Molecular Pharmaceutics最新文献

Pretargeted imaging harnessing tetrazine ligation has gained increased interest over recent years. Targeting vectors with slow pharmacokinetics may be visualized using short-lived radionuclides, such as fluorine-18 (¹⁸F) for positron emission tomography (PET), and result in improved target-to-background ratios compared to conventionally radiolabeled slowly accumulating vectors. We recently developed different radiochemical protocols enabling the direct radiofluorination of various tetrazine scaffolds, resulting in the development of various highly reactive and polar ¹⁸F-labeled tetrazines as lead candidates for pretargeted imaging. Here, we performed a direct head-to-head-comparison of our lead candidates to evaluate the most promising for future clinical translation. For that, all ¹⁸F-labeled tetrazine-scaffolds were synthesized in similar molar activity for improved comparability of their in vivo pretargeting performance. Intriguingly, previously reported dicarboxylic acid lead candidates with a net charge of -1 were outperformed by respective monocarboxylic acid derivatives bearing a net charge of 0, warranting further evaluation of such scaffolds prior to their clinical translation.

Delivering drugs to the posterior eye segment is a complex task, particularly for treating retinal diseases. Neuroprotective approaches to maintain neuronal integrity have garnered significant attention in recent research. Here, we developed a mucoadhesive nanoparticulate system based on thiolated hyaluronic acid-modified cationic liposomes (HA-SH@liposomes) for topical administration. To fabricate these liposomes, we utilized microfluidic technology with a toroidal mixer to ensure consistent size and stability. Cationic liposomes were prepared by using the microfluidic method, and Epoetin-β (EPOβ), a neuroprotective agent, was loaded into the liposomes. Following this, HA-SH was conjugated to the EPOβ/HA-SH@liposomes using a postmicrofluidics conjugation method, wherein HA-SH was added dropwise to facilitate electrostatic interactions between the cationic liposomes and the anionic polymer. The resulting liposomes exhibited a mean size of 144 ± 1.3 nm and a polydispersity index (PDI) of 0.09 ± 0.01, indicating their uniformity. We evaluated the biocompatibility of the EPOβ/HA-SH@liposomes in vitro using live/dead and MTS assays on the RGC-5 cell line, demonstrating no notable cytotoxicity compared to the controls. To assess the in vivo performance, we conducted extensive ophthalmological examinations in C57/BL6 mice, including immunofluorescence staining to track the distribution of EPOβ and EPOβ/HA-SH@liposomes within the eyeball. Additionally, we quantified EPOβ levels in the retina using an enzyme-linked immunosorbent assay (ELISA) kit after the topical application of free EPOβ and the EPOβ/HA-SH@liposome formulation. The immunofluorescence staining revealed efficient delivery of EPOβ into the retina and choroid via the transcorneal route when administered as EPOβ/HA-SH@liposomes. ELISA results showed that the liposomal formulation achieved approximately 1.9× greater penetration efficiency than free EPOβ. Furthermore, optokinetic response (OKR) assays indicated that animals treated with EPOβ/HA-SH@liposomes exhibited slightly improved visual acuity compared with those treated with free EPOβ, though the difference was not statistically significant. In conclusion, the topical ocular administration of EPOβ/HA-SH@liposomes facilitated the efficient delivery of EPOβ to the retina, promoting retinal recovery and confirming its neuroprotective properties. This preclinical study provides a foundation for innovative strategies in the topical delivery of neuroprotective agents in ocular therapy.

Ribonucleic acid (RNA)-based therapies represent a promising class of drugs for the treatment of non-small cell lung cancer (NSCLC) due to their ability to modulate gene expression. Therapies leveraging small interfering RNA (siRNA), messenger RNA (mRNA), microRNA (miRNA), and antisense oligonucleotides (ASOs) offer various advantages over conventional treatments, including the ability to target specific genetic mutations and the potential for personalized medicine approaches. However, the clinical translation of these therapeutics for the treatment of NSCLC faces challenges in delivery due to their immunogenicity, negative charge, and large size, which can be mitigated with delivery platforms. In this review, we provide a description of the pathophysiology of NSCLC and an overview of RNA-based therapeutics, specifically highlighting their potential application in the treatment of NSCLC. We discuss relevant classes of RNA and their therapeutic potential for NSCLC. We then discuss challenges in delivery and non-viral delivery strategies such as lipid- and polymer-based nanoparticles that have been developed to address these issues in preclinical models. Furthermore, we provide a summary table of clinical trials that leverage RNA therapies for NSCLC [which includes their National Clinical Trial (NCT) numbers] to highlight the current progress in NSCLC. We also discuss how these NSCLC therapies can be integrated with existing treatment modalities to enhance their efficacy and improve patient outcomes. Overall, we aim to highlight non-viral strategies that tackle RNA delivery challenges while showcasing RNA's potential as a next-generation therapy for NSCLC treatment.

