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Background: Metastasis is a complex process involving multiple factors and stages, in which tumor cells and the tumor microenvironment (TME) play significant roles. A combination of orally bioavailable therapeutic agents that target both tumor cells and TME is conducive to prevent or impede the progression of metastasis, especially when undetectable. However, sequentially overcoming intestinal barriers, ensuring biodistribution in tumors and metastatic tissues, and enhancing therapeutic effects required for efficient therapy remain challenging. Methods: Inspired by the unique chemical features of natural herbs, we propose an oral herb-nanoparticle hybrid system (HNS) formed through the self-binding of Platycodon grandiflorum-Curcuma zedoaria (HG), a herb pair/group used in clinical practice to treat breast cancer metastasis, to lipid-polymer nanoparticles (LPNs) loaded with silibinin. The molecular structure responsible for HG association with LPNs was assessed using surface-enhanced Raman spectroscopy for HNS surface chemistry characterization. Moreover, the molecular class of HG was identified using UPLC-Orbitrap-MS/MS to further confirm the surface binding. Mucus diffusion and in vivo biodistribution were evaluated using in vitro multiple-particle tracking and environment-responsive fluorescence probe in 4T1 tumor-bearing mice, respectively. The alleviation of breast cancer metastasis was assessed in 4T1 tumor-bearing mice, and the underlying mechanism was investigated. Results: The HNS reduced particle-mucus interactions by altering hydrophilicity and surface characteristics compared to LPNs. The epithelium transportation of HNS and absorption through Peyer's patch in mice were improved, promoting their biodistribution in the lung and tumor tissues. Furthermore, the HNS alleviated lung metastasis by inducing cell apoptosis and regulating the expression of MMP-9 and TGF-ß1, which altered the TME in 4T1 tumor-bearing mice. Conclusion: HNS provides an appealing system with multi-component binding of herbal medicine to facilitate both oral nanoparticle delivery efficiency and the alleviation of lung metastasis. This strategy may potentially help improve treatment for patients with breast cancer.
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Neoplasias da Mama , Neoplasias Pulmonares , Camundongos Endogâmicos BALB C , Nanopartículas , Animais , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Administração Oral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Camundongos , Linhagem Celular Tumoral , Distribuição Tecidual , Nanopartículas/química , Nanopartículas/administração & dosagem , Humanos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Regulating the process of epithelial-mesenchymal transition(EMT) is an essential strategy to inhibit tumor growth and metastasis. This study is based on the EMT process of retinoblastoma and constructs quercetin(QUE) and doxorubicin(DOX) co-loaded liposome(QD Lipo) to investigate the therapeutic effect and mechanisms of combined QUE and DOX treatment on retinoblastoma. Single-factor experiments were conducted to optimize the prescription process of QD Lipo. Eventually, spherical particles with a diameter of(108.87±1.93) nm, a PDI of 0.13±0.02, and a Zeta potential of(-34.83±1.92) mV were obtained. The encapsulation rates of QUE and DOX were 96.20%±4.40% and 91.17%±4.41%, respectively. Y79 human retinoblastoma cells were used as an in vitro cellular model, and confocal microscopy demonstrated that QD Lipo could enhance Y79 uptake efficiency. The CCK-8 assay confirmed that the optimal combination therapy effect of QUE and DOX occurred at a mass ratio of 1â¶1 to 1â¶2. Flow cytometry showed that QD Lipo enhanced the induction of apoptosis in Y79 cells. Western blot analysis revealed that QD Lipo significantly reduced the expression of EMT pathway-related proteins vimentin and α-SMA. Fluorescence assays detected a significant decrease in ROS levels in Y79 cells after treatment with QD. These results indicated that liposomal co-delivery of QUE and DOX can enhance drug delivery efficiency to retinoblastoma cells, inhibit the EMT process in retinoblastoma by downregulating ROS levels, and enhance the cytotoxicity of DOX against retinoblastoma.
