Drug Delivery最新文献

Genistein (GEN), an isoflavonoid, offers multifunctional biological activities. However, its poor oral bioavailability, aqueous solubility, extensive metabolism, and short half-life restricted its clinical use. Therefore, the Phospholipon^®90H complex of genistein (GPLC) was prepared to enhance its biopharmaceutical properties and anti-inflammatory activity. GPLC was characterized by employing particle size and zeta potential, Fourier transforms infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry, proton nuclear magnetic resonance, aqueous solubility, in vitro dissolution, ex vivo permeation, oral bioavailability and in vivo anti-inflammatory activity. The complex showed high entrapment of GEN (∼97.88% w/w) within the Phospholipon^®90H matrix. Particle size and zeta potential studies confirmed the small particle size with the modest stability of GPLC. The characterization analysis supported the formation of GPLC through the participation of hydrogen bonding between GEN and Phospholipon^®90H. GPLC significantly enhanced the aqueous solubility (∼2-fold) compared to GEN. Dissolution studies revealed that GPLC drastically improved the GEN dissolution rate compared to GEN. Likewise, the complex improved the permeation rate across the membrane compared to GEN. GPLC formulation significantly enhanced the oral bioavailability of GEN via improving its Cmax, tmax, AUC, half-life and mean residence time within the blood circulation compared to GEN. The GPLC (∼20 mg/kg, p.o.) remarkably inhibited the increase in paw edema up to 5 h, compared to GEN and diclofenac. Results suggest that the Phospholipon^®90 complex is a superior and promising carrier for enhancing the biopharmaceutical parameters of GEN and other bioactive with similar properties.

It is evident that site-specific systemic drug delivery can reduce side effects, systemic toxicity, and minimal dosage requirements predominantly by delivering drugs to particular pathological sites, cells, and even subcellular structures. The endoplasmic reticulum (ER) and associated cell organelles play a vital role in several essential cellular functions and activities, such as the synthesis of lipids, steroids, membrane-associated proteins along with intracellular transport, signaling of Ca²⁺, and specific response to stress. Therefore, the dysfunction of ER is correlated with numerous diseases where cancer, neurodegenerative disorders, diabetes mellitus, hepatic disorder, etc., are very common. To achieve satisfactory therapeutic results in certain diseases, it is essential to engineer delivery systems that can effectively enter the cells and target ER. Nanoparticles are highly biocompatible, contain a variety of cargos or payloads, and can be modified in a pliable manner to achieve therapeutic effectiveness at the subcellular level when delivered to specific organelles. Passive targeting drug delivery vehicles, or active targeting drug delivery systems, reduce the nonselective accumulation of drugs while reducing side effects by modifying them with small molecular compounds, antibodies, polypeptides, or isolated bio-membranes. The targeting of ER and closely associated organelles in cells using nanoparticles, however, is still unsymmetrically understood. Therefore, here we summarized the pathophysiological prospect of ER stress, involvement of ER and mitochondrial response, disease related to ER dysfunctions, essential therapeutics, and nanoenabled modulation of their delivery to optimize therapy.

To improve the anti-metastasis effects of honokiol (HNK) on breast cancer, we designed cationic liposomes (Lip) in which HNK was encapsulated into Lip, and its surface was modified with negatively charged polysialic acid (PSA-Lip-HNK) for efficient treatment of breast cancer. PSA-Lip-HNK possessed a homogeneous spherical shape and high encapsulation efficiency. In vitro 4T1 cell experiments indicated that PSA-Lip-HNK increased cellular uptake and cytotoxicity via the endocytosis pathway mediated by PSA and selectin receptors. Furthermore, the significant antitumor metastasis impact of PSA-Lip-HNK was confirmed by wound healing and cell migration and invasion. Enhanced in vivo tumor accumulation of the PSA-Lip-HNK was observed in 4T1 tumor-bearing mice by living fluorescence imaging. For in vivo antitumor experiments using 4T1 tumor-bearing mice, PSA-Lip-HNK exhibited a higher tumor growth and metastasis inhibition compared with unmodified liposomes. Therefore, we believe that PSA-Lip-HNK well combined biocompatible PSA nano-delivery and chemotherapy, providing a promising drug delivery approach for metastatic breast cancer therapy.

Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.

Cyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP (in vitro), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection (in vivo). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study's outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1β (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-β-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-β1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson's' trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.

Atorvastatin calcium (ATV) is a well-known anti-hyperlipidemic drug currently being recognized for possessing an anti-inflammatory effect. Introducing it as a novel remedy for periodontitis treatment necessitates developing a syringeable modified delivery system capable of targeting inflammation within the periodontal pockets. Thus, a 3³ Box-Behnken design was used to generate eugenol enriched PEGylated cubosomes. Based on the desirability function, the optimized formulation (OEEPC) was selected exhibiting a solubilization efficiency (SE%) of 97.71 ± 0.49%, particle size (PS) of 135.20 ± 1.11 nm, polydispersity index (PDI) of 0.09 ± 0.006, zeta potential (ZP) of -28.30 ± 1.84 mV and showing a sustained drug release over 12 h. It displayed a cubic structure under the transmission electron microscope, furthermore, it was stable upon storage for up to 30 days. Hence, it was loaded into an optimum syringeable in-situ gel (ISG) which displayed the desired periodontal gelation temperature (34 ± 0.70 °C) and an adequate gelation time (46 ± 2.82 sec), it also released approximately 75% of the drug within 72 h. Clinical evaluation of the ISG showed a promising percentage reduction of about 58.33% in probing depth, 90% in the bleeding index, 81.81% in the plaque index, and 70.21% in gingival levels of transforming growth factor-β1. This proved that the formulated syringeable intra-pocket delivery system of ATV is an efficient candidate for diminishing inflammation in periodontitis.

Polymeric drug-releasing vaginal rings are useful for both local and systemic administration of drugs via the intravaginal route. Typically, they provide continuous sustained or controlled release of drug(s) over extended time periods, thereby avoiding overdose and improving adherence. This first-in-human study (EudraCT number: 2020-0050044-30) evaluated the pharmacokinetics, safety, and tolerability of a single dose of oxybutynin administered by a novel microprocessor-controlled vaginal ring (MedRing). Eight healthy female subjects received an electronically controlled single intravaginal dose of 3 mg oxybutynin hydrochloride (100 mg/mL) dissolved in 1:1 water/propylene glycol administered via MedRing. Following dosing, MedRing was kept in situ for up to 6 h. Blood samples were collected 1 h prior to oxybutynin dosing and subsequently at regular intervals post-dose for the assessment of plasma concentrations of oxybutynin and its active metabolite N-desethyloxybutynin. The results showed that MedRing efficiently administered oxybutynin via the intravaginal route, resulting in plasma oxybutynin levels comparable to orally administered oxybutynin. The mean ± standard deviation pharmacokinetic parameters for oxybutynin were C_max 5.4 ± 2.7 ng/mL, AUC_inf 34.9 ± 17.4 h ng/mL, t_1/2 8.5 ± 3.5 h and for N-desethyloxybutynin were C_max 3.9 ± 2.5 ng/mL, AUC_inf 51.1 ± 43.1 h ng/mL, t_1/2 7.7 ± 5.9 h. No serious adverse events were reported. The study demonstrates that intravaginal administration of oxybutynin hydrochloride using the MedRing device was well tolerated.

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (-18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ's antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets.

Chemotherapy is the first choice for the treatment of cancer but it is still limited by insufficient kill efficiency and drug resistance. These problems urgently need to be overcome in a way that minimizes damage to the body. In this study, we designed the nanocomposite microparticles (NMPs) modified by cetuximab (Cet) and loaded anti-tumor agents- quercetin (QUE) and paclitaxel (PTX)- for eliciting specific drugs homing and enhancing the killing efficiency of chemotherapy drugs (P/Q@CNMPs). Physicochemical characteristics results presented that P/Q@CNMPs have a suitable aerodynamic diameter and uniform morphology that could meet the requirements of particles deposition in the lung. And it also had the characteristics of sustained-release and pH-responsive which could release the agents in the right place and has a continuous effect. In vitro and in vivo analysis results presented that P/Q@CNMPs have the accuracy targeting ability and killing effect on non-small cell lung cancer (NSCLC) which express positive epidermal growth factor receptor (EGFR) on the membrane. Furthermore, this system also has low toxicity and good biocompatibility. These results demonstrated that P/Q@CNMPs could be a potential intelligent targeting strategy used for chemo-resistant NSCLC therapies.