RESUMO
Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.
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Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Imageamento por Ressonância Magnética , Nanomedicina , Telomerase , Telômero , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Telomerase/antagonistas & inibidores , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Nanomedicina/métodos , Telômero/metabolismo , Imageamento por Ressonância Magnética/métodos , Animais , Camundongos , Linhagem Celular Tumoral , Aminoácidos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêuticoRESUMO
The quick diffusion of nanomedicines in the polysaccharide-gel-filling tumor interstitium and precise active targeting are two major obstacles that have not yet been overcome. Here, a poly(L-glutamyl-L-lysine(EK) (p(EK))-camouflaged, doxorubicin (Dox)-conjugated nanomedicine is developed to demonstrate the underlying mechanism of zwitterionic shell in synchronous barrier-penetration and biconditional active targeting. The zwitterionic p(EK) shell liquifies its surrounding water molecules in the polysaccharide gel of tumor interstitium, leading to five times faster diffusion than the pegylated Doxil with similar size in tumor tissue. Its doped sulfonate groups lead to more precise active tumor-targeting than disialoganglioside (GD2) antibody by meeting the dual requirements of tumor microenvironment (TME) pH and overexpression of GD2 on tumor. Consequently, the concentrations of the nanomedicine in tumor are always higher than in life-supported organs in whole accumulation process, reaching over ten times higher Dox in GD2-overexpressing MCF-7 tumors than in life-supporting organs. Furthermore, the nanomedicine also avoids anti-GD2-like accumulation in GD2-expressing kidney in a mouse model. Thus, the nanomedicine expands the therapeutic window of Doxil by more than three times and eliminates tumors with negligible myocardial and acute toxicity. This new insight paves an avenue to design nanodelivery systems for highly precise and safe chemotherapy.
Assuntos
Nanomedicina , Neoplasias , Camundongos , Animais , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Polissacarídeos , Microambiente TumoralRESUMO
To overcome the hypoxia barrier in tumor therapy, a hypoxia-activated prodrug of docetaxel (DTX-PNB) was synthesized and self-assembled with indocyanine green (ICG), forming a combination nanomedicine ISDNN. With the guidance of molecular dynamic simulation, the ISDNN construction could be accurately controlled, achieving uniform size distribution and high drug loading up to 90%. Within the hypoxic tumor environment, ISDNN exerted ICG-mediated photodynamic therapy and aggravated hypoxia to boost DTX-PNB activation for chemotherapy, enabling enhanced antitumor efficacy.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Nanomedicina , Simulação de Dinâmica Molecular , Verde de Indocianina/uso terapêutico , Hipóxia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
For pancreatic ductal adenocarcinoma (PDAC) treatment, the deactivation of pancreatic stellate cells (PSCs) by blocking the transforming growth factor ß (TGF-ß) pathway is a promising strategy to inhibit stroma, enhance drug penetration, and greatly amplify chemotherapeutic efficacy. It is known that photothermal therapy (PTT) locally depletes stroma and enhances permeability but whether and how PTT reacts in the molecular pathway to induce PSC deactivation in PDAC has rarely been investigated so far. Herein, C-G NPs are synthesized by loading both acid-responsive photothermal molecules and gemcitabine for investigating both the combinatory chemophotothermal therapy and the interaction between the PTT and TGF-ß pathway in PDAC. Notably, C-G NPs exhibit tumoral acidic pH-activated PTT and succeeded in deactivating PSCs and suppressing the expression level for both TGF-ß and collagen fiber. Furthermore, hyperthermia remodels the tumoral extracellular matrix, significantly improves NP penetration, and boosts the ultimate synergistic chemophotothermal therapeutic efficacy. Importantly, the molecular biology study reveals that hyperthermia leads to the decrease in the mRNA expression of TGF-ß1, SMAD2, SMAD3, α-SMA, and Collagen I in the tumor tissue, which is the key to suppress tumor progression. This research demonstrates that combinatory chemophotothermal therapy holds great promise for PDAC treatment.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Terapia Fototérmica , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Colágeno , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
Fluorescence imaging-guided surgery is one of important techniques to realize precision surgery. Although second near-infrared window (NIR-II) fluorescence imaging has the advantages of high resolution and large penetration depth in surgical navigation, its major drawback is that NIR-II images cannot be detected by our naked eyes, which demands a high hand-eye coordination for surgeons and increases the surgical difficulty. On the contrary, visible fluorescence can be observed by our naked eyes but has poor penetration. Here, we firstly propose a kind of NIR-II and visible fluorescence hybrid navigation surgery assisted via a cocktail of aggregation-induced emission nanoparticles (AIE NPs). NIR-II imaging helps to locate deep targeted tissues and judge the residual, and visible fluorescence offers an easily surgical navigation. We apply this hybrid navigation mode in different animals and systems, and verify that it can accelerate surgical process and compatible with a visible fluorescence endoscopy. To deepen the understanding of lymph node (LN) labelling, the distribution of NPs in LNs after local administration is initially analyzed by NIR-II fluorescence wide-filed microscopy, and two fates of the NPs are summarized. An alternative strategy which combines indocyanine green and berberine is also reported as a compromise for rapidly clinical translation.