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Doxorrubicina , Transição Epitelial-Mesenquimal , Lipossomos , Quercetina , Retinoblastoma , Quercetina/administração & dosagem , Quercetina/farmacologia , Quercetina/química , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Retinoblastoma/tratamento farmacológico , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lipossomos/química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Immunotherapy has been a research hotspot due to its low side effects, long-lasting efficacy, and wide anti-tumor spectrum. Recently, NK cell-based immunotherapy has gained broad attention for its unique immunological character of tumor identification and eradication and low risk of graft-versus-host disease and cytokine storm. With the cooperation of a drug delivery system (DDS), NK cells activate tumoricidal activity by adjusting the balance of the activating and inhibitory signals on their surface after drug-loaded DDS administration. Moreover, NK cells or NK-derived exosomes can also be applied as drug carriers for distinct modification to promote NK activation and exert anti-tumor effects. In this review, we first introduce the source and classification of NK cells and describe the common activating and inhibitory receptors on their surface. Then, we summarize the strategies for activating NK cells in vivo through various DDSs. Finally, the application prospects of NK cells in tumor immunotherapy are also discussed.
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Since human skin is an immune organ, a large number of immune cells are distributed in the epidermis and the dermis of the skin. Transdermal immunotherapy shows great therapeutic advantages in innate immunotherapy and adaptive immunotherapy. To solve the problem that macromolecules are difficult to penetrate into the skin, the microneedle technology can directly break through the skin barrier using micron-sized needles in a non-invasive and painless way for transdermal drug delivery. Therefore, it is considered to be an effective technology to increase drug transdermal absorption. In this review, the types of preparation, the combinations with different techniques and the mechanisms of microneedles in transdermal immunotherapy were summarized. Compared with traditional immunotherapy like intramuscular injection and subcutaneous injection, the microneedle has many advantages in transdermal immunotherapy, such as reducing patient pain, enhancing vaccine stability, and inducing stronger immune responses. Although there are still some limitations to be solved, the application of microneedle technology in transdermal immunotherapy is undoubtedly a promising means of drug delivery.
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Administração Cutânea , Sistemas de Liberação de Medicamentos , Imunoterapia , Agulhas , Humanos , Animais , Sistemas de Liberação de Medicamentos/métodos , Imunoterapia/métodos , Microinjeções/métodos , Pele/metabolismo , Pele/imunologia , Absorção CutâneaRESUMO
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.
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Compostos de Bifenilo , Neoplasias da Mama , Liberação Controlada de Fármacos , Glutationa , Verde de Indocianina , Lignanas , Estruturas Metalorgânicas , Fotoquimioterapia , Verde de Indocianina/administração & dosagem , Verde de Indocianina/química , Animais , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células MCF-7 , Fotoquimioterapia/métodos , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Estruturas Metalorgânicas/química , Glutationa/metabolismo , Lignanas/administração & dosagem , Lignanas/química , Lignanas/farmacologia , Camundongos Endogâmicos BALB C , Ciclodextrinas/química , Camundongos , Apoptose/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Nus , Portadores de Fármacos/química , Compostos Alílicos , FenóisRESUMO
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.
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Dexametasona , Hidrogênio , Rinite Alérgica , Animais , Ratos , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Dexametasona/química , Rinite Alérgica/tratamento farmacológico , Hidrogênio/química , Estruturas Metalorgânicas/química , Agulhas , Ciclodextrinas/química , Ratos Sprague-Dawley , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Administração Intranasal , Masculino , Acetofenonas/química , Acetofenonas/farmacologia , Acetofenonas/administração & dosagemRESUMO
The combination of shikonin (SKN) and gefitinib (GFB) can reverse the drug resistance of lung cancer cells by affecting energy metabolism. However, the poor solubility of SKN and GFB limits their clinical application because of low bioavailability. Wheat germ agglutinin (WGA) can selectively bind to sialic acid and N-acetylglucosamine on the surfaces of microfold cells and enterocytes, and is a targeted biocompatible material. Therefore, we created a co-delivery micelle system called SKN/GFB@WGA-micelles with the intestinal targeting functions to enhance the oral absorption of SKN and GFB by promoting mucus penetration for nanoparticles via oral administration. In this study, Caco-2/HT29-MTX-E12 co-cultured cells were used to simulate a mucus/enterocyte dual-barrier environment, and HCC827/GR cells were used as a model of drug-resistant lung cancer. We aimed to evaluate the oral bioavailability and anti-tumor effect of SKN and GFB using the SKN/GFB@WGA-micelles system. In vitro and in vivo experimental results showed that WGA promoted the mucus penetration ability of micelles, significantly enhanced the uptake efficiency of enterocytes, improved the oral bioavailability of SKN and GFB, and exhibited good anti-tumor effects by reversing drug resistance. The SKN/GFB@WGA-micelles were stable in the gastrointestinal tract and provided a novel safe and effective drug delivery strategy.
