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Stem cell-based therapies offer promising avenues for treating inflammatory diseases owing to their immunomodulatory properties. However, challenges persist regarding their survival and efficacy in inflamed tissues. Our study introduces a novel approach by engineering adipose-derived stem cells (ADSCs) to enhance their viability in inflammatory environments and boost the secretion of paracrine factors for treating inflammatory bowel disease (IBD). An arginine-glycine-aspartate peptide-poly (ethylene glycol)-chlorin e6 conjugate (RPC) was synthesized and coupled with ADSCs, resulting in RPC-labeled ADSCs (ARPC). This conjugation strategy employed RGD-integrin interaction to shield stem cells and allowed visualization and tracking using chlorin e6. The engineered ARPC demonstrated enhanced viability and secretion of paracrine factors upon light irradiation, regulating the inflammatory microenvironment. RNA-sequencing analysis unveiled pathways favoring angiogenesis, DNA repair, and exosome secretion in ARPC(+) while downregulating inflammatory pathways. In in vivo models of acute and chronic IBD, ARPC(+) treatment led to reduced inflammation, preserved colon structure, and increased populations of regulatory T cells, highlighting its therapeutic potential. ARPC(+) selectively homed to inflammatory sites, demonstrating its targeted effect. Overall, ARPC(+) exhibits promise as an effective and safe therapeutic strategy for managing inflammatory diseases like IBD by modulating immune responses and creating an anti-inflammatory microenvironment.
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Herein, we present human adipose-derived stem cells (ADSCs) inserted with the receptor-interacting protein kinase-3 (RIP3) gene (RP@ADSCs), which induces cell necroptosis, for tumor immunotherapy. Necroptosis has characteristics of both apoptosis, such as programmed cell death, and necrosis, such as swelling and plasma membrane rupture, during which damage-related molecular patterns are released, triggering an immune response. Therefore, necroptosis has the potential to be used as an effective anticancer immunotherapy. RP@ADSCs were programmed to necroptosis after a particular time after being injected in vivo, and various pro-inflammatory cytokines secreted during the stem cell death process stimulated the immune system, showing local and sustained anticancer effects. It was confirmed that RIP3 protein expression increased in ADSCs after RP transfection. RP@ADSCs continued to induce ADSCs death for 7 days, and various pro-inflammatory cytokines were secreted through ADSCs death. The efficacy of RP@ADSCs-mediated immunotherapy was evaluated in mouse models bearing GL-26 (glioblastoma) and K1735 (melanoma), and it was found that RP resulted in an increase in the population of long-term cytotoxic T cells and a decrease in the population of regulatory T cells. This shows that RP@ADSCs have potential and applicability as an excellent anticancer immunotherapy agent in clinical practice.
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Imunoterapia , Necroptose , Humanos , Animais , Camundongos , Necroptose/genética , Imunoterapia/métodos , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Células-Tronco/metabolismo , Células-Tronco/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Linhagem Celular TumoralRESUMO
Herein, we describe the 3'-sialyllactose-polyethyleneimine-chlorine e6 conjugate (3PC), meticulously engineered to effectively target Helicobacter bacteria (H. pylori) within the gastric environment. The composition of 3PC comprises polyethyleneimine, a cationic polymer, 3'-sialyllactose, which exhibits a specific binding affinity for H. pylori surface proteins, and a photosensitizer capable of generating oxygen radicals in response to specific wavelengths. The distinctive feature of 3PC lies in its capacity to enhance interaction with the anionic mucus layer facilitated by electrostatic forces. This interaction results in prolonged residence within the intestinal environment. The extended vacation in the intestinal milieu overcomes inherent limitations that have historically impeded conventional antibiotics from efficiently reaching and targeting H. pylori. 3PC can be harnessed as a potent tool for antibacterial photodynamic therapy, and its versatility extends to addressing the challenges posed by various antibiotic-resistant strains. The exceptional efficacy of 3PC in enhancing intestinal residence time and eradicating H. pylori has been robustly substantiated in animal models, particularly in mice. In summary, 3PC is a formidable agent capable of eradicating H. pylori, irrespective of its antibiotic resistance status, by efficiently penetrating and selectively targeting the mucus layer within the gastric environment.
