Pharmaceutics最新文献

Background/Objectives: Cell viability assays play a crucial role in cancer research and the development of effective treatments. Evaluating the efficacy of conventional treatments across different tumor profiles is essential for understanding patient resistance to chemotherapy and relapse. The IC50 index has been commonly used as a guide in these assays. The idea behind the IC50 index is to compare cell proliferation under treatment with respect to a control population exposed to the same treatment. The index requires normalization to a control and is time dependent. These aspects are disadvantages, as small variations yield different results. In this article, we propose a new method to analyze cell viability assays. Methods: This method involves calculating the effective growth rate for both control (untreated) cells and cells exposed to a range of drug doses for short times, during which exponential proliferation can be assumed. The concentration dependence of the effective growth rate gives a real estimate of the treatment on cell proliferation. A curve fit of the effective growth rate related to concentration yields the concentration corresponding to a given effective growth rate. Results: We use this estimation to calculate the IC50 index and introduce two new parameters (ICr0 and ICrmed) to compare treatment efficacy under different culture conditions or cell lines. Conclusions: In summary, this study presents a new method to analyze cell viability assays and introduces two more precise parameters, improving the comparison and evaluation of efficacy under different conditions.

Recent advancements in nanotechnology have revolutionized cancer therapy-one of the most pressing global health challenges and a leading cause of death-through the development of liposomes (L), lipid-based nanovesicles known for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic drugs. More recent innovations have led to the creation of stimuli-responsive L that release their payloads in response to specific endogenous or exogenous triggers. Dual- and multi-responsive L, which react to multiple stimuli, offer even greater precision, improving therapeutic outcomes while reducing systemic toxicity. Additionally, these smart L can adjust their physicochemical properties and morphology to enable site-specific targeting and controlled drug release, enhancing treatment efficacy while minimizing adverse effects. This review explores the latest advancements in endogenous stimuli-responsive liposomal nanocarriers, as well as dual- and multi-responsive L that integrate internal and external triggers, with a focus on their design strategies, mechanisms, and applications in cancer therapy.

Background/Objectives: Biomaterials are an essential part of healthcare for both diagnostic and therapeutic procedures. Although some biomaterials possess antimicrobial properties, introducing biomaterial into the body may lead to infections due to bacterial adhesion on their surfaces and still poses a major clinical problem. Peptides derived from the human cartilage-specific C-type lectin domain family 3 member A (CLEC3A) show a potent antimicrobial effect. In addition, coating titanium, a commonly used prosthetic material, with the CLEC3A-derived AMPs HT-47 and WRK-30 greatly reduces the number of adherent bacteria in vitro. The aim of this study was to evaluate the effectiveness of CLEC3A-derived peptides HT-47 and WRK-30 in reducing bacterial adhesion and mitigating infection in vivo in a murine biomaterial-associated infection model. Methods: To do so, an in vivo mouse infection model was used, where titanium plates-either uncoated or coated with chimeric CLEC3A-derived peptides TiBP-HT-47 and TiBP-WRK-30-were implanted subcutaneously into mice. This was followed by the introduction of Staphylococcus aureus bacterial cultures to induce a biomaterial-associated infection. After 24 h, the titanium plates, surrounding tissue, and mice blood samples were investigated. Results: CLEC3A-coated titanium plates lead to a significantly lower bacterial count than uncoated ones. Additionally, they prevent the infection from spreading to the surrounding tissue. Moreover, mice with CLEC3A-coated implants display lower IL-6 serum levels and therefore decreased systemic inflammation. Conclusions: In conclusion, in this biomaterial-associated infection mouse-model, CLEC3A-derived peptides show in vivo antimicrobial activity by reducing bacterial burden on biomaterial and wound tissue and decreasing systemic inflammation, making them promising candidates for clinical applications.

