Drug Delivery and Translational Research最新文献

Modernization and lifestyle changes have resulted in a number of diseases, including cancer, that require complicated and thorough treatments. One of the most important therapies is the administration of antibiotics and medicines. This is known as chemotherapy for cancer, and it is a regularly utilised treatment plan in which the medications used have negative side effects. This has resulted in extensive research on materials capable of delivering pharmaceuticals to particular targets over an extended period of time. Biopolymers have often been preferred as effective drug delivery carriers. Of these, β-glucan, a natural polysaccharide, has not been extensively studied as a drug delivery carrier, despite its unique properties. This review discusses the sources, extraction techniques, structures, and characteristics of β-glucan to provide an overview. Furthermore, the different methods employed to encapsulate drugs into β-glucan and its role as an efficient drug, SiRNA and Plasmid DNA carrier have been elaborated in this article. The capacity of β-glucan-based to specifically target and alter tumour-associated macrophages, inducing an immune response ultimately resulting in tumour suppression has been elaborated. Finally, this study aims to stimulate further research on β-glucan by thoroughly describing its many characteristics and demonstrating its effectiveness as a drug delivery vehicle.

Vaginal atrophy affects up to 57% of post-menopausal women, with symptoms ranging from vaginal burning to dysuria. Estradiol hormone replacement therapy may be prescribed to alleviate these symptoms, though many vaginal products have drawbacks including increased discharge and local tissue toxicity due to their hypertonic nature. Here, we describe the development and characterization of a Pluronic F127-coated estradiol nanosuspension (NS) formulation for improved vaginal estradiol delivery. We compare the pharmacokinetics to the clinical comparator vaginal cream (Estrace) and demonstrate increased delivery of estradiol to the vaginal tissue. We utilized ovariectomized (OVX) mice as a murine model of post-menopausal vaginal atrophy and demonstrated equivalent efficacy in vaginal re-epithelialization when dosed with either the estradiol NS or Estrace cream. Further, we demonstrate compatibility of the estradiol NS with vaginal bacteria in vitro. We demonstrate that a Pluronic F127-coated estradiol NS may be a viable option for the treatment of post-menopausal vaginal atrophy.

Emodin has been proven to have weight-reducing and lipid-lowering effects. In order to make emodin play a better anti-obesity role, we designed and developed an emodin loaded dissolving microneedle patch, in which emodin existed in the form of emodin-polyvinylpyrrolidone co-precipitate (Emodin-PVP). Meanwhile, polydopamine (PDA) was added to the microneedle patch (PDA-Emodin-PVP-MN) for photothermal-enhanced chemotherapy of obesity. The average weight of the patch was 0.1 ± 0.05 g and the drug loading was 0.37 ± 0.031 mg. After 5 min of NIR irradiation (808 nm, 0.6 W/cm²), the rat abdominal temperature could reach 48 ℃, and the cumulative release of emodin reached 96.25%. The diffusion coefficient of emodin in the in vitro agar diffusion experiment was 249.27 mm² h^-1. No obvious toxicity was observed in hemolysis test, CCK-8 assay and microscopic histopathological analysis. The patch significantly reduced the percent of body weight ( P < 0.01), lipid-body ratio ( P < 0.001), serum FFAs ( P < 0.01) and the cell volume of peritesticular adipose tissue in the high-fat diet induced obese rats, indicating the patch had good anti-obesity effect. The mechanism of action may be related to the up-regulation of HSL and LPL protein levels in rat peritesticular adipose tissue.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

In this study, DOX (Doxorubicin) and Fe₃O₄ magnetic nanocrystals (SPIONs (Superparamagnetic iron oxide nanocrystals)) were encapsulated in the PLGA-PEG: poly(lactide-co-glycolide)-b-poly(ethylene glycol) nanoparticles for theranostic purposes. The final prepared formulation which is called NPs (Nanoparticles) exhibited a particle size with a mean diameter of ~ 209 nm and a sufficient saturation magnetization value of 1.65 emu/g. The NPs showed faster DOX release at pH 5.5 compared to pH 7.4. Also, the cytotoxicity effect of NPs increased compared to Free-DOX alone in C6 glioma cancer cells. For in vivo investigations, the 2.2 Kg rabbits were injected with NPs formulations via a central articular anterior vein in their ears. Furthermore, the images of rabbit organs were depicted via MR (Magnetic resonance) and fluorescent imaging techniques. A negative contrast (dark signal) was observed in T₂ (Relaxation Time) weighted MR images of IV (Intravenously)-injected rabbits with NPs compared to the control ones. The organ's florescent images of NPs-injected rabbits showed a high density of red color related to the accumulation of DOX in liver and kidney organs. These data showed that the NPs have no cytotoxicity effect on the heart. Also, the results of histopathological tests of different organs showed that the groups receiving NPs and Free-DOX were almost similar and no significant difference was seen, except for the cardiac tissue in which the pathological effects of NPs were significantly less than the Free-DOX. Additionally, pharmacokinetic studies were also conducted at the sera and whole bloods of IV-injected rabbits with NPs and Free-DOX. The pharmacokinetic parameters showed that NPs could enhance the DOX retention in the serum compared to the Free-DOX. Altogether, we aimed to produce a powerful delivery nanosystem for its potential in dual therapeutic and diagnostic applications which are called theranostic agents.

