -conjugated (BUT-Glu) to enhance BBB penetration, referred to as BUT-chol-NPs and BUT-Glu-chol-NPs. We characterized key technological and pharmaceutical properties of these NPs and assessed their ability to cross the BBB and reach different brain regions and cell types following systemic administration in wild-type mice. Both BUT-chol-NPs and BUT-Glu-chol-NPs may represent new delivery systems for supplying cholesterol to the HD brain or to treat other neurological disorders in which cholesterol metabolism is impaired.
Global disease patterns are being rapidly reshaped by environmental changes such as rising temperatures, pollution, and more frequent natural disasters. Notable effects include a rise in skin infections, such as cellulitis, as well as upper respiratory and urinary tract infections. Cellulitis, an acute bacterial infection predominantly caused by S. aureus and Streptococcus species, is clinically challenging due to recurrence, primarily because of antimicrobial resistance and limitations of standard systemic therapies. Oral antibiotics like ofloxacin, though effective, are associated with significant suboptimal drug localization, systemic adverse effects and necessitate reliable and more targeted therapeutic approaches. This study reports the development and optimization of a pH-sensitive nanoparticle-loaded in situ gel for the local management of cellulitis. As the encapsulating polymer, Eudragit® S100 was used to load Ofloxacin via the nanoprecipitation method and optimized through Design of Experiments, achieving high entrapment efficiency of ∼96% and a nano size of 85-110 nm. These nanoparticles were incorporated into a Carbopol-HPMC-based in situ gel containing lidocaine to provide immediate pain-relieving action. The system exhibited pH-triggered sol-gel transition, enhanced viscosity under simulated wound conditions, and sustained drug release following controlled kinetics. In vitro and ex vivo studies demonstrated prolonged drug release post permeation, effective antimicrobial activity driven by MIC and MBC tests, and improved retention. In vivo evaluation in S. aureus-infected rat models confirmed reduced lesion severity, absence of skin irritation, inflammation and accelerated healing. Overall, this dual-delivery platform renders a promising scheme for concurrent pain management and sustained antimicrobial therapy, potentially improving patient compliance by altering therapeutic outcomes in cellulitis treatment.
Onychomycosis is a prevalent and therapeutically challenging fungal infection, largely due to the highly keratinised nail plate that severely restricts drug penetration. Voriconazole (VCZ) is a broad-spectrum antifungal agent; however, its poor aqueous solubility and limited permeability hinder its use in topical and localised delivery. Rather than relying on transungual drug transport, minimally invasive hollow microneedles (MNs) offer an alternative strategy by enabling direct administration of liquid formulations into the periungual and subungual soft tissues surrounding the nail unit. In this study, a choline-geranic acid (CAGE) ionic liquid (IL)-based submicron ionic liquid-in-water (IL/W) emulsion (1:9 v/v CAGE:2% w/v poloxamer 188 aqueous phase) was developed as an antifungal delivery platform with particular relevance to nail fungal infections. CAGE ILs with different choline-to-geranic acid molar ratios were synthesised and structurally confirmed. VCZ solubility increased markedly with increasing geranic acid content, reaching 13.27 ± 0.09 mg/g in CAGE 1:4 compared with negligible solubility in aqueous media. A CAGE-based emulsion exhibited a mean droplet size of 582.50 ± 9.97 nm, a low polydispersity index (0.263 ± 0.015), and a zeta potential of -8.80 ± 2.98 mV, and demonstrated good droplet size stability at 25 °C and 37 °C. Syringeability testing showed low break-loose forces (< 1.5 N) for all formulations, while the CAGE 1:4 emulsion required a significantly lower glide force (1.15 ± 0.07 N) compared with neat CAGE 1:4 (14.57 ± 0.24 N), supporting its suitability for hollow MNs assisted delivery. Ex vivo studies using neonatal porcine skin as a proof-of-concept soft tissue model demonstrated efficient formulation delivery following hollow MN-assisted administration. VCZ delivery was markedly enhanced by the combined use of the selected CAGE composition and hollow MNs. VCZ-loaded CAGE 1:4 delivered via hollow MNs achieved 80.66 ± 12.58 µg permeation at 24 h (87.23 ± 13.60% of the administered dose), while the CAGE-based emulsion maintained high permeation efficiency (74.47 ± 14.40% of dose) at a reduced VCZ loading. Cytocompatibility assessment using human skin-derived primary fibroblasts showed cell viability above 80% at concentrations ≤ 100 µg/mL. In vitro disk diffusion assessment against Candida albicans showed that CAGE-containing formulations produced clear zones of inhibition, whereas VCZ-alone discs did not produce an observable inhibition zone under these diffusion-limited assay conditions. This study demonstrates that the integration of CAGE IL, emulsion formulation, and hollow MNs-assisted delivery provides an effective strategy to enhance antifungal drug solubility, injectability, and delivery performance, offering a promising proof-of-concept periungual/subungual delivery platform for antifungal therapy of nail fungal infections.
Sustainability and environmental aspects of medicines are generally omitted in pharmacy curricula, despite the recognized burden of the pharmaceutical footprint. Pharmaceutical footprint refers to the societal, economic and environmental impact of pharmaceutical pollution produced during manufacture, distribution, prescription, consumption and waste management of medicines. In order to mitigate the impact of the pharmaceutical sector, a new educational approach based on Sustainable Pharmacy is required. Sustainable Pharmacy integrates education, society, economy, pharmacology, culture and environment into Pharmaceutical Sciences. Current and future drug professionals should receive comprehensive training that includes sustainable aspects across all main disciplines that constitute pharmaceutical science. In the current article, the following six pharmacy disciplines are revisited from a Sustainable Pharmacy perspective: pharmaceutical chemistry, pharmaceutics, pharmacology, pharmaceutical care, public health and pharmacoepidemiology, and drug legislation. Each section provides essential information about the pharmaceutical footprint of medicines, to facilitate understanding of the problem and enable sustainable pharmacy practices. Aside from the essential aspects of the environmental impact, the article compiles additional sources that can serve both as inspiration and as tools for developing training exercises. Furthermore, it introduces new concepts, such as LADME+, lysophore and sustainable and rational use of medicines that can further aid the education of pharmacists. The provided information may be used to inform the integration of environmental considerations into various subjects, or to update current pharmacy curricula to include these aspects.