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Antibacterianos , Infecções por Helicobacter , Helicobacter pylori , Mucinas , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Mucinas/metabolismo , Mucinas/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Mutação , Camundongos , Fotoquimioterapia/métodos , Polímeros/química , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Adesivos/química , Adesivos/farmacologiaRESUMO
Achieving effective mRNA expression in vivo requires careful selection of an appropriate delivery vehicle and route of administration. Among the various routes of administration, intranasal administration has received considerable attention due to its ability to induce potent immune responses. In this context, we designed a specialized cationic polymer tailored for delivery of mRNA into the nasal cavity. These polymers are designed with varying degrees of substitution in different amine groups to allow for identification of the most suitable amine moiety for effective mRNA delivery. We also incorporated a photosensitizer within the polymer structure that can trigger the generation of reactive oxygen species when exposed to light. The synthesized cationic polymer is complexed with anionic mRNA to form a polyplex. Illuminating these polyplexes with laser light enhances their escape from intracellular endosomes, stimulating mRNA translocation into the cytoplasm, followed by increased mRNA expression at the cellular level. Through intranasal administration to C57BL/6 mice, it was confirmed that these photoactive polyplexes effectively induce mRNA expression and activate immune responses in vivo using photochemical effects. This innovative design of a photoactivated cationic polymer presents a promising and reliable strategy to achieve efficient intranasal mRNA delivery. This approach has potential applications in the development of mRNA-based vaccines for both prophylactic and therapeutic purposes.
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Herein, we present an approach for manipulating paracrine factors and signaling pathways in adipose-derived stem cells (ADSCs) to achieve highly effective tumor immunotherapy. Our method involves precise control of reactive oxygen species concentration using the CD90-maleimide-pluronic F68-chlorin e6 conjugate (CPFC) to create ACPFC, which is then attached to ADSCs through the CD90 receptor-specific interaction. By regulating the irradiated laser power, ACPFC promotes signaling pathways such as cascade-3, VEGFR2, α2ß1, C3AR1, CR1-4, and C5AR1, leading to the secretion of various inflammatory cytokines such as IFN-γ, TGF-ß, and IL-6, while inhibiting AKT, ERK, NFkB, PAR1, and PAR3/4 signaling pathways to reduce the secretion of cell growth factors like TIMP-1, TIMP-2, VEGF, Ang-2, FGF-2, and HGF. When ACPFC is injected intravenously into a tumor animal model, it autonomously targets and accumulates at the tumor site, and upon laser irradiation, it generates various anti-inflammatory factors while reducing angiogenesis growth factors. The resulting antitumor response recruits CD3+CD8+ cytotoxic T cells and CD3+CD4+ helper T cells into the tumor and spleen, leading to highly effective melanoma and pancreatic tumor treatment in mice. Our technology for regulating stem cell paracrine factors holds significant promise for the treatment of various diseases.
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Melanoma , Fator de Células-Tronco , Camundongos , Animais , Fator de Células-Tronco/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Imunoterapia , Melanoma/metabolismo , Células-Tronco/metabolismoRESUMO
Here, a novel approach is presented to improve the efficacy of antibody-drug conjugates (ADC) by integrating antibody-mediated immunotherapy and photodynamic therapy (PDT) in a combination therapy system utilizing an antibody-photosensitizer conjugate (APC) platform based on a poloxamer polymer linker. To specifically target Kirsten rat sarcoma 2 viral oncogene homolog (KRAS)-mutated cancer cells, an antibody antiepidermal growth factor receptor (EGFR), cetuximab, with a poloxamer linker coupled with the photosensitizer chlorin e6 through click chemistry (cetuximab-maleimide-poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)-chlorine e6 conjugate, CMPXC) is synthesized. CMPXC is cytotoxic upon laser treatment, achieving a 90% cell death by suppressing KRAS downstream signaling pathways associated with ERK and AKT proteins, confirmed using RNA sequencing analysis. In KRAS-mutated colorectal cancer mouse models, CMPXC significantly enhances antitumor efficacy compared with cetuximab treatment alone, resulting in an 86% reduction in tumor growth. Furthermore, CMPXC treatment leads to a 2.24- and 1.75-fold increase in dendritic and priming cytotoxic T cells, respectively, highlighting the immune-activating potential of this approach. The findings suggest that the APC platform addresses the challenges associated with ADC development and EGFR-targeted therapy, including the synergistic advantages of antibody-mediated immunotherapy and PDT.
