A case of death after the severing three appendiceal arteries during appendectomy.

INTRODUCTION: Acute appendicitis is one of the most common acute abdominal issues requiring surgery and is usually treated by appendectomy. During the process of removing the appendix, the appendiceal artery is severed. In most individuals, the appendix is supplied by only one appendiceal artery. CASE PRESENTATION: A 50-year-old man underwent appendectomy. During the surgical procedure, the appendix artery and two accessory arteries of the appendix were severed, leading to massive hemorrhaging in the abdominal cavity, which ultimately resulted in the patient's unfortunate demise. CONCLUSION: Through this case, we hope that surgeons can learn more about the anatomy of the appendiceal artery and understand the possibility of accessory arteries to the appendix. During surgery, the blood vessels supplying the appendix should be carefully explored, and the "one-size-fits-all approach" should be avoided. Moreover, attention should be given to complications after appendectomy, and timely symptomatic treatment should be provided. Key points 1. Rare typing: The case of death due to improper handling of the accessory appendicular artery during appendectomy in patients with three appendiceal arteries is currently unreported. 2. Detailed anatomical knowledge: Surgeons performing an appendectomy need to make a detailed exploration of the blood vessel supply of the appendix to avoid ignoring anatomically different blood vessels. 3. Avoid a one-size-fits-all approach: In the surgical process, a "one-size-fits-all" approach should be avoided, that is, the same surgical approach should not be used in all cases, but should be adjusted according to the anatomical characteristics of the individual. 4. Observation of postoperative bleeding: In the perioperative period, peritoneal drainage should be closely observed. If a large amount of bloody fluid is found, timely surgical treatment should be carried out. 5. Attention to complications: Surgeons should pay.

Glutathione-responsive CD-MOFs co-loading honokiol and indocyanine green biomimetic active targeting to enhance photochemotherapy for breast cancer.

Breast cancer has now replaced lung cancer as the most prevalent malignant tumor worldwide, posing a serious health risk to women. We have recently designed a promising option strategy for the treatment of breast cancer. In this work, cyclodextrin metal-organic frameworks with high drug-carrying properties were endo-crosslinked by 3,3'dithiodipropionyl chloride to form cubic phase gel nanoparticles, which were drug-loaded and then coated by MCF-7 cell membranes. After intravenous injection, this multifunctional nanomedicine achieved dramatically homologous targeting co-delivery of honokiol and indocyanine green to the breast tumor. Further, the disulfide bonds in the nanostructures achieved glutathione-responsive drug release, induced tumor cells to produce reactive oxygen species and promoted apoptosis, resulting in tumor necrosis, and at the same time, inhibited Ki67 protein expression, which enhanced photochemotherapy, and resulted in a 94.08 % in vivo tumor suppression rate in transplanted tumor-bearing mice. Thereby, this nanomimetic co-delivery system may have a place in breast cancer therapy due to its simple fabrication process, excellent biocompatibility, efficient targeted delivery of insoluble drugs, and enhanced photochemotherapy.

Sustained-Release Hydrogen-Powered Bilateral Microneedles Integrating CD-MOFs for In Situ Treating Allergic Rhinitis.

Glucocorticoids are widely used for treating allergic rhinitis, but conventional intranasal administration encounters unfavorable nasal cilia clearance and nasal mucosal barrier. Herein, a bilateral microneedle patch is fabricated for delivering cyclodextrin-based metal-organic frameworks (CD-MOF) encapsulating dexamethasone (DXMS) and paeonol (Pae), while NaH particles are mounted on the basal part of each microneedle. By intranasal administration, the microneedles are propelled into the nasal mucosa by NaH-generated hydrogen and then swell to form a hydrogel for sustainedly releasing drugs. The DXMS/Pae combination is demonstrated to be superior to more than the twofold dose of DXMS alone for improving allergic rhinitis in rats. It involves reducing mast cell degranulation and modulating Treg/Th17 cell homeostasis, whereas inhibiting Th1 to Th2 differentiation is associated with regulating the GATA3/T-bet pathway, as well as repairing epithelial barrier function by increasing MUC1 and downregulating periostin. In addition, this delivery system modulates the lipid metabolism of the nasal mucosa. Notably, the newly designed device significantly enhances the drug's therapeutic effect, and NaH-generated hydrogen may have the potential adjunctive therapeutic effect. Collectively, such an emerging microneedle-mediated nasal drug delivery creates a new form for alleviating immune inflammation and contributes a promising solution to reduce clinical glucocorticoid abuse.

Extrapolation study for determining the time since injury in a rat subcutaneous hematoma model utilizing ATR-FTIR spectroscopy.