Background/Objectives: A novel ophthalmic formulation, XanterDES, containing 0.2% xanthan gum and 0.025% desonide sodium phosphate (DES), was developed to alleviate ocular surface discomfort and irritation. This study aimed to evaluate its pharmacodynamic properties and to characterize its rheological behavior and mucoadhesive characteristics, compared to another formulation containing 0.2% hyaluronic acid and 0.001% hydrocortisone (HYD). Methods: A rabbit (New Zealand White) model of LPS-induced uveitis was used to test different concentrations of DES on ocular markers of inflammation. The efficacy of XanterDES and HYD on induced dry eye was evaluated by assessing tear volume and corneal damage in C57BL/6 mice exposed to a controlled environmental chamber. The rheological and mucoadhesive properties of XanterDES and HYD were assessed using a HAAKE RheoStress RS600 rheometer and a TA-XT2 texture analyzer, respectively. Results: In the uveitis model, unlike DES 0.25%, a low concentration of 0.025% DES showed a significant inhibitory activity localized to the eye surface and effectively reduced corneal edema. In the dry eye model, XanterDES demonstrated superior efficacy compared to HYD, effectively preventing both tear volume reduction and corneal damage. XanterDES also demonstrated pseudoplastic and enhanced mucoadhesive properties compared to HYD. Conclusions: The ancillary anti-inflammatory effects of a low dose of DES combined with the biophysical properties of xanthan gum are supportive of a favorable therapeutic profile, promoting the maintenance or restoration of ocular surface homeostasis while minimizing the risk of adverse effects typically associated with standard-dose corticosteroids. The comparison with another low-dose corticosteroid highlights the superiority of XanterDES in pharmacodynamic and biophysical performance.

Photodynamic therapy has established itself as a clinical treatment for certain superficial cancers by converting oxygen into cytotoxic singlet oxygen to eradicate cancer cells. Porphyrin-based nanoscale metal-organic frameworks have emerged as promising photosensitive platforms due to their ability to prevent the hydrophobic aggregation quenching of porphyrin molecules and enhance accumulation at the tumor site, thereby becoming a focal point in photodynamic materials research. However, the elevated levels of glutathione and other reductive substances within cancer cells can alleviate the oxidative stress induced by singlet oxygen from the photodynamic therapy process, thus protecting intracellular biomolecular structures from damage. Consequently, it is crucial to design functionalized nanoplatforms that integrate glutathione depletion with porphyrin-based metal-organic frameworks to significantly boost photodynamic therapy efficacy. Moreover, the excess glutathione within cells can disrupt the structure of porphyrin-based metal-organic frameworks, which not only increases the capacity of porphyrin molecules to generate singlet oxygen upon light exposure but also aids in the recovery of their fluorescence imaging capabilities. Additionally, this specificity minimizes the photosensitizing harm of porphyrin-based metal-organic frameworks to other normal tissues. This review compiles recent advancements in developing porphyrin-based metal-organic frameworks for enhanced phototherapy through glutathione depletion. It aims to promote the further application of porphyrin-based metal-organic frameworks in phototherapy and provide valuable insights for preclinical applications. By highlighting strategies that improve therapeutic outcomes while maintaining safety profiles, this summary seeks to advance the development of more effective and targeted cancer treatments.

Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term injections are accompanied by inconvenience and low compliance. Oral administration is preferred, but the delivery of biomacromolecules is challenging due to gastrointestinal barriers. In this article, we introduce the available biomacromolecule drugs for the treatment of metabolic diseases. The gastrointestinal barriers to oral drug delivery and strategies to overcome these barriers are also explored. We then discuss strategies for alleviating metabolic defects, including glucose metabolism, lipid metabolism, and energy metabolism, with oral biomacromolecules such as insulin, glucagon-like peptide-1 receptor agonists, proprotein convertase subtilisin/kexin type 9 inhibitors, fibroblast growth factor 21 analogues, and peptide YY analogues.