The stabilization mechanism of mesoporous silica (MS) of two different pore sizes (21 and 2.5 nm) on overloaded celecoxib (CEL) glass was investigated. Differential scanning calorimetry (DSC) measurements revealed the presence of three fractions with different molecular mobilities: free, intermediate, and rigid ones. The free fraction exhibited cold crystallization during DSC heating and was assumed to have almost the same properties as those of the bulk molecules. The rigid fraction did not exhibit either glass transition or cold crystallization behavior, which should be stabilized by interactions with the MS surface. The remaining molecules exhibited glass transition behavior without any tendency toward cold crystallization during heating, which is called the intermediate fraction. The molecular dynamics of each fraction was investigated by using broadband dielectric spectroscopy (BDS). While the intermediate and free fractions exhibited comparable mobility, the rigid fraction demonstrated pore-size-dependent behavior: enhanced and suppressed molecular mobility was observed for the rigid fraction confined in 21 and 2.5 nm-pores, respectively. Isothermal crystallization of CEL glass was investigated using DSC and BDS at 95 °C. The results revealed that the CEL glass mixed with MS with large pores exhibited slower crystallization compared to the CEL glass without MS, whereas accelerated crystallization was observed for the CEL mixed with a small amount of MS of small pores. The pore size of 21 nm was much larger than the cooperatively rearranging region (CRR) of the CEL glass, whereas the pore size of 2.5 nm was comparable to that. When the pore size was larger than that of the CRR, most of the loaded CEL molecules behaved as an intermediate fraction, presumably because the molecules could exchange inside and outside the pore. In contrast, the exchange was not likely to proceed when the pore size was comparable to or smaller than that of the CRR, leaving a large free fraction. This finding provides a deep understanding of the stabilization mechanism of overloaded pharmaceutical glass by using mesoporous materials.

Antiangiogenic medications for cancer treatment have generally failed in showing substantial benefits in terms of prolonging life on their own; their effects are noticeable only when combined with chemotherapy. Moreover, treatments based on prolonged antiangiogenics administration have demonstrated to be ineffective in stopping tumor progression. In this scenario, nanotherapeutics can address certain issues linked to existing antiangiogenic treatments. More specifically, they can provide the ability to target the tumor's blood vessels to enhance drug accumulation and manage release, ultimately decreasing undesired side effects. Additionally, they enable the administration of multiple angiogenesis inhibitors at the same time as chemotherapy. Key reports in this field include the design of polymeric nanoparticles, inorganic nanoparticles, vesicles, and hydrogels for loading antiangiogenic substances like endostatin and interleukin-12. Furthermore, nanoformulations have been proposed to efficiently control relevant pro-angiogenic pathways such as VEGF, Tie2/Angiopoietin-1, HIF-1α/HIF-2α, and TGF-β, providing powerful approaches to block tumor growth and metastasis. In this article, we outline a selection of nanoformulations for antiangiogenic treatments for cancer that have been developed in the past ten years.

Isocitrate dehydrogenase wild-type glioblastoma is the most aggressive primary brain tumor classified as grade 4 of malignancy. Standard treatment, combining surgical resection, radiotherapy, and chemotherapy, often leads to severe side effects, with the emergence of tumor recurrence in all cases. Nucleic acid-based therapy has emerged as a promising strategy for cancer treatment. Non-viral nanosystems have become the vehicles of choice for gene delivery, due to their efficient nucleic acid encapsulation, protection, and intracellular transport. This work explores the potential of a formulation of low molecular weight protamine (LMWP) and dextran sulfate for gene delivery. The nanoparticles (NPs) were evaluated in terms of particle size, surface charge, morphology, and capacity to condense different nucleic acids. NPs formed by ionic complexation resulted in a homogeneous population of spherical particles with a low polydispersity index (PDI), small size, and positive surface charge. Competitive displacement assay demonstrated that the NPs could condense nucleic acids without alterations in their morphology and physicochemical characteristics, even after long-term storage. The efficacy of this formulation as a gene delivery system was evaluated in vitro in different glioblastoma cell lines and three-dimensional (3D) spheroids and in vivo using zebrafish models, showing negligible toxicity, efficient internalization, and consistent expression of fluorescent/luminescent proteins. Overall, these cationic polymeric NPs show promising features for their use as non-viral gene delivery vehicles for glioblastoma treatments.

Photothermal therapy (PTT) is a promising minimally invasive treatment that converts light energy into localized heat for tumor ablation. Indocyanine green (ICG), the only clinically approved photothermal agent (PTA), suffers from rapid photobleaching and poor tumor retention, underscoring the urgent need for next-generation PTAs with improved properties. In this study, we report AzuGlu-BODIPY, a novel azulene-containing BODIPY-based PTA incorporating 1,2,3,4-tetrahydroquinoline and glucose, designed to overcome these limitations. AzuGlu-BODIPY demonstrates a high photothermal conversion efficiency (PCE) of 51%, effective near-infrared (NIR) absorption, and thermal stability in both dimethyl sulfoxide (DMSO) and aqueous solutions. In vitro studies revealed potent photothermal efficacy against cancer cell lines, with IC₅₀ values of 3.1-4.6 μM under 808 nm laser irradiation, while in vivo experiments showed complete tumor regression in 4T1 tumor-bearing mice following localized administration and laser treatment. These results suggest AzuGlu-BODIPY as a promising PTA and provide a versatile platform for advancing azulene-based PTAs with enhanced functionality for PTT.