The determination of the time of an injury has been a major problem in forensic science due to the lack of objective, reliable and portable methods. In this study, a subcutaneous hemorrhage model in rats was established over six days, and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy coupled with chemometrics was used to determine the time since injury. Initial principal component analysis (PCA) showed variance among hematoma sites. Subsequently, spectral data were acquired to establish a dependable partial least square (PLS) regression model with predictive abilities. The root mean square error of cross-validation (RMSECV) and the root mean square error of prediction (RMSEP) values produced by a genetic algorithm (GA) were 0.64 d (R2 = 0.88) and 0.57 d (R2 = 0.90), respectively. Few variables were involved in the model, and significantly better results were obtained in comparison to the conventional full-spectrum PLS model. In combination with the results of variable importance in projection (VIP) scores, all components, including proteins, nucleic acids and phospholipids, provided inferences regarding the samples at different time points; additionally, amide I and II bands represented the secondary structure of proteins and provided the largest contribution. Based on our preliminary study, the combination of swift and nondamaging ATR-FTIR spectroscopy with chemometrics could prove to be an advantageous approach for gauging the age of an injury in the forensic field.

Synergistic treatment of androgenetic alopecia with follicular co-delivery of minoxidil and cedrol in metal-organic frameworks stabilized by covalently cross-linked cyclodextrins.

Androgenetic alopecia seriously affects the physical and mental health of patients. The main clinical therapeutic agent, minoxidil tincture, is challenged by solvent irritation and dose-dependent side effects. Our recent work has identified a biosafety natural product, cedrol, that is synergistic in combination with minoxidil, thereby improving medication safety by substantially reducing the clinical dose of minoxidil. In addition, ccross-linked CD-MOF were designed as carriers for hair follicle delivery, and γ-CD in the carriers was cross-linked by diphenyl carbonate with covalent bonds to protect the CD-MOF from rapid disintegration in an aqueous environment. This improved nanocarrier has a drug loading of 25%, whereas nanocarriers increased drug delivery to the hair follicles through ratchet effect, and increased human dermal papilla cells uptake of drugs via endocytosis pathways mainly mediated by lattice proteins, energy-dependent active transport, and lipid raft-dependent, thus improved cell viability, proliferation, and migration, followed by significantly enhancing the anti-androgenetic alopecia effect, with cedrol focusing on inhibiting 5α-reductase and activating Shh/Gli pathway, and minoxidil, which up-regulated VEGF, down-regulated TGF-ß, and activated ERK/AKT pathway. This drug combination provides a new therapeutic strategy for androgenetic alopecia, while the newly developed cross-linked CD-MOF has been shown to serve as a promising follicular delivery vehicle.

TPGS-mediated Transethosomes Enhance Transdermal Administration of Curcumin via Effects on Deformability and Stability.

BACKGROUND: Adding a suitable surfactant can enhance the transdermal permeability of transethosomes while also leveraging its functionality as a functional material. In this study, transethosomes were prepared using D-α-tocopherol acid polyethylene glycol succinate (TPGS) as edge activators for transdermal delivery of curcumin (Cur). METHODS: The TPGS-mediated curcumin-loaded transethosomes (Cur@TES) were prepared and formulated optimally, and the optimized formulations were characterized for their morphology, particle size, entrapment efficiency (EE) and drug loading (DL). The stability and deformability of Cur@TES were investigated, while the transdermal delivery of Cur@TES was investigated through in vitro transdermal assays and fluorescence imaging. A mouse ear swelling model was performed to determine the anti-inflammatory effect of Cur@TES. RESULTS: Cur@TES appeared round or elliptical in shape. The particle size, EE and DL for the optimized formulation were observed as 131.2 ± 7.2 nm, 97.68 ± 2.26%, and 6.58 ± 0.62%, respectively. X-ray diffraction analysis confirmed the formation of disordered structures in the inner core of the vesicles. Moreover, Cur@TES system demonstrated better stability and deformability compared to the curcumin-loaded ethosomes (Cur@ES). In-vitro transdermal experiments demonstrated that Cur@TES significantly increased the amount of drug retained in the skin (P＜0.05). Fluorescence imaging confirmed that the skin distribution were distinctly enhanced with the delivery by TPGS mediated transethosomes. In addition, Cur@TES showed a significant inhibitory effect on Inflammatory swelling in the mouse ear-swelling model. CONCLUSION: TPGS-mediated transethosomes exhibit significant transdermal advantages and enhanced anti-inflammatory effects, providing a new perspective for the transdermal delivery of curcumin.

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and ß-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease ß-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.