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Antineoplásicos , Neoplasias Colorretais , Animais , Camundongos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/uso terapêutico , Poloxâmero , Neoplasias Colorretais/tratamento farmacológico , Antineoplásicos/uso terapêutico , Mutação , Receptores ErbB/genética , Receptores ErbB/metabolismo , Linhagem Celular TumoralRESUMO
Herein, we introduce a novel approach involving the utilization of a human serum albumin-coated zeolite imidazolate framework-8 containing a photosensitizer (HPZ) that exhibits targeted recognition of the tumor microenvironment, enabling the rapid elevation of zinc ion concentrations while facilitating the controlled release of an encapsulated photosensitizer (PS). At a physiological pH of 7.4, HPZ demonstrates a size of approximately 170 nm, significantly decreasing to less than 10 nm under pH 6.5 acidic conditions. Acid-induced decomposition of HPZ triggers a rapid increase in zinc ion concentration, eliciting potent cytotoxic effects against colorectal, breast, and pancreatic cancers. Additionally, upon laser irradiation, the encapsulated PS within HPZ initiates the generation of reactive oxygen species, synergistically augmenting the cytotoxicity induced by zinc ions. Intravenous administration of HPZ in a CT26 tumor-bearing mouse model resulted in a notable expansion of CD3+CD4+ helper T cells and CD3+CD8+ cytotoxic T cells, accompanied by a reduction in the CD4+CD25+Foxp3+ regulatory T-cell population. These changes led to significant inhibition of tumor growth, highlighting the efficacy of HPZ in this experimental model. Importantly, HPZ exhibits favorable safety characteristics, displaying no toxicity toward vital organs and inducing no weight loss. Thus, HPZ holds immense promise as a standalone treatment or in combination with diverse anticancer immunotherapies, underscoring its potential in the field of anticancer immunotherapy.
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Nanopartículas , Neoplasias , Humanos , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Zinco , Imunoterapia , Íons , Concentração de Íons de HidrogênioRESUMO
Herein, we synthesized a lipid-mimicking organic material (PCD_FA) that can surpass the efficacy of lipid-based nanoparticles and demonstrated its potential as a delivery vehicle for various hydrophilic drugs. PCD_FA is a conjugate of pH-sensitive carbon dots (PCDs) and fatty acids (FAs) and has potential applications in several fields owing to various combinations of carbon dots (CDs) and FAs. Similar to phospholipids, PCD-FAs have hydrophilic heads and hydrophobic tails that allow them to self-form nanoparticles (Coposomes) in the aqueous phase. Coposomes can easily combine various hydrophilic head and hydrophobic tail combinations, and several drugs can be encapsulated, or drug release patterns can be controlled according to each property. We analyzed the differences in size, drug loading efficiency, and drug release patterns of Coposomes depending on the type of FAs and characteristics of the encapsulated drugs. Additionally, cell entry and intracellular drug release mechanisms of the Coposomes were identified. The applicability of Coposomes as drug delivery carriers for tumor treatment has been demonstrated in comparison with that of liposomes formulation in tumor-bearing mouse models. Consequently, this study presents possibilities for the synthesis and application of various amphiphilic lipid-mimicking organic materials via the combination of CDs and FAs with various functions.
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Nanopartículas , Neoplasias , Camundongos , Animais , Carbono/química , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , Nanopartículas/química , Lipídeos , Concentração de Íons de HidrogênioRESUMO
Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs) that i) have extremely high or low solubility in intestinal fluids, ii) are large in size, iii) are subject to digestive and/or metabolic enzymes present in the gastrointestinal tract (GIT), brush border, and liver, and iv) are P-glycoprotein substrates. Over the past decades, efforts to increase the oral bioavailability of APIs have led to the development of nanoparticles (NPs) with non-specific uptake pathways (M cells, mucosal, and tight junctions) and target-specific uptake pathways (FcRn, vitamin B12, and bile acids). However, voluminous findings from preclinical models of different species rarely meet practical standards when translated to humans, and API concentrations in NPs are not within the adequate therapeutic window. Various NP oral delivery approaches studied so far show varying bioavailability impacted by a range of factors, such as species, GIT physiology, age, and disease state. This may cause difficulty in obtaining similar oral delivery efficacy when research results in animal models are translated into humans. This review describes the selection of parameters to be considered for translational potential when designing and developing oral NPs.