RESUMO
A living therapeutic system based on attenuated Salmonella was developed via metabolic engineering using an aggregation-induced emission (AIE) photosensitizer MA. The engineered bacteria could localize in the tumor tissues and continue to colonize and express exogenous genes. Under light irradiation, the encoded VEGFR2 gene was released and expressed in tumor tissues, which can suppress angiogenesis induced by a T cell-mediated autoimmune response and inhibit tumor growth.
Assuntos
Neoplasias , Bactérias , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treated patients ultimately develop disease progression, about 50% of which are involved in the emergence of a p.Thr790Met (T790M) mutation acquiring drug resistance. In order to solve the aforementioned problem, a therapeutic nanoparticles DGA is developed to overcome EGFR-T790M resistance via downstream anti-apoptotic signal transduction blocking by a combination with persuading mitochondrial dysfunction and inhibiting miRNA expression. As the concept of design, chitosan-derived nanocarrier DCAFP, capable of persuading mitochondrial dysfunction, is demonstrated to convey gefitinib (GFT) and miR21 inhibitor (anti-miR21) to form DGA nanoparticles. The superior accumulation of antitumor therapeutics and synergistic blocking of downstream signal transduction by mitochondrial dysfunction and miRNA regulation lead to high sensitivity of DGA nanoparticles to EGFR-T790M mutated non-small cell lung cancer (NSCLC) cells with significant inhibition of tumor cell growth. The in vivo study demonstrates superior safety and antitumor efficacy of EGFRT790M mutated lung cancer mouse models. These results highlight the promise of DGA nanoparticles for enhancing GFT sensitivity to EGFRT790M NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quitosana , Neoplasias Pulmonares , Nanopartículas , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics.
Assuntos
Glucosídeos/química , Prolina/química , Resveratrol/química , Estilbenos/química , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Cristalização , Composição de Medicamentos , Glucosídeos/farmacocinética , Células HEK293 , Humanos , Técnicas In Vitro , Conformação Molecular , Resveratrol/farmacocinética , Solubilidade , Estilbenos/farmacocinéticaRESUMO
Nanoformulations of mononuclear Pt complexes cis-PtCl2 (PPh3 )2 (1), [Pt(PPh3 )2 (L-Cys)] â H2 O (3, L-Cys=L-cysteinate), trans-PtCl2 (PPh2 PhNMe2 )2 (4; PPh2 PhNMe2 =4-(dimethylamine)triphenylphosphine), trans-PtI2 (PPh2 PhNMe2 )2 (5) and dinuclear Pt cluster Pt2 (µ-S)2 (PPh3 )4 (2) have comparable cytotoxicity to cisplatin against murine melanoma cell line B16F10. Masking of these discrete molecular entities within the hydrophobic core of Pluronic® F-127 significantly boosted their solubility and stability, ensuring efficient cellular uptake, giving inâ vitro IC50 values in the range of 0.87-11.23â µM. These results highlight the potential therapeutic value of Pt complexes featuring stable Pt-P bonds in nanocomposite formulations with biocompatible amphiphilic polymers.
Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Modelos Moleculares , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Tamanho da PartículaRESUMO
Sorafenib (Sor) is an oral multi-kinase inhibitor, but its water solubility is very low. To improve its solubility, sorafenib hydrochloride hydrate, sorafenib hydrobromide and sorafenib hydrobromide hydrate were prepared in the mixed solvent of the corresponding acid solution, and tetrahydrofuran (THF). The crystal structures of sorafenib hydrochloride trihydrate (Sor·HCl.3H2O), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrochloride trihydrate, C21H17ClF3N4O3+·Cl-.3H2O (I), sorafenib hydrochloride monohydrate (Sor·HCl.H2O), C21H17ClF3N4O3+·Cl-.H2O (II), its solvated form (sorafenib hydrochloride monohydrate monotetrahydrofuran (Sor·HCl.H2O.THF), C21H17ClF3N4O3+·Cl-.H2O.C4H8O (III)), sorafenib hydrobromide (Sor·HBr), 4-(4-{3-[4-chloro-3-(trifluoro-methyl)phenyl]ureido}phenoxy)-2-(N-methylcarbamoyl) pyridinium hydrobromide, C21H17ClF3N4O3+·Br- (IV) and sorafenib hydrobromide monohydrate (Sor·HBr.H2O), C21H17ClF3N4O3+·Br-.H2O (V) were analysed. Their hydrogen bond systems and topologies were investigated. The results showed the distinct roles of water molecules in stabilizing their crystal structures. Moreover, (II) and (V) were isomorphous crystal structures with the same space group P21/n, and similar unit cell dimensions. The predicted morphologies of these forms based on the BFDH model matched well with experimental morphologies. The energy frameworks showed that (I), and (IV) might have better tabletability than (II) and (V). Moreover, the solubility and dissolution rate data exhibited an improvement in the solubility of these salts compared with the free drug.
Assuntos
Antineoplásicos/química , Ligação de Hidrogênio , Inibidores de Proteínas Quinases/química , Sorafenibe/química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Cristais Líquidos/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Solubilidade , Sorafenibe/farmacologia , Análise EspectralRESUMO
The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.
Assuntos
Solubilidade/efeitos dos fármacos , Sorafenibe/química , Acetona/química , Biofarmácia/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Pós/química , Difração de Raios X/métodosRESUMO
Understanding the host-guest chemistry of α-/ß-/γ- cyclodextrins (CDs) and a wide range of organic species are fundamentally attractive, and are finding broad contemporary applications toward developing efficient drug delivery systems. With the widely used ß-CD as the host, we herein demonstrate that its inclusion behaviors toward an array of six simple and bio-conjugatable adamantane derivatives, namely, 1-adamantanol (adm-1-OH), 2-adamantanol (adm-2-OH), adamantan-1-amine (adm-1-NH2), 1-adamantanecarboxylic acid (adm-1-COOH), 1,3-adamantanedicarboxylic acid (adm-1,3-diCOOH), and 2-[3-(carboxymethyl)-1-adamantyl]acetic acid (adm-1,3-diCH2COOH), offer inclusion adducts with diverse adamantane-to-CD ratios and spatial guest locations. In all six cases, ß-CD crystallizes as a pair supported by face-to-face hydrogen bonding between hydroxyl groups on C2 and C3 and their adjacent equivalents, giving rise to a truncated-cone-shaped cavity to accommodate one, two, or three adamantane derivatives. These inclusion complexes can be terminated as (adm-1-OH)2âCD2 (1, 2:2), (adm-2-OH)3âCD2 (2, 3:2), (adm-1-NH2)3âCD2 (3, 3:2), (adm-1-COOH)2âCD2 (4, 2:2), (adm-1,3-diCOOH)âCD2 (5, 1:2), and (adm-1,3-diCH2COOH)âCD2 (6, 1:2). This work may shed light on the design of nanomedicine with hierarchical structures, mediated by delicate cyclodextrin-based hosts and adamantane-appended drugs as the guests.
Assuntos
Adamantano/química , Adamantano/farmacologia , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , Adamantano/análogos & derivados , Calorimetