International Journal of Pharmaceutics最新文献

Photothermal therapy has been observed to upregulate the heat shock protein 70 (HSP 70) expression in tumor cells, consequently diminishing the anti-tumor efficacy of the treatment. The expression of HSP 70 is intricately linked to the adenosine triphosphate (ATP) levels within tumors, suggesting that modulating energy metabolism could potentially enhance the effectiveness of photothermal therapy. To address these challenges, ATO-QUE-Fe²⁺-PVP K30 nanoparticles (AQFP NPs) were synthesized through the coordinated self-assembly of the oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO) and the glycolysis inhibitor quercetin (QUE) with ferrous ions (Fe²⁺) for synergetic energy depletion and low-temperature photothermal therapy (LTPTT). The synthesized AQFP NPs exhibited a small particle size and demonstrated high encapsulation efficiency of ATO and QUE. AQFP NPs could effectively downregulate the expression of HSP 70 by inhibiting the activity of mitochondrial complex Ⅲ and hexokinase Ⅱ (HK Ⅱ) to inhibiting suppress mitochondrial OXPHOS and glycolytic pathways in 4T1 cells, respectively. This inhibition resulted in a reduction of ATP levels within tumor cells, subsequently leading to decreased expression of HSP 70 and enhancing the therapeutic efficacy of LTPTT. Furthermore, AQFP NPs can remarkably inhibit the growth of tumors when subjected to laser irradiation. Furthermore, the analysis of blood biochemical indices and hematoxylin and eosin (H&E) staining of major organs suggested that AQFP NPs exhibit a preferable in vivo safety profile. In conclusion, the anti-tumor efficacy of LTPTT could be substantially enhanced by concurrently inhibiting OXPHOS and glycolysis, thereby offering an innovative therapeutic for the clinical treatment of tumors.

The present study introduces a novel formulation approach for utilizing Lyotropic Liquid Crystals (LLCs) as sustained oral delivery systems. For this purpose, we have developed a novel bottom-up fabrication process that enables the LLC beads to be formulated with precise control over their diameter by pre-determining their surface area. By directly controlling the effective diffusional interfacial surface of the LLCs, their release rate from the LLC beads can be determined. The LLC beads were formulated as pH-responsive systems, attenuating the Higuchian primary diffusional burst in a gastric environment, and increasing the release of the solubilized load at an elevated pH environment (pH 6.4). To demonstrate the applicability of this approach, the LLC beads were loaded with a lipophilic low water solubility (< 5 µg/mL) model drug, Celecoxib (CLXB). Although the CLXB water solubility is not pH dependent, CLXB's Higuchian release constant increased from 9.31 at pH 1.5 to 15.03 at pH 6.4. The pH dependency of CLXB release was achieved by the co-solubilization of additional compounds in the LLC structure, creating a pH-dependent environment that influences both the LLC structure and the release of the co-solubilized compounds. The enhanced release of CLXB in an elevated pH environment enables gaining a zero-order (R² > 0.99) sustained release profile extending beyond 10 h in a release medium simulating the gastrointestinal (GI) tract environment. Additionally, the study investigated the association between the release of co-solubilized compounds and the micellar structure using techniques such as small-angle X-ray diffraction, nuclear magnetic resonance, and electron paramagnetic resonance. The results revealed a co-dependent relationship between the release of lipophilic compounds and changes in the curvature of LLCs at different pH levels, suggesting that a compensatory mechanism operates between these two processes. These insights, combined with the innovative bottom-up fabrication method for LLC beads, provide valuable tools for controlling the release of lipophilic compounds from LLCs and for enhancing their effectiveness as controlled oral delivery systems.

Hormone-related cancers, also known as hormone-sensitive or hormone-dependent cancers, rely on hormones such as estrogen, testosterone, and progesterone for growth. These malignancies, including breast, pituitary, thyroid, ovarian, uterine, cervical, and prostate cancers, often exhibit accelerated progression in response to hormonal signaling. Small interfering RNA (siRNA) has emerged as a groundbreaking gene suppression therapy since the FDA approval of its first product in 2018. With over 200 ongoing clinical trials, siRNA is being actively explored as a targeted treatment for hormone-related cancers. Its ability to silence specific oncogenes offers significant advantages over conventional therapies, which are often associated with toxicity, resistance, and non-specific targeting. However, challenges in siRNA delivery remain a major barrier to its clinical translation, limiting its ability to reach target cells effectively. This review evaluates the potential of siRNA in hormone-related cancers, addressing the shortcomings of traditional treatments while examining novel strategies to enhance siRNA delivery and overcome tumor microenvironment obstacles. Notably, no existing literature comprehensively consolidates siRNA-based therapies for these cancers, emphasizing the importance of this manuscript in bridging current knowledge gaps and advancing the translational application of siRNA therapeutics.

Small volume dissolution systems are commonly used in dissolution testing, primarily in method development for low dose formulations compared to standard dissolution apparatuses used with evaluation of larger formulations. This is typically done because of cost savings associated with using smaller media volumes and sample sizes, to overcome the lack of material in early development, and to provide higher analytical sensitivity and discrimination ability. The Chinese Pharmacopoeia (CP) includes a small dissolution apparatus in their list ("Method 3 (Small Vessel)") (The State Pharmacopoeia Commission of P.R. China (2015a). 0931 Dissolution and Drug Release Test). Currently, limited information is available in the literature on the dissolution performance of small apparatuses in general and the CP small apparatus in particular (referred to here as Chinese Small Vessel System (ChSVS)). Therefore, the objective of this work was to experimentally investigate the hydrodynamics in the ChSVS operating at different paddle agitation speeds (35-100 rpm) using Particle Image Velocimetry (PIV). Results indicated that the flow field in the ChSVS is mostly dominated by tangential velocities. Axial velocities and radial velocities are typically one or two orders of magnitude lower than the tangential velocities. The non-dimensional velocity profiles, scaled with the paddle tip speed, are generally self-similar, implying that the velocities in most regions of the ChSVS are directly proportional to the paddle rotational speed. The hydrodynamics in ChSVS is extremely sensitive to even minute deviations from perfect symmetry about the vertical centerline. This work provides a significant insight into the flow inside the ChSVS and is expected to be of relevance for scientists and practitioners developing new dissolution methods and working in the dissolution testing area.