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Nanopartículas , Animais , Humanos , Preparações Farmacêuticas , Administração Oral , Disponibilidade Biológica , Transporte Biológico , Absorção Intestinal , Portadores de FármacosRESUMO
Here, we describe a multidrug-resistant nanocracker (MDRC) that can treat multi-drug resistant (MDR) cancer by recognizing the acidic microenvironment and inhibiting two mechanisms of MDR such as P-glycoprotein (P-gp) and vacuolar-type ATPase (V-ATPase). MDRC is a liposome formulation co-loading pantoprazole (PZ) and paclitaxel (PTX). PZ acts as a chemosensitizer that enhances the MDR cancer treatment effect of PTX by disrupting the pH gradient and inhibiting P-gp. MDRC-encapsulated PZ and PTX have different release rates, with PZ released within 12 h and PTX sustained release for 48 h in the plasma. MDRC could increase cell uptake by inhibiting the P-gp overexpressed MCF-7/mdr cells and UV-2237M cells, which are human breast MDR cancer cells and murine fibrosarcoma cells, respectively. MDRC can also increase the cytotoxic efficacy of PTX by increasing intracellular pH. MDRC has a 10.5-fold reduced IC50 value in the P-gp overexpressed human breast adenocarcinoma and a 6.3- to 9.5-fold reduced IC50 value in the P-gp non-expressed human breast adenocarcinoma compared to the mixture of PZ and PTX, respectively. Intravenous injection of MDRC did not cause weight loss, liver dysfunction, or major organ toxicity. MDRC exhibited 80% complete remission of murine fibrosarcoma. The excellent therapeutic effect of MDRC on MDR tumors was accompanied by an increase in dendritic cell maturation and cytotoxic T cells. In other words, MDRC has the potential to terminate MDR therapy through the complete remission of MDR tumors.
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Adenocarcinoma , Fibrossarcoma , Camundongos , Humanos , Animais , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Microambiente Tumoral , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Paclitaxel , Subfamília B de Transportador de Cassetes de Ligação de ATP , Pantoprazol/farmacologia , Adenosina Trifosfatases/farmacologia , Linhagem Celular TumoralRESUMO
Here, we describe an intracellular pH-regulating nanoparticle (IPRN), coencapsulated with chemosensitizers and anticancer agents for effective and safe cancer treatment. IPRN contains a tubulysin derivative (TUB), a hydrophobic anticancer drug, and pantoprazole (PTZ), a hydrophilic proton-pump inhibitor. IPRN with a size of 62 nm has an anionic surface charge and is stable for at least two weeks under storage conditions, though PTZ and TUB encapsulated in IPRN showed different drug release patterns. PTZ was released before TUB, controlling the cancer's intracellular pH, maintaining a pH at which TUB can work well. The encapsulated PTZ increased the pH of endolysosomes and inhibited ion trapping, with TUB ionization, thereby exhibiting increased cytotoxicity compared with free TUB observed in various cancer cell lines, such as human liver adenocarcinoma, human glioblastoma, and human pancreatic carcinoma. IPRN exhibited a 1.9-fold improved tumor growth inhibitory effect in a human liver adenocarcinoma-bearing mouse model, while minimizing the hepatotoxicity of free TUB. Thus, nanomedicines that contain both a chemosensitizer and an anticancer agent, such as IPRN, are expected to be next-generation anticancer agents that reduce the side effects of anticancer drugs and increase the therapeutic effect.