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Androgenic alopecia (AGA) has a considerable impact on the physical and mental health of patients. Nano preparations have apparent advantages and high feasibility in the treatment of AGA. Cardamonin (CAR) has a wide range of pharmacological activities, but it has the problems of poor solubility in water and low bioavailability. There are few, if any, researches on the use of nano-loaded CAR to improve topical skin delivery of AGA. In this study, a CAR-loaded liposomal formulation (CAR@Lip and CAR@Lip Gel) was developed and characterized. The prepared CAR@Lip exhibited a uniform and rounded vesicle in size. CAR@Lip and CAR@Lip Gel can significantly improve the cumulative release of CAR. Additionally, CAR@Lip can obviously promote the proliferation and migration of human dermal papilla cells (hDPCs). Cell uptake revealed that the uptake of CAR@Lip significantly increased compared with the free drug. Furthermore, both CAR@Lip and CAR@Lip Gel groups could markedly improve the transdermal performance of CAR, and increase the topical content of the drug in the hair follicle compared with CAR. The ratchet effect of hair follicles could improve the skin penetration depth of nanoformulations. Notably, Anti-AGA tests in the mice showed that CAR@Lip and CAR@Lip Gel groups could promote hair growth, and accelerate the transition of hair follicles to the growth stage. The anti-androgen effect was revealed by regulating the expression of IGF-1, VEGF, KGF, and TGF-ß, participating in SHH/Gli and Wnt/ß-catenin pathways. Importantly, the nanoformulations had no obvious skin irritation. Thus, our study showed that CAR-loaded liposomal formulation has potential application in the treatment of AGA.
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Administração Cutânea , Alopecia , Chalconas , Folículo Piloso , Lipossomos , Absorção Cutânea , Alopecia/tratamento farmacológico , Animais , Humanos , Chalconas/administração & dosagem , Chalconas/farmacocinética , Chalconas/química , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/metabolismo , Camundongos , Masculino , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Movimento Celular/efeitos dos fármacosRESUMO
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.
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Ciclodextrinas , Estruturas Metalorgânicas , Sesquiterpenos Policíclicos , Humanos , Minoxidil/farmacologia , Minoxidil/uso terapêutico , Ciclodextrinas/uso terapêutico , Alopecia/tratamento farmacológico , Resultado do TratamentoRESUMO
The occurrence and development of tumors are associated with the cell energy metabolism. Inhibiting energy metabolism of lung cancer cells is an important strategy to overcome drug resistance. Based on the cellular energy metabolism pathway, this study observed the effect of combination of shikonin(SKN) and gefitinib(GFB) on the drug resistance in non-small cell lung cancer and explored the underlying mechanism. The human non-small cell lung cancer line HCC827/GR resistant to gefitinib was used as the cell model in vitro. The CCK-8 assay and flow cytometry were employed to investigate the cell viability and apoptosis, respectively. The high performance liquid chromatography was employed to measure the intracellular accumulation of GFB. A Seahorse XFe96 Analyzer was used to detect the changes of cellular energy metabolism. Western blot was employed to determine the expression of the proteins involved in the drug resistance. The tumor-bearing nude mouse model was used to verify the efficacy of SKN+GFB in overcoming drug resistance in vivo. The results showed that SKN+GFB significantly reduced the IC_(50) of GFB on HCC827/GR cells, with the combination index of 0.628, indicating that the combination of the two drugs had a synergistic effect and promoted cell apoptosis. SKN increased the intracellular accumulation of GFB. SKN+GFB lowered the oxygen consumption rate(OCR) and glycolytic proton efflux rate(GlycoPER) in cell energy metabolism, and down-regulated the overexpression of PKM2, p-EGFR, P-gp, and HIF-1α in drug resistance. The results of reversing drug resistance test in vivo showed that GFB or SKN alone had no significant antitumor effect, while the combination at different doses induced the apoptosis of the tumor tissue and inhibited the expression of PKM2 and P-gp, demonstrating a significant antitumor effect. Moreover, the tumor inhibition rate in the high-dose combination group reached 64.01%. In summary, SKN+GFB may interfere with the energy metabolism to limit the function of HCC827/GR cells, thus reversing the GFB resistance in non-small cell lung cancer.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Naftoquinonas , Animais , Camundongos , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Quinazolinas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proliferação de Células , Linhagem Celular Tumoral , ApoptoseRESUMO
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.