Cannabinoids are widely recognized for their potential therapeutic effects, making them significant and valuable candidates for medical research and applications across various fields. This review aims to analyze the pharmacokinetics of Cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC), along with their corresponding acidic forms, Cannabidiolic acid (CBDA), Cannabigerolic acid (CBGA), and Cannabichromenic acid (CBCA). Among these cannabinoids, CBD is the most extensively studied. Nevertheless, research involving all the mentioned cannabinoids has shown that their pharmacokinetic parameters are highly variable, depending significantly on factors such as dose, formulation, route of administration, and diet. Furthermore, challenges such as brain penetration and first-pass metabolism have been highlighted. In conclusion, this review demonstrates significant progress in understanding the pharmacokinetics of non-psychotropic cannabinoids. However, it also underscores the need for further research, particularly on CBG, CBC, and their respective acidic forms, with the most significant gap being in clinical investigations. Expanding these studies is essential to facilitate their optimized use in medical treatments.

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus^®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus^® NMs increased the drug's apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 °C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2-7.5 and its storage micellar physicochemical stability at 4 °C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI > 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy.

Background/Objectives: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its application in therapeutic formulations. This study aims to enhance the bioavailability and efficacy of C24 ceramide by developing ceramide-based lipid nanoparticles (C24-LNP) and evaluate their impact on skin regeneration and wound healing. Methods: C24-LNP was synthesized and characterized for aqueous stability and bioavailability. In vitro experiments were conducted to assess its effects on keratinocyte proliferation and migration. Molecular biological analysis examined key signaling pathways, including AKT and ERK1/2 phosphorylation. Additionally, an in vivo mouse wound model was utilized to evaluate wound healing efficacy, with histological analysis performed to assess epidermal and dermal regeneration. Results: C24-LNP exhibited improved aqueous stability and bioavailability compared to free C24 ceramide. In vitro studies demonstrated that C24-LNP significantly promoted keratinocyte proliferation and migration. Molecular analysis revealed activation of the AKT and ERK1/2 signaling pathways, which are critical for cell growth and skin regeneration. In vivo wound healing experiments showed that C24-LNP accelerated wound closure compared to the control group. Histological analysis confirmed enhanced epidermal and dermal regeneration, leading to improved structural and functional skin repair. Conclusion: The lipid nanoparticle formulation of C24 ceramide effectively increases its bioavailability and enhances its therapeutic efficacy in skin regeneration and wound healing. C24-LNP presents a scalable and cost-effective alternative to traditional growth factor-based therapies, offering significant potential for clinical applications in wound care and dermatological treatments.

Background: Methotrexate (MTX), a folic acid antagonist used in chemotherapy, faces limitations due to cancer cell resistance, high toxicity, and low bioavailability. Objective: This study developed nanoparticles (NPs) of chitosan (QS) and hydroxypropylmethylcellulose phthalate (HPMCP) to encapsulate MTX for potential effect investigation on glioblastoma cell targeting and P-gp efflux inhibition. Method: NPs were produced by the polyelectrolyte complexation method and were characterized by DLS, PDI, DSC, FTIR, PXRD, MEV, drug release profile, and an in vitro mucoadhesion test. Cell viability, flow cytometry, and LSCM using U251MG (glioblastoma) and CCD 1059Sk (fibroblasts) cells were used to evaluate glioblastoma and the P-gp efflux effect. Results: NPPM29 (QS3:1) showed 91.72% encapsulation efficiency, a mean diameter of 452.6 nm, and a zeta potential of +22.5 mV. DSC, FTIR, and PXRD confirmed the QS-HPMCP supramolecular interaction. Liquid falling mucoadhesion tests demonstrated strong retention of NPPM29 (84%) compared to free MTX (10.5%). In vitro release studies indicated controlled drug release at pH 7.4. Cytotoxicity assays in U251MG revealed enhanced efficacy of NPPM29 (IC₅₀ = 68.79 µg/mL) compared to free MTX (IC₅₀ = 80.54 µg/mL), with minimal impact on fibroblasts, confirming tumor specificity. Flow cytometry and LSCM confirmed improved cellular internalization and P-gp inhibition. Conclusions: These findings highlight the potential of MTX-QS-HPMCP-NPs for glioblastoma therapy.