Pretomanid (PTM), an oral antibiotic used in the treatment of adults with pulmonary extensively drug-resistant, nonresponsive multidrug-resistant tuberculosis (MDR-TB). It is a poor glass former, that shows high recrystallization tendency from the amorphous and supersaturated state, resulting in low aqueous solubility and suboptimal absorption through the gastrointestinal tract. The present investigation aimed to develop high drug loaded ternary amorphous solid dispersions (ASDs) of PTM with improved stability and enhanced biopharmaceutical performance by utilizing a combination of polymers. The polymers were comprehensively screened based on drug-polymer miscibility and saturation solubility analysis. A combination of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS-HF) and Polyvinylpyrrolidone K-30 (PVP K-30) showed synergism in drug-polymer miscibility as evidenced through pronounced depression in the melting endotherm of PTM. The Powder X-ray Diffraction (P-XRD) diffractograms of 30% w/w PTM loaded ternary ASDs displayed the halo pattern, contrary to the binary ASDs. Drug-polymer interactions (hydrophobic forces) involved between PTM and polymers were detected through Fourier Transform Infrared Spectroscopy (FT-IR) and Nuclear Magnetic Resonance Spectroscopy (¹³C-NMR) which contributed to the synergistic enhancement in solubility and dissolution of ternary ASDs with sustained release over 12 h. Ternary ASDs demonstrated better in-vivo performance compared to the binary ASDs, showing a 4.63-fold increase in maximum plasma concentration. All ASDs remained stable and resisted phase separation during short-term stability studies for 3 months at ambient conditions. It was concluded that the hydrophobic and hydrophilic polymeric combination (HPMCAS-HF and PVP K-30, respectively) effectively prevented the crystallization and ensured sustained drug release with improved in-vivo absorption of PTM.

Multifunctional therapies have emerged as innovative strategies in cancer treatment. In this research article, we proposed a nanostructured lipid carrier (NLC) designed for the topical treatment of cutaneous melanoma, which simultaneously delivers 5-FU and Bcl-2 siRNA. The characterized nanoparticles exhibited a diameter of 259 ± 9 nm and a polydispersion index of 0.2, indicating a uniform size distribution. The NLCs were primarily localized in the epidermis, effectively minimizing the systemic release of 5-FU across skin layers. The ex vivo skin model revealed the formation of a protective lipid film, decreasing the desquamation process of the stratum corneum which can be associated to an effect of increasing permeation. In vitro assays demonstrated that A375 melanoma cells exhibited a higher sensitivity to the treatment compared to non-cancerous cells, reflecting the expected difference in their metabolic rates. The uptake of NLC by A375 cells reached approximately 90% within 4 h. The efficacy of Bcl-2 knockdown was thoroughly assessed using ELISA, Western blot, and qRT-PCR analyses, revealing a significant knockdown and synergistic action of the NLC formulation containing 5-FU and Bcl-2 siRNA (at low concentration --100 pM). Notably, the silencing of Bcl-2 mRNA also impacted other members of the Bcl-2 protein family, including Mcl-1, Bcl-xl, BAX, and BAK. The observed modulation of these proteins strongly indicated the activation of the apoptosis pathway, suggesting a successful inhibition of melanoma growth and prevention of its in vitro spread.

Cataract surgery is followed by post-operative eye drops for a duration of 4-6 weeks. The multitude of ocular barriers, coupled with the discomfort experienced by both the patient and their relatives in frequently administering eye drops, significantly undermines patient compliance, ultimately impeding the recovery of the patient. This study aimed to design and develop an ocular drug delivery system as an effort to achieve a drop-free post-operative care after cataract surgery. An implant was prepared containing a biodegradable polymer Poly-lactic-co-glycolic acid (PLGA), Dexamethasone (DEX) as an anti-inflammatory drug, and Moxifloxacin(MOX) as an antibiotic. Implant characterization and drug loading analysis were conducted. In vitro drug release profile showed that the release of the two drugs are correlated with the clinical prescription for post operative eye drops. In vivo study was conducted on New Zealand albino rabbits where one eye underwent cataract surgery, and the drug delivery implant was inserted into the capsular bag after placement of the synthetic intraocular lens (IOL). Borderline increase in the intraocular pressure (IOP) was noted in the test sample group. Slit-lamp observations revealed no significant anterior chamber reaction in all study groups. Histopathology study of the operated eye revealed no significant pathology in the test samples. This work aims at developing the intra ocular drug delivery implant which will replace the post-operative eye drops and help the patient with the post-operative hassle of eye drops.

Gerresheimer and Midas Pharma have developed a novel cartridge-based autoinjector concept in which the cartridge as primary packaging is under constant pressure. In this article standard cartridge primary packaging material of five different companies were analyzed for their behavior under long-term pressure. Materials of 3 glass manufacturers and 2 manufacturers for cartridge rubber parts were considered. Within the test program septum stability, septum piercing, glide forces (GF), break-loose forces (BLF), glass breaking as well as a regulatory approved and marketed antibody drug product under pressure were subject to analysis. Under pressure the cartridge septum bulge grew within the first 14 days and then relevantly slowed down. An accelerated study in different atmospheric conditions allowed to extrapolate values for 24 months storage, not showing any signs of decay or problematic septum bulge increase. Pierce forces were in normal ranges and septum rupture could not be observed at the end of 42 days of pressurization. GF and BLF were within acceptable ranges and changes due to pressure could not be observed. Lowest glass breaking pressures at 4922 kPa turned out to be at least 3.5 times higher than pressures used in the autoinjector concept. Degradation of the Adalimumab antibody drug product due to pressure or device fluid pathway could not be observed with size exclusion chromatography, electrophoresis or sub-visible particles tested as a release testing in a GMP setting.