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Alcaloides , Doença de Alzheimer , Ciclodextrinas , Polifenóis , Sesquiterpenos , Animais , Ratos , Doença de Alzheimer/tratamento farmacológico , Acetilcolinesterase , Peróxido de Hidrogênio , Encéfalo , Mucosa Nasal , Peptídeos beta-Amiloides , EscopolaminaRESUMO
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 (Pï¼0.05). 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.
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BACKGROUND: The stratum corneum (SC) is the main barrier of the skin, and cosmeceuticals are different from ordinary cosmetics in that they need to deliver active ingredients targeting specific skin problems through the SC into the deeper layers of the skin. Thus, we designed a compound essential oil (CEO) extracted from Salvia miltiorrhiza Bge and Cinnamomum cassia Presl, supplemented with borneol to deliver active ingredients through the SC. METHODS: The CEO was prepared by flash extraction combined with the microwave method. Moreover, the main components of the CEO were determined using gas chromatography-mass spectrometry (GCMS). Visualization techniques, such as scanning electron microscopy (SEM), haematoxylin-eosin (HE) staining, and confocal laser scanning microscopy (CLSM), were used to study the permeationpromoting mechanism of the CEO on the skin. Furthermore, the permeation-promoting effects of the CEO on both hydrophobic and hydrophilic ingredients were tested via in vitro skin penetration experiments and in vivo microdialysis experiments. RESULTS: The results indicated the ability of the CEO to alter the structure of the SC, leading to enhanced transdermal permeation of hydrophobic and hydrophilic ingredients. The 1.5% CEO group demonstrated the best permeation-promoting effect compared to the other CEO groups and blank groups (P<0.05). Furthermore, the CEO displayed an expedited permeability-promoting effect on hydrophobic ingredients compared to hydrophilic ingredients. CONCLUSION: It is concluded that the prepared CEO can promote the transdermal permeation of hydrophobic and hydrophilic ingredients. This study will provide a reference for the application of the prepared CEO in the development of cosmeceuticals with natural efficacy.
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Cosmecêuticos , Óleos Voláteis , Absorção Cutânea , Óleos Voláteis/farmacologia , Óleos Voláteis/metabolismo , Administração Cutânea , Pele/metabolismoRESUMO
Chemoimmunotherapy is a promising strategy in tumor treatments. In this study, immunogenic dead cells were engineered by the sequential treatment of live tumor cells with ultraviolet (UV) irradiation and cryo-shocking. The dead cells could serve as a lung-targeting vehicle and tumor vaccine after differential loading of the chemo-drug 10-hydroxycamptothecin (HCPT) and immune adjuvant Quillaja saponin-21 (QS-21) via physical absorption and chemical conjugation, respectively. After intravenous administration, the dead cells could be trapped in pulmonary capillaries and could fast release HCPT to enhance the drug accumulation in local tissues. Further, the immunogenic dead cells elicited antitumor immune responses together with the conjugated adjuvant QS-21 to achieve the elimination and long-term surveillance of tumor cells. In a lung tumor-bearing mice model, this drug-delivery system achieved synergistic antitumor efficacy and prolonged the survival of mice.
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Antineoplásicos , Vacinas Anticâncer , Camundongos , Animais , Linhagem Celular Tumoral , Pulmão , VacinaçãoRESUMO
INTRODUCTION: Intravenous nanocrystals (INCs) have shown intrinsic advantages in antitumor applications, particularly their properties of high drug loading, low toxicity, and controllable size. Therefore, it has a very bright application prospect as a drug delivery system. AREAS COVERED: The ideal formulation design principles, fabrication, solidification, in vivo fate of INCs, the applications in drug delivery system (DDS) and the novel applications are covered in this review. EXPERT OPINION: It is vital to select a suitable formulation and fabrication method to produce a stable and sterile INCs. Besides, the type of stabilizers and physical characteristics can also influence the in vivo fate of INCs, which is worthy of further studying. Based on wide researches about applications of INCs in cancer, biomimetic INCs are concerned increasingly for its favorable compatibility. The output of these studies suggested that INCs-based drug delivery could be a novel strategy for addressing the delivery of the drug that faces solubility, bioavailability, and toxicity problems.