Breast cancer treatment is often limited by toxicity of systemic chemotherapy and by the development of drug resistance, which reduces the effectiveness of anticancer drugs. Delivering therapeutics directly into the mammary ducts has emerged as a promising strategy to increase drug concentrations at the tumor site while limiting unwanted systemic effects. In this study, we assessed two nanoparticle-based systems to locally co-deliver the anticancer drug paclitaxel with elacridar, an inhibitor of drug-efflux transporters that contribute to chemotherapy resistance. One formulation consisted of nanostructured lipid carriers (NLCs), whereas the other was a NLC-polymeric hybrid nanoparticle (H-NP), in which the polymeric poly(N-isopropylacrylamide) shell was functionalized with SILY, a collagen I-binding peptide, to enhance mammary tissue retention. All formulations exhibited diameter below 400 nm, and negative zeta potential (-16.0 to -8.8 mV). Elacridar was incorporated into the lipid matrix of the NLC (>80% encapsulation efficiency) and in the polymeric shell of the H-NPs (∼70%), which justifies its faster release from H-NPs after 120 h (∼92% compared to 75% from NLC). Compared to nanoparticles containing only paclitaxel, co-encapsulation improved cytotoxicity and reduced IC50 (up to 4.2-fold) in monolayers of paclitaxel-resistant MDA-MB-231 breast cancer and Kasumi-1 (characterized by overexpression P-glycoprotein) cells, as well as in MCF-7 3D spheroids. In an in vivo model of breast cancer, intraductal H-NPs reduced tumor incidence and volume compared to a drug solution, and increased the mammary tissue-to-plasma ratio of paclitaxel by 105-fold, supporting an improved tissue retention. These findings support H-NPs as promising platforms for localized breast cancer therapy.
Probiotic therapy offers a new approach to the treatment of ulcerative colitis (UC), but oral drug delivery still faces challenges such as low gastrointestinal survival rates, insufficient intestinal retention, and poor inflammatory targeting. In this study, a layer-by-layer encapsulation probiotic delivery system (HGM-L.re PM) was developed. Lactobacillus reuteri (L.re) was loaded onto poly-L-lactic acid porous microspheres, followed by in situ assembly of a tea polyphenol/Fe3+ metal-polyphenol network (MPN) coating, and then layer-by-layer electrostatic deposition of an ethylene glycol chitosan/ hyaluronate (GCS/HA) polysaccharide gel layers via electrostatic interactions. The porous microspheres provide efficient probiotic loading and physical protection; the MPN coating confers transferrin-responsive degradability, enabling on-demand release at sites of inflammation; the GCS/HA outer layer synergistically forms a dense gel network via acid-triggered electrostatic cross-linking to resist gastric erosion, while the terminal HA moiety specifically binds to CD44 to enhance colonic adhesion. Compared to unencapsulated probiotics, HGM-L.re PM demonstrated significantly enhanced viability protection throughout all simulated stages of gastrointestinal digestion and achieved retention for up to 72 h in mice with colitis. In a DSS-induced acute UC model, this formulation effectively alleviated weight loss and colonic shortening, reduced mucosal damage, downregulated IL-6, IL-1β, and TNF-α levels, upregulated IL-10, restored the expression of mucin and tight junction proteins, and reshaped the gut microbiota composition by enriching beneficial bacteria such as Lactobacillus species. The underlying mechanism involves metabolic reorientation and stress resolution. The formulation also demonstrated good in vivo safety. This layer-by-layer encapsulated probiotic delivery platform offers a new strategy for enhancing the efficacy of oral probiotic therapy for UC.
Protein-based therapeutics at high-concentrations often face significant development challenges, including high viscosity, limited solubility, poor injectability, and instability concerns. Non-aqueous protein suspensions offer a promising strategy to achieve high protein concentrations while maintaining acceptable viscosity and injectability. In this study, we evaluated the impact of two polymeric excipients (hydrolyzed gelatin, hydroxypropyl-β-cyclodextrin or HPβCD) and their combinations on the viscosity, injectability, and stability of high-concentration non-aqueous suspensions containing bovine serum albumin (BSA). Suspension viscosity was characterized by rheological measurement, while injectability was assessed using a custom-built setup to measure plunger force through a syringe with a 27G needle. Spray-dried powders and the corresponding suspensions were subjected to accelerated physical stability (monomer loss) studies. Protein stability and structural integrity were evaluated using size-exclusion chromatography (SEC), circular dichroism (CD), and solid-state NMR (ssNMR), while X-ray photoelectron spectroscopy (XPS) was used to assess surface chemical properties of spray-dried particles. Hydrolyzed gelatin provided approximately five-fold greater preservation of monomer content during storage, indicating enhanced protein stability (∼1.5% monomer loss in 90-day stressed storage). In contrast, HPβCD significantly improved injectability, reducing injection force by approximately 5 N compared with formulations containing protein alone (13 N reduced to 8 N). The combination of hydrolyzed gelatin and HPβCD yielded stable and injectable suspensions with protein loadings of 150 - 250 mg/mL. The current work highlighted the potential of polymer-based excipient systems for developing high-concentration injectable suspensions of proteins.
