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1.
J Mater Chem B ; 12(6): 1604-1616, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38269414

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory disease that affects the gastrointestinal tract and is characterized by immune dysregulation. Oral administration of nanoformulations containing immunomodulators is a desirable approach to treating UC. However, low drug-loading (<10%, typically), premature drug release, and systemic absorption of these nanoformulations continue to be significant challenges restricting clinical applications. Herein, we developed colon-targeted piperine-glycyrrhizic acid nanocrystals (ES100-PIP/GA NCs) to treat UC through the regulation of macrophages. The ES100-PIP/GA NCs exhibited ultra-high drug loading and colon-specific drug release. In vitro studies demonstrated that the ES100-PIP/GA NCs could effectively be internalized by lipopolysaccharide (LPS)-induced RAW 264.7 and Caco-2 cells. More importantly, the ES100-PIP/GA NCs could downregulate pro-inflammatory factors (IL-1ß, IL-17A), upregulate anti-inflammatory factors (TGF-ß1), and repair the intestinal mucosal barrier. In a murine model of acute colitis induced by dextran sodium sulfate (DSS), ES100-PIP/GA NCs could protect PIP and GA from gastric acid destruction, reach the colon, and significantly inhibit colitis. Surprisingly, ES100-PIP/GA NCs enhance M2 macrophages by increasing the mammalian target of rapamycin (mTOR), and inhibit M1 macrophages by reducing hypoxia-inducible factor-1α (HIF-1α). Overall, this study shows that ES100-PIP/GA NCs have synergistic immunotherapy capabilities with macrophage regulation, which offers a promising blueprint for the oral delivery of multicomponent drugs in UC therapy.


Assuntos
Alcaloides , Benzodioxóis , Colite Ulcerativa , Colite , Nanopartículas , Piperidinas , Alcamidas Poli-Insaturadas , Humanos , Animais , Camundongos , Colite Ulcerativa/tratamento farmacológico , Ácido Glicirrízico/efeitos adversos , Células CACO-2 , Colite/tratamento farmacológico , Macrófagos , Mamíferos
2.
Acta Biomater ; 167: 387-400, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37276955

RESUMO

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is the main block for the penetration of chemotherapy. In the tumor microenvironment, a dense matrix composed of fibrin is formed on the exterior, while the interior is featured by high reduction, hypoxia and low pH. How to match the special microenvironment to on-demand drug release is the key to improve chemotherapeutic efficacy. Herein, a microenvironment-responsive micellar system is developed to deepen tumoral penetration. Briefly, the conjugation of a fibrin-targeting peptide to PEG-poly amino acid has been utilized to achieve accumulation of micelles in the tumor stroma. By modification of micelles with hypoxia-reducible nitroimidazole which becomes protonated under acidic conditions, their surface charge is more positive, facilitating deeper penetration into tumors. Paclitaxel was loaded onto the micelles via a disulfide bond to enable glutathione (GSH)-responsive release. Therefore, the immunosuppressive microenvironment is relived through the alleviation of hypoxia and depletion of GSH. Hopefully, this work could establish paradigms by designing sophisticated drug-delivery systems to tactfully employ and retroact the tamed tumoral microenvironment to improve the therapeutic efficacy based on understanding the multiple hallmarks and learning the mutual regulation. STATEMENT OF SIGNIFICANCE: Tumor microenvironment(TME) is an unique pathological feature of pancreatic cancer and an inherent barrier to chemotherapy. Numerous studies regard TME as the targets for drug delivery. In this work, we propose a hypoxia-responsive nanomicellar drug delivery system that aiming hypoxia TME of pancreatic cancer. The nanodrug delivery system could respond to the hypoxic microenvironment and enhance the penetration of the inner tumor at the same time preserving the outer tumor stroma, thus achieving targeted treatment of PDAC by preserving the integrity of the outer stroma. Simultaneously, the responsive group can reverse the degree of hypoxia in TME by disrupting the redox balance in the tumor region, thus achieving precise treatment of PDAC by matching the pathological characteristics of TME. We believe our article would provide new design ideas for the future treatments for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Micelas , Microambiente Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Hipóxia , Glutationa , Terapia de Imunossupressão , Linhagem Celular Tumoral , Neoplasias Pancreáticas
3.
Int J Biol Macromol ; 242(Pt 2): 124819, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37178894

RESUMO

Due to its poor prognosis and propensity for metastasizing, colon cancer, a frequent cancer of the gastrointestinal system, has a high morbidity and mortality rate. However, the harsh physiological conditions of the gastrointestinal tract can cause the anti-cancer medicine bufadienolides (BU) to lose some of its structure, impairing its ability to fight cancer. In this study, pH-responsive bufadienolides nanocrystals decorated by chitosan quaternary ammonium salt (HE BU NCs) were successfully constructed by a solvent evaporation method to improve the bioavailability, release characteristics and intestinal transport ability of BU. In vitro, studies have shown that HE BU NCs could improve BU internalization, significantly induce apoptosis, decrease mitochondrial membrane potential, and increase ROS levels in tumour cells. In vivo, experiments showed that HE BU NCs effectively targeted intestinal sites, increased their retention time, and exerted antitumor activity through Caspase-3 and Bax/Bcl-2 ratio pathways. In conclusion, pH-responsive bufadienolides nanocrystals decorated by chitosan quaternary ammonium salt could protect bufadienolides from the destruction of an acidic environment, achieve synergistic release in the intestinal site, improve oral bioavailability, and ultimately exert anti-colon cancer effects, which is a promising strategy for the treatment of colon cancer.


Assuntos
Compostos de Amônio , Bufanolídeos , Quitosana , Neoplasias do Colo , Nanopartículas , Humanos , Quitosana/química , Bufanolídeos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Nanopartículas/química , Concentração de Íons de Hidrogênio
4.
Int J Pharm ; 616: 121522, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35093460

RESUMO

Using nanocrystals (NCs) technology may be a promising drug delivery strategy for oral administration of multicomponent anticancer drugs. However, the intestinal epithelium and the mucus layer on the intestine extremely limited drug transport and absorption by orally. In this study, we selected multicomponent inartificial compound Bufadienolides (BU) with broad spectrum antitumor activity as the model drug to prepare BU NCs with different stabilizers by wet grinding, and explored the efficiency of penetrating through the mucus layer and transporting intestinal epithelial cells in vitro and ex vivo. Results revealed that BU NCs can dramatically improve dissolution behavior synergistically and the efficiency of mucus permeation. Besides, we found that BU NCs with different stabilizers enhanced cellular uptake, which was mainly attributed to increasing or changing the endocytosis pathway and plasma membrane/Endoplasmic reticulum (ER) pathway involved in the transmembrane transport of NCs. Furthermore, BU NCs could definitely improve intestinal absorption efficiency and change the absorption site of BU ex vivo. This multi-angle exploration will provide reference for the development of BU oral delivery formulations.


Assuntos
Bufanolídeos , Nanopartículas , Administração Oral , Absorção Intestinal , Muco/metabolismo , Nanopartículas/química
6.
AAPS PharmSciTech ; 22(7): 239, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34590204

RESUMO

The purpose of this study was to enhance the antitumor effect of piperine by constructing the nanoparticles modified with transferrin (Tf-PIP-NPs) and evaluating their efficacy in vitro and in vivo. The Tf-PIP-NPs were prepared by the solvent evaporation method, and their properties were characterized. The effects of Tf-PIP-NPs on cytotoxicity, cell uptake, apoptosis, and mitochondrial membrane potential were evaluated in HepG2 cells, MDA-MB-231 cells, and 4T1 cells. In a 4T1 tumor-bearing mouse model, the antitumor efficacy of Tf-PIP-NPs was assessed in terms of tumor volumes, changes in body weight, HE staining, and immunohistochemical analysis. With a mean particle size of 112.2 ± 1.27 nm, the zeta potential of (- 28.0 ± 1.6 mV) Tf-PIP-NPs were rapidly internalized by tumor cells after 1 h through the transferrin receptor (TfR)-mediated endocytosis pathway, significantly inducing cellular apoptosis and mitochondrial membrane potential loss. Although Tf-PIP-NPs had no significant difference with PIP-NPs in tumor volume inhibition due to the presence of tumor microenvironment, it could significantly upregulate the expression of related pro-apoptotic proteins and induce tumor necrosis. We used the self-assembly properties of glycyrrhizic acid (GL) and polymer-PLGA to encapsulate piperine and modified with the transferrin, which provided a promising approach to improve the antitumor efficacy for anticarcinogen.