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Nanopartículas , Neoplasias , Humanos , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/química , Disponibilidade Biológica , Nanopartículas/química , Solubilidade , Neoplasias/tratamento farmacológicoRESUMO
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.
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Enterocyte uptake with high binding efficiency and minor endogenous interference remains a challenge in oral nanocarrier delivery. Enterocyte membrane-biomimetic lipids may universally cooperate with endogenous phosphatidyl choline via a biorthogonal group. In this study, we developed a sophorolipid-associated membrane-biomimetic choline phosphate-poly(lactic-co-glycolic) acid hybrid nanoparticle (SDPN). Aided by physical stability in the gastrointestinal tract and rapid mucus diffusion provided by association with sophorolipid, these nanoparticles show improved endocytosis, driven by dipalmitoyl choline phosphate-phosphatidyl choline interaction as well as its optimized membrane fluidity and rigidity. Luteolin- and silibinin-co-loaded with SDPN alleviated breast cancer metastasis in 4T1 tumor-bearing mice by regulating the conversion of tumor-associated M2 macrophages into the M1 phenotype and reducing the proportion of the M2-phenotype through co-action on STAT3 and HIF-1α. In addition, SDPN reduces angiogenesis and regulates the matrix barrier in the tumor microenvironment. In conclusion, this membrane-biomimetic strategy is promising for improving the enterocyte uptake of oral SDPN and shows potential to alleviate breast cancer metastasis.
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Nanopartículas , Neoplasias , Camundongos , Animais , Macrófagos Associados a Tumor , Biomimética , Fosforilcolina , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
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.
Assuntos
Fitosteróis , Absorção Cutânea , Camundongos , Animais , Administração Cutânea , Fitosteróis/metabolismo , Fitosteróis/farmacologia , Pele/metabolismo , Lipossomos , Esfingolipídeos/metabolismo , Esfingolipídeos/farmacologiaRESUMO
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.
Assuntos
Lesões Pré-Cancerosas , Fator A de Crescimento do Endotélio Vascular , Ratos , Feminino , Animais , Ratos Sprague-Dawley , Proteína X Associada a bcl-2 , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Caspase 3 , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Fator 2 de Crescimento de Fibroblastos , Proteínas Proto-Oncogênicas c-bcl-2 , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Hiperplasia , Receptores de Quimiocinas , RNA MensageiroRESUMO
This study combined the herbal pair Platycodonis Radix-Curcumae Rhizoma(PR-CR) possessing an inhibitory effect on tumor cell proliferation and metastasis with the active component of traditional Chinese medicine(TCM) silibinin-loaded nanoparticles(NPs) with a regulatory effect on tumor microenvironment based on the joint effect on tumor cells and tumor microenvironment to inhi-bit cell metastasis. The effects of PR-CR on the cellular uptake of NPs and in vitro inhibition against breast cancer proliferation and metastasis were investigated to provide an experimental basis for improving nanoparticle absorption and enhancing therapeutic effects. Silibinin-loaded lipid-polymer nanoparticles(LPNs) were prepared by the nanoprecipitation method and characterized by transmission electron microscopy. The NPs were spherical or quasi-spherical in shape with obvious core-shell structure. The mean particle size was 107.4 nm, Zeta potential was-27.53 mV. The cellular uptake assay was performed by in vitro Caco-2/E12 coculture cell model and confocal laser scanning microscopy(CLSM), and the results indicated that PR-CR could promote the uptake of NPs. Further, in situ intestinal absorption assay by the CLSM vertical scanning approach showed that PR-CR could promote the absorption of NPs in the enterocytes of mice. The inhibitory effect of NPs on the proliferation and migration of 4T1 cells was analyzed using 4T1 breast cancer cells and co-cultured 4T1/WML2 cells, respectively. The results of the CCK8 assay showed that PR-CR-containing NPs could enhance the inhibition against the proliferation of 4T1 breast cancer cells. The wound healing assay indicated that PR-CR-containing NPs enhanced the inhibition against the migration of 4T1 breast cancer cells. This study enriches the research on oral absorption of TCM NPs and also provides a new idea for utilizing the advantages of TCM to inhibit breast cancer metastasis.