Obesity is a global metabolic health epidemic characterized by excessive lipid and fat accumulation, leading to severe conditions such as diabetes, cancer, and cardiovascular disease. Immediate attention and management of obesity-related health risks are most warranted. The imbalance between fat absorption, metabolic rate, and environmental and genetic factors is responsible for obesity. Treatment typically involves lifestyle modifications, pharmacotherapy, and surgery. While lifestyle changes are crucial, effective treatment often necessitates medication as a preferred adjunct strategy. However, medications commonly used, such as oral pharmacotherapy, often show side effects due to systemic exposure and, thus, may not effectively target the intended areas, leading to drug loss. On the other hand, transdermal administration of drugs with microneedle (MN)-based technologies, a painless drug delivery approach with patient compliance, is gaining interest as an alternative obesity treatment, as it directly targets adipose tissue via local delivery, minimizing system exposure and dose reduction. This Review addresses the pathophysiology of obesity, current treatment strategies, challenges in the treatment of obesity using conventional formulations, the importance of the use of nano-based medications through transdermal delivery, and the use of MNs as a promising platform for the effective delivery of nanoparticle-based anti-obesity medications. The potential of combining MNs with stimuli-responsive and non-responsive adjuvant therapies to enhance treatment efficacy and patient outcomes is explored. In addition, the limitations and future perspectives related to the use of MNs for obesity are addressed to highlight the transformative potential of this technology for obesity management. MNs hold promise in precisely delivering anti-obesity drugs while requiring lower dosages and minimizing side effects compared to conventional oral or injectable therapies and ultimately improving the quality of life for individuals struggling with obesity and its associated comorbidities.

Palbociclib (PCB), categorized as a BCS class II drug, is characterized by low aqueous solubility. The drug's limited aqueous solubility and poor dissolution rate pose significant challenges, potentially affecting its absorption and overall therapeutic efficacy. Co-amorphous (CAM) systems have been extensively investigated as a potential solution to overcome the issue of poor water solubility in numerous active pharmaceutical ingredients. This research study hypothesized that the coamorphization process involving the compounds PCB and naringin (NG) would lead to an increase in the aqueous solubility of PCB. Additionally, it was proposed that this process would also enhance the anticancer impact of PCB since NG is recognized for its pharmacological impact on breast cancer cells. In silico studies, it was revealed that PCB could interact with NG via hydrogen bonding. Furthermore, the prepared CAM (PCB-NG-CAM) system using PCB and NG was characterized by PXRD, DSC, FTIR, Raman spectroscopy, solid-state ¹³C nuclear magnetic resonance, and SEM. PCB-NG-CAM exhibited a significant increase in solubility, dissolution rate, and intestinal permeation compared to crystalline PCB. Furthermore, PCB-NG-CAM exhibited excellent physical stability at 40 °C/75% RH for up to 3 months. In addition, PCB-NG-CAM showed superior in vitro efficacy on MDA-MB-231 triple-negative breast cancer cell lines. PCB-NG-CAM resulted in a 2.24 times higher apoptosis rate and a 1.6 times greater ROS production than free PCB. Additionally, the inhibitory effect on cell migration and alterations in MMP was more pronounced in cells treated with PCB-NG-CAM. Therefore, this study indicated that PCB-NG-CAM has the potential to significantly improve the oral administration, solubility, and therapeutic efficacy of PCB.

Nanocarriers have been extensively utilized to improve the stability of photothermal agents in vivo, enhance delivery efficiency, and reduce drug side effects. However, challenges, such as the low safety of carrier materials, insufficient loading of therapeutic agents, and complex preparation procedures, still persist. In this study, the photothermal agent IR780 was encapsulated in network TA-Fe³⁺ (TF) which was self-assembled by tannic acid (TA) and Fe³⁺ to synthesize an acid-responsive multifunctional nanophotothermal agent TF@IR780 (TR). In the slightly acidic tumor microenvironment (TME), network shell TF is degraded, and the internal photothermal agent IR780 is exposed. On the one hand, the TF network can improve the solubility and stability of photothermal agent IR780 in vivo and significantly increase the uptake efficiency in tumor cells. On the other hand, Fe³⁺ exhibits magnetic resonance imaging (MRI) functionality, which combined with the fluorescence imaging of IR780 endows TR with multimodal imaging capabilities. In addition, TR is easy to release photosensitizers through acid response in the low pH environment of TME, and achieves precise damage to mitochondria through mitochondrial anchoring and light regulation. This overcomes the drawbacks of traditional tumor treatment methods, such as poor specificity, and demonstrates efficient and controllable antitumor activity.