Assuntos
Nanopartículas , Transferrina , Alcaloides , Animais , Benzodioxóis , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Ácido Glicirrízico , Camundongos , Tamanho da Partícula , Piperidinas , Alcamidas Poli-Insaturadas
7.
Biol Pharm Bull ; 44(10): 1473-1483, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34305072

RESUMO

The "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system is a new type of pharmaceutic preparation that can cause cancer cell oncosis. In the present study, we used different experimental methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cycle assay, reactive oxygen species (ROS) assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI), Giemsa stainings, transmission electron microscopy, immunofluorescence staining and Western blotting to study the mechanism of expansion death by using Hydroxychloroquine (HCQ) as a positive control and 5-Fluorouracil (5-Fu) as reference. The results showed that DMF exhibited a better anti-tumor effect than 5-Fu in the process of cell death, and the pharmacological mechanism of 5-Fu was changed by its preparation DMF. The mechanism of cancer cell death induced by DMF was similar to that of HCQ. But DMF intervention did not cause a large amount of accumulation of mitochondrial reactive oxygen species, and the location of lysosomotropic LysoTracker Red (LTR) staining induced by DMF was closer to the nucleus or nuclear membrane. Lysosomal membrane permeability (LMP) and its subsequent the explosive death of cancer cells may be mainly related to the direct action of DMF with different organelles.


Assuntos
Antineoplásicos/administração & dosagem , Morte Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Fluoruracila/administração & dosagem , Lisossomos/metabolismo , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Corantes Azur , Western Blotting , Linhagem Celular Tumoral , Dextranos , Imunofluorescência , Fluoruracila/uso terapêutico , Humanos , Metástase Linfática/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro , Microscopia Eletrônica de Transmissão , Permeabilidade , Neoplasias Gástricas/tratamento farmacológico
8.
AAPS PharmSciTech ; 22(5): 179, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34128132

RESUMO

With the limitation of solubility and dissolution rate of insoluble drugs, following oral administration, they would rifely prove poor and volatile bioavailability, which may fail to realize its therapeutic value. The drug nanocrystals are perceived as effective tactic for oral administration of insoluble drugs attributes to possess many prominent properties such as elevating dissolution rate and saturation solubility, high drug loading capacity, and improving oral bioavailability. Based on these advantages, the application of nanocrystals in oral drug delivery has acquired significant achievement, and so far more than 20 products of drug nanocrystals have been confirmed in the market. However, the oral absorption of drug nanocrystals is still facing huge challenges due to the limitation of many factors. Intrinsic properties of the drugs and complex physiological environment of the intestinal tract are the two most important factors affecting the oral bioavailability of drugs. In addition, the research on the multi-aspect mechanisms of nanocrystals promoting gastrointestinal absorption and bioavailability has been gradually deepened. In this review, we summarized recent advances of the nanocrystals delivered orally, and provided an overview to the research progress for crossing the intestinal tract transport mechanisms of the nanocrystals by some new research techniques. Meanwhile, the factors relevant to the transport of drug nanocrystals were also elaborated in detail. Graphical Abstract.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Absorção Intestinal/efeitos dos fármacos , Nanopartículas/administração & dosagem , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Absorção Intestinal/fisiologia , Nanopartículas/química , Nanopartículas/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Solubilidade
9.
Drug Dev Ind Pharm ; 47(10): 1587-1597, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35037805

RESUMO

The poor aqueous solubility of 1,4-dihydropyridine drugs needs to be solved urgently to improve bioavailability. Nanotechnology can improve drug solubility and dissolution by reducing particle size, but usually, a specific polymer or surfactant is required for stabilization. In this study, Poloxamer-407(P-407) was screened as the optimal stabilize through energy simulation, molecular docking, and particle size. the morphological study, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, Raman, in vitro dissolution test, and molecular simulation of interactions were utilized to explore the formation mechanisms of four 1,4-dihydropyridine drugs/P-407 nanosuspensions. The result shows that the optimized nanosuspensions had the particle size in the nano-size range and maintained the original crystal state. The in vitro dissolution rate of the nanosuspension was 3-4 times higher than the corresponding API and could reduce the restriction of drug dissolution in different pH environments. Raman spectroscopy, FTIR, and molecular docking simulations provided strong supporting evidence for the formation mechanism of 1,4-dihydropyridine drugs/P-407 nanosuspensions at the molecular level, which confirmed that the stable intermolecular hydrogen bond adsorption and hydrophobic interaction were formed between the drug and P-407. This research will provide practical concepts and technologies, which are helpful to develop nanosuspensions for the same class of drugs.


Assuntos
Nanopartículas , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Di-Hidropiridinas , Desenho de Fármacos , Simulação de Acoplamento Molecular , Nanopartículas/química , Tamanho da Partícula , Solubilidade , Suspensões , Difração de Raios X
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