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Adenocarcinoma , Antineoplásicos , Neoplasias Hepáticas , Nanopartículas , Camundongos , Animais , Humanos , Nanopartículas/química , Concentração de Íons de Hidrogênio , Antineoplásicos/farmacologia , Portadores de Fármacos , Linhagem Celular TumoralRESUMO
Here, antigen and adjuvant encapsulated dendritic cell-targeted nanoparticles for immune activation in the small intestinal lymphatic system to inhibit melanoma development are described. This strategy is demonstrated using chondroitin sulfate-coated nanoparticles (OPGMN) grafted with glycocholic acid and mannose for cationic liposomes encapsulated with ovalbumin as an antigen and polyinosine-polycytidylic acid as a cancer-specific adjuvant. OPGMN is absorbed in the gastrointestinal tract and delivered to the lymph nodes when orally administered. Oral delivery of OPGMN induces increased dendritic cell maturation compared to the intradermal route in the lymph node and induces T helper type 1 and type 2 responses, such as immunoglobulin G1 and G2c, interferon-gamma, and interleukin-2, in the blood. Repeated oral administration of OPGMN increases the population of CD3+ CD8+ T cells, CD44high CD62Llow memory T cells, and CD11b+ CD27+ natural killer cells in the blood. OPGMN completely prevents melanoma development in the B16F10-bearing C57BL/6 mouse model by reducing the population of CD4+ CD25+ Foxp3+ regulatory T cells in the blood. This strategy is expected to prevent the recurrence of tumors after various cancer treatments.
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Melanoma , Nanopartículas , Camundongos , Animais , Ovalbumina/metabolismo , Poli I-C/metabolismo , Linfócitos T CD8-Positivos , Camundongos Endogâmicos C57BL , Células Dendríticas , Antígenos/metabolismo , Adjuvantes Imunológicos , Linfonodos/metabolismo , Melanoma/metabolismoRESUMO
BACKGROUND: Layered double hydroxides (LDHs) are one type of 2-dimensional material with unique structure and strongly positive surface charge. Particularly, LDHs can be exfoliated by mono-layered double hydroxides (MLHs) as a single layer, showing an increased surface area. Therefore, there is a large focus on LDHs for drug delivery applications. Furthermore, most photosensitizers are hydrophobic that they cannot be soluble in aqueous solvents. Herein, we designed a simple way to solubilize hydrophobic photosensitizers by MLH with electrostatic interactions for anticancer photodynamic therapy (PDT), which has tremendous therapeutic advantages. The photosensitizer solubilized via loading on the MLH exhibited fluorescence and singlet oxygen-generation activities in aqueous solvent without chemical modification, resulting in photo-mediated anticancer treatment. METHODS: Negatively charged hydrophobic photosensitizers, chlorin e6 (Ce6) were solubilized by loading on the MLHs through the electrostatic interaction between positively charged MLHs. MLH/Ce6 complexes evaluated for physico-chemical characterization, pH-sensitive release property, in vitro photocytotoxicity, and in vivo tumor ablation. RESULTS: The photosensitizer solubilized via MLH exhibited fluorescence intensity and singlet-oxygen generation activities in aqueous solvent without chemical modification, resulting photocytotoxicity in cancer cells. The encapsulation efficiency of Ce6 increased to 21.2% through MLH compared to 0.6% when using LDH. In tumor-bearing mice, PDT with solubilized MLH/Ce6 indicated a tumor-suppressing effect approximately 3.4-fold greater than that obtained when Ce6 was injected alone. CONCLUSIONS: This study provided the solubilized Ce6 by the MLH in a simple way without chemical modification. We demonstrated that MLH/Ce6 complexes would have a great potential for anticancer PDT.
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BACKGROUND: Computed tomography (CT) imaging has been widely used for the diagnosis and surveillance of diseases. Although CT is attracting attention due to its reasonable price, short scan time, and excellent diagnostic ability, there are severe drawbacks of conventional CT contrast agents, such as low sensitivity, serious toxicity, and complicated synthesis process. Herein, we describe iodine-doped carbon dots (IDC) for enhancing the abilities of CT contrast agents. METHOD: IDC was synthesized by one-pot hydrothermal synthesis for 4 h at 180 â and analysis of its structure and size distribution with UV-Vis, XPS, FT-IR, NMR, TEM, and DLS. Furthermore, the CT values of IDC were calculated and compared with those of conventional CT contrast agents (Iohexol), and the in vitro and in vivo toxicities of IDC were determined to prove their safety. RESULTS: IDC showed improved CT contrast enhancement compared to iohexol. The biocompatibility of the IDC was verified via cytotoxicity tests, hemolysis assays, chemical analysis, and histological analysis. The osmotic pressure of IDC was lower than that of iohexol, resulting in no dilution-induced contrast decrease in plasma. CONCLUSION: Based on these results, the remarkable CT contrast enhancement and biocompatibility of IDC can be used as an effective CT contrast agent for the diagnosis of various diseases compared with conventional CT contrast agents.
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Bile acid-modified nanoparticles provide a convenient strategy to improve oral bioavailability of poorly permeable drugs by exploiting specific interactions with bile acid transporters. However, the underlying mechanisms are unknown, especially considering the different absorption sites of free bile acids (ileum) and digested fat molecules from bile acid-emulsified fat droplets (duodenum). Here, glycocholic acid (GCA)-conjugated polystyrene nanoparticles (GCPNs) are synthesized and their transport in Caco-2 cell models is studied. GCA conjugation enhances the uptake by interactions with apical sodium-dependent bile acid transporter (ASBT). A new pathway correlated with both ASBT and chylomicron pathways is identified. Meanwhile, the higher uptake of GCPNs does not lead to higher transcytosis to the same degree compared with unmodified nanoparticles (CPNs). The pharmacological and genomics study confirm that GCA conjugation changes the endocytosis mechanisms and downregulates the cellular response to the transport at gene levels, which works as a negative feedback loop and explains the higher cellular retention of GCPNs. These findings offer a solid foundation in the bile acid-based nanomedicine design, with utilizing advantages of the ASBT-mediated uptake, as well as inspiration to take comprehensive consideration of the cellular response with more developed technologies.
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Ácidos e Sais Biliares , Quilomícrons , Nanopartículas , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/farmacologia , Células CACO-2 , Quilomícrons/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Endocitose/fisiologia , Humanos , Nanopartículas/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Simportadores/farmacologia , Transcitose/efeitos dos fármacos , Transcitose/fisiologiaRESUMO
Helicobacter pylori (H. pylori) infection is closely associated with the development of gastric inflammatory diseases and cancer. However, the continued abuse and misuse of antibiotics has accelerated the spread of antibiotic-resistant strains, which poses a tremendous challenge for antibiotic-based H. pylori treatment. In this study, a H. pylori-targeting photodynamic therapy (PDT) system is proposed that multiple 3'-sialyllactose (3SL)-conjugated, poly-l-lysine-based photosensitizer (p3SLP). p3SLP facilitates H. pylori-targeting PDT via the specific interaction between 3SL and sialic acid-binding adhesin (SabA) in the H. pylori membrane. p3SLP can be orally administered to H. pylori infected mice and irradiated using an endoscopic laser system. The gastrointestinal pathological analysis of the H. pylori-infected mice demonstrated significant H. pylori specific antibacterial effects of PDT without side effects to normal tissue. In addition, an anti-inflammatory response was observed at the site of infection after p3SLP treatment. Consequently, this study demonstrates the superior efficacy of anti-H. pylori PDT with p3SLP in H. pylori-infected mice, and this approach shows great potential for replacing antibiotic-based therapy.
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Infecções por Helicobacter , Helicobacter pylori , Fotoquimioterapia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Camundongos , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Here, we describe the absorption pathways of nanoparticles whose surface is modified with bile acid and present environmental factors that influence oral bioavailability (BA) from the gastrointestinal tract (GIT). The approach utilized 100 nm sized fluorescence-labeled, carboxylated polystyrene nanoparticles (CPN) conjugated with glycocholic acid (G/CPN) to exclude potential artifacts, if existing, and instability issues in evaluating the transit of G/CPN in the GIT and measuring BA. The in vitro study using SK-BR-3 that expresses the apical sodium bile acid transporter showed that once G/CPN is internalized, it stayed 2.9 times longer in the cells than CPN, indirectly suggesting that G/CPN takes intracellular trafficking pathways different from CPN in SK-BR-3 cells. In a Caco-2 cell monolayer, G/CPN passed through the monolayer without damaging the tight junction. G/CPN, when administered orally in rodents, showed sustained transit time in the GIT for at least 4 h and was absorbed into the intestinal lymphatic system and circulated into the blood. Ingestion of food before and after oral administration delays G/CPN absorption and decreases BA. A decrease in gastrointestinal motility by anesthetic condition increased the relative BA of G/CPN by up to 74%. Thus, the oral BA of G/CPN can be optimized by taking food ingestion and gastrointestinal motility into account.
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Portadores de Fármacos/química , Ácido Glicocólico/administração & dosagem , Ácido Glicocólico/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Vasos Linfáticos/metabolismo , Nanopartículas/química , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Humanos , Vasos Linfáticos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Poliestirenos/química , Ratos , Ratos Sprague-Dawley , Junções Íntimas/efeitos dos fármacos , Distribuição TecidualRESUMO
The maximally tolerated dose (MTD) approach in conventional chemotherapy accompanies adverse effects, primarily due to high drug concentrations in the blood after intravenous administration and non-specific damages to highly proliferating cells, including immune cells. This causes the immune system to dysfunction. To rather boost intrinsic tumor-fighting immune capacity, we demonstrate a new oral route treatment regimen of docetaxel (DTX) without apparent toxicity. The DTX-loaded cationic solid lipid nanoparticles (DSLN-CSG) were coated with an anionic polymer conjugated with glycocholic acid. The resulting nanoparticles (DSLN-CSG, ~120â¯nm in diameter) were actively absorbed in the distal ileum mediated by interactions with the apical sodium bile acid transporter. The plasma DTX profile was sustained up to 24â¯h after a single oral dose and did not impair the functions of the immune system. In mouse models, daily oral DSLN-CSG administration inhibited the growth of existing tumors and tumor formation by medication prior to cancer cell inoculation. The extent of effects depended on the cancer cell lines of melanoma, colorectal adenocarcinoma, and breast carcinoma. It was most effective for melanoma in growth inhibition and in preventing tumor formation in mice. During the medication, the cytotoxic T cell population increased while the populations of tumor-associated macrophage and regulatory T cell declined. The low dose daily oral treatment may help patients with intermittent maintenance therapy between MTD cycles and prevent tumor recurrence after completing remission for certain tumors.
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Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Linfócitos T Citotóxicos/efeitos dos fármacos , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sulfatos de Condroitina/administração & dosagem , Sulfatos de Condroitina/química , Docetaxel/química , Liberação Controlada de Fármacos , Ácido Glicocólico/administração & dosagem , Ácido Glicocólico/química , Humanos , Íleo/metabolismo , Vasos Linfáticos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/patologia , Ratos Sprague-Dawley , Linfócitos T Citotóxicos/imunologiaRESUMO
Exendin-4 is a glucagon-like peptide-1 (GLP-1) receptor agonist and potent insulinotropic agent for type 2 diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. Long-acting agonists reduce the number of injections, but they can compromise potency. In this study, chondroitin sulfate-g-glycocholic acid-coated and Exendin-4 (Ex-4)-loaded liposomes (EL-CSG) were prepared for oral administration of Ex-4. The Ex-4 loading efficiency was 77% and the loading content in the nanoparticles was 1 wt-%. In rat models, a single oral dose (200⯵g/kg) of EL-CSG showed a relative oral bioavailability of 19.5%, compared with subcutaneous administration (20⯵g/kg), and sustained pharmacokinetics for up to 72â¯h. The overall long-term pharmacodynamic effects, assessed by hemoglobin A1c (HbA1c), body weight, and blood lipid concentrations, of daily oral EL-CSG (300⯵g/kg) for four weeks were equivalent to or better than daily subcutaneous injections of free Ex-4 solution (20⯵g/kg).
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Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Exenatida/sangue , Exenatida/farmacocinética , Hemoglobinas Glicadas/análise , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Intestino Delgado/metabolismo , Lipossomos , Masculino , Ratos Sprague-DawleyRESUMO
Herein, we describe a simple and promising nanoparticle oral delivery phenomenon and propose pathways for oral nanoparticle absorption from the gastrointestinal tract (GIT), combining apical sodium-dependent bile acid transporter-mediated cellular uptake and chylomicron transport pathways. This strategy is proven to employ bile-acid-conjugated, solid fluorescent probe nanoparticles (100 nm diameter) to exclude any potential artifacts and instability issues in observing transport pathways and measuring oral bioavailability. The results of the in vitro studies showed that there is no interference from bile acid and no simultaneous uptake of nanoparticles and dextran. The probe nanoparticle exhibited a significantly enhanced average oral bioavailability (47%) with sustained absorption in rats. Particle-size- and dose-dependent oral bioavailability was observed for oral nanoparticle dosing up to 20 mg/kg. The probe nanoparticles appear to be transported to systemic circulation via the gut lymphatic system. Thus, we propose a pathway for oral nanoparticle absorption from the GIT, combining apical bile acid transporter-mediated cellular uptake and chylomicron transport pathways.