NMNATs expression inhibition mediated NAD+ deficiency plays a critical role in doxorubicin-induced hepatotoxicity in mice.

Doxorubicin (DOX) is one of the most widely used antineoplastic drugs with known cardiotoxicity while other organ toxicity, such as hepatotoxicity is not well defined. This study was to explore the role of nicotinamide adenine dinucleotide (NAD+) in DOX-induced hepatotoxicity. DOX (20 mg/kg) induced acute liver injury and oxidative stress in C57BL/6 J mice at 48 h. Notably, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H dehydrogenase quinone 1 (NQO1) were downregulated. NAD+ deficiency was confirmed due to DOX exposure. Mechanistically, the downregulation of nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1), NMNAT2 and NMNAT3, while no alteration of nicotinamide phosphoribosyl transferase was proved. As a consequence of NAD+ deficiency, the expression of poly-ADP-ribose polymerase1 (PARP1), CD38 and Sirtuin1 (SIRT1) were reduced. Furthermore, supplementation of NAD+ (200 mg/kg/day) or its precursor nicotinamide mononucleotide (NMN) (500 mg/kg/day) alleviated liver injury, attenuated oxidative stress, and elevated the downregulation of Nrf2 and NQO1. More importantly, compromised expression of NMNAT1-3, PARP1, CD38 and SIRT1 were improved by NAD+ and NMN. In conclusion, NAD+ deficiency due to NMNATs expression inhibition may attribute to the pathogenesis of DOX-induced hepatotoxicity, thus providing new insights for mitigating DOX side effects.

Advances and Prospects for Hydrogel-Forming Microneedles in Transdermal Drug Delivery.

Transdermal drug delivery (TDD) is one of the key approaches for treating diseases, avoiding first-pass effects, reducing systemic adverse drug reactions and improving patient compliance. Microneedling, iontophoresis, electroporation, laser ablation and ultrasound facilitation are often used to improve the efficiency of TDD. Among them, microneedling is a relatively simple and efficient means of drug delivery. Microneedles usually consist of micron-sized needles (50-900 µm in length) in arrays that can successfully penetrate the stratum corneum and deliver drugs in a minimally invasive manner below the stratum corneum without touching the blood vessels and nerves in the dermis, improving patient compliance. Hydrogel-forming microneedles (HFMs) are safe and non-toxic, with no residual matrix material, high drug loading capacity, and controlled drug release, and they are suitable for long-term, multiple drug delivery. This work reviewed the characteristics of the skin structure and TDD, introduced TDD strategies based on HFMs, and summarized the characteristics of HFM TDD systems and the evaluation methods of HFMs as well as the application of HFM drug delivery systems in disease treatment. The HFM drug delivery system has a wide scope for development, but the translation to clinical application still has more challenges.

[Effect and mechanism of Xihuang Pills on rats with precancerous lesions of breast].

The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.

Phytosterol-mediated glycerosomes combined with peppermint oil enhance transdermal delivery of lappaconitine by modulating the lipid composition of the stratum corneum.

Although the introduction of glycerosomes has enriched strategies for efficient transdermal drug delivery, the inclusion of cholesterol as a membrane stabilizer has limited their clinical application. The current study describes the development and optimization of a new type of glycerosome (S-glycerosome) that is formed in glycerol solution with ß-sitosterol as the stabilizer. Moreover, the transdermal permeation properties of lappaconitine (LA)-loaded S-glycerosomes and peppermint oil (PO)-mediated S-glycerosomes (PO-S-glycerosomes) are evaluated, and the lipid alterations in the stratum corneum are analyzed via lipidomics. The LA-loaded S-glycerosomes prepared by the preferred formulation from the uniform design have a mean size of 145.3 ± 7.81 nm and an encapsulation efficiency of 73.14 ± 0.35%. Moreover, the addition of PO positively impacts transdermal flux, peaking at 0.4% (w/v) PO. Tracing of the fluorescent probe P4 further revealed that PO-S-glycerosomes penetrate deeper into the skin than S-glycerosomes and conventional liposomes. Additionally, treatment with PO-S-glycerosomes alters the isoform type, number, and composition of sphingolipids, glycerophospholipids, glycerolipids, and fatty acids in the stratum corneum, with the most notable effect observed for ceramides, the main component of sphingolipids. Furthermore, the transdermal administration of LA-loaded PO-S-glycerosomes improved the treatment efficacy of xylene-induced inflammation in mice without skin irritation. Collectively, these findings demonstrate the feasibility of ß-sitosterol as a stabilizer in glycerosomes. Additionally, the inclusion of PO improves the transdermal permeation of S-glycerosomes, potentially by altering the stratum corneum lipids.

[Comparison of in vivo plasma pharmacokinetics and urine excretion of main components in Xihuang Formula in rats with precancerous lesions of breast cancer].

The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and ß-boswellic acid(ß-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and ß-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and ß-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of ß-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of ß-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of ß-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of ß-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.

Microneedle-based interstitial fluid extraction for drug analysis: Advances, challenges, and prospects.

Similar to blood, interstitial fluid (ISF) contains exogenous drugs and biomarkers and may therefore substitute blood in drug analysis. However, current ISF extraction techniques require bulky instruments and are both time-consuming and complicated, which has inspired the development of viable alternatives such as those relying on skin or tissue puncturing with microneedles. Currently, microneedles are widely employed for transdermal drug delivery and have been successfully used for ISF extraction by different mechanisms to facilitate subsequent analysis. The integration of microneedles with sensors enables in situ ISF analysis and specific compound monitoring, while the integration of monitoring and delivery functions in wearable devices allows real-time dose modification. Herein, we review the progress in drug analysis based on microneedle-assisted ISF extraction and discuss the related future opportunities and challenges.

Diethylene glycol monoethyl ether-mediated nanostructured lipid carriers enhance trans-ferulic acid delivery by Caco-2 cells superior to solid lipid nanoparticles.

This work aimed to compare the performance of trans-ferulic acid-encapsulated nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) for transport by Caco-2 cells. The NLC particles (diameter: 102.6 nm) composed of Compritol® 888 ATO, ethyl oleate, Cremophor® EL, and Transcutol® P were larger than the SLNs (diameter: 86.0 nm) formed without liquid lipid (ethyl oleate), and the former had a higher encapsulation efficiency for trans-ferulic acid (p < 0.05). In vitro cultured Caco-2 cell transport was used to simulate intestinal absorption, and the cellular uptake of NLCs was higher than that of SLNs (p < 0.05). Compared to SLNs, NLCs greatly enhanced trans-ferulic acid permeation through the MillicellTM membrane (p < 0.05). This work confirms that NLCs have better properties than SLNs in terms of increasing drug transport by Caco-2 cells. This helps to comprehend the approach by which NLC-mediated oral bioavailability of trans-ferulic acid is better than that mediated by SLNs, as shown in our previous report.

A case of cardiac tamponade caused by T4N2M1 lung squamous cell carcinoma invading the aorta.

In patients with known lung squamous cell carcinoma, it is necessary to be alert to the presence of cancer cell infiltration in the large blood vessels and the heart. In this report, we report a case of a 49-year-old man who was previously diagnosed with squamous cell carcinoma of the lung, underwent autoimmune cell therapy, and was diagnosed posthumously with lung cancer invading the aorta and heart, resulting in severe cardiac tamponade. This case illustrates the value and key points of autopsy in evaluating sudden deaths.

Biochemical Toxicological Study of Insulin Overdose in Rats: A Forensic Perspective.

Due to nonspecific pathological changes and the rapid degradation of insulin in postmortem blood samples, the identification of the cause of death during insulin overdose has always been a difficulty in forensic medicine. At present, there is a lack of studies on the toxicological changes and related mechanisms of an insulin overdose, and the specific molecular markers of insulin overdose are still unclear. In this study, an animal model of insulin overdose was established, and 24 SD rats were randomly divided into a control group, insulin overdose group, and a recovery group (n = 8). We detected the biochemical changes and analyzed the toxicological mechanism of an insulin overdose. The results showed that after insulin overdose, the rats developed irregular convulsions, Eclampsia, Opisthotonos, and other symptoms. The levels of glucose, glycogen, and C-peptide in the body decreased significantly, while the levels of lactate, insulin, and glucagon increased significantly. The decrease in plasma K+ was accompanied by the increase in skeletal muscle K+. The PI3K-AKT signaling pathway was significantly activated in skeletal muscle, and the translocation of GLUT4/Na+-K+-ATPase to sarcolemma was significantly increased. Rare glycogenic hepatopathy occurred in the recovery group after insulin overdose. Our study showed that insulin overdose also plays a role in skeletal muscle cells, mainly through the PI3K-Akt signaling pathway. Therefore, the detection of signaling pathway proteins of the skeletal muscle cell membrane GLUT4 and Na+-K+-ATPase has a certain auxiliary diagnostic value for forensic insulin overdose identification. Glycogen detection in the liver and skeletal muscle is important for the diagnosis of insulin overdose, but it still needs to be differentiated from other causes of death. Skeletal muscle has great potential for insulin detection, and the ratio of insulin to the C-peptide (I:C) can determine whether an exogenous insulin overdose is present.

B16F10 Cell Membrane-Based Nanovesicles for Melanoma Therapy Are Superior to Hyaluronic Acid-Modified Nanocarriers.

Some cancer cell membrane (CCM)-derived nanovesicles show strong homing effects and are used for targeted cancer therapy. By co-constructing the B16F10 cell membrane with a PEGylated phospholipid membrane, a new nanocarrier with a composite nanocrown structure was developed, which can evade immune recognition and actively target homologous melanoma. The nanocrowns have an encapsulation efficiency of more than 90% for paclitaxel and showed no significant difference (p > 0.05) from the PEGylated phospholipid membrane vesicles. Compared with the hyaluronic acid-modified PEGylated phospholipid membrane vesicles, the biomimetic nanocrowns enhanced the escape of nanovesicles from reticuloendothelial cells in vitro and extended the circulation time in vivo; moreover, the nanocrowns showed superior melanoma-targeted drug delivery capability and improved anticancer effects of paclitaxel as demonstrated by the inhibition of B16F10 cell proliferation and induction of apoptosis by interfering with microtubule formation. In contrast, the modification of hyaluronic acid did not increase the targeting capacity or antitumor effects of the nanocrowns, confirming that the superior targeting capacity was mediated by the exposed homologous CCMs rather than by hyaluronic acid. Our results demonstrate the potential of using biomimetic nanocrowns for active melanoma-targeted therapy.

Cholesterol and Phospholipid-free Multilamellar Niosomes Regulate Transdermal Permeation of a Hydrophobic Agent Potentially Administrated for Treating Diseases in Deep Hair Follicles.

We designed cholesterol- and phospholipid-free multilamellar niosomes (MLNs) structured by glyceryl monooleate (GMO) and poloxamer 407 (F127), and evaluated their capacity for transdermal drug delivery. The optimized MLNs had a mean size of 97.88 ± 63.25 nm and an encapsulation efficiency of 82.68% ± 2.14%. The MLNs exhibited a remarkable sustained cargo release, and improved the permeation of the stratum corneum. Compared with the tincture, lower transdermal flux but higher skin deposition of aconitine in vitro were achieved in the MLN group (p < 0.05). Additionally, both water-soluble rhodamine B- and liposoluble coumarin 6-labeled MLNs were found to penetrate deeply into the skin through the hair follicles and could be internalized by fibroblasts Notably, the MLNs possessed greater wettability, and the study focused on delivery to deeper hair follicles and up to the outer hair sheath, which showed advantages for treating diseases of hair follicles, and was potentially superior to the hydrophobic PLGA nanoparticles (diameter: 637.87 ± 22.77 nm) which mainly accumulated in superficial hair follicles. Hair follicles were therefore demonstrated to be an important way to enhance skin permeability, and MLNs are a promising alternative for topical and transdermal drug delivery.

Optimizing glycerosome formulations via an orthogonal experimental design to enhance transdermal triptolide delivery.

Triptolide exerts strong anti-inflammatory and immunomodulatory effects; however, its oral administration might be associated with side effects. Transdermal administration can improve the safety of triptolide. In this study, glycerosomes were prepared as the transdermal vehicle to enhance the transdermal delivery of triptolide. With entrapment efficiency and drug loading as dependent variables, the glycerosome formulation was optimized using an orthogonal experimental design. Phospholipid-to-cholesterol and phospholipid-to-triptolide mass ratios of 30:1 and 5:1, respectively and a glycerol concentration of 20 % (V/V) were used in the optimization. The glycerosomes prepared with the optimized formulation showed good stability, with an average particle size of 153.10 ± 2.69 nm, a zeta potential of -45.73 ± 0.60 mV and an entrapment greater than 75 %. Glycerosomes significantly increased the transdermal delivery of triptolide compared to conventional liposomes. As efficient carriers for the transdermal delivery of drugs, glycerosomes can potentially be used as an alternative to oral triptolide administration.

Microneedle-mediated transdermal nanodelivery systems: a review.

The greatest limitation in the development of transdermal drug delivery systems is that only a few drugs can permeate the skin due to the barrier function of the stratum corneum. Active and passive methods are generally available for improving the ability of drug transdermal delivery. However, nanoparticles, as a passive approach, exhibit capacity-constrained permeation enhancement. Thus, microneedle-mediated nanoparticles possess enormous potential and broad prospects. Microneedles promote the penetration of macromolecules by creating microchannels on the skin surface. In this review, the prevailing subknowledge on microneedles (mechanism, classification, and applications of microneedles combined with nanoparticles) is discussed to provide a guideline for readers and a basic reference for further in-depth studies of this novel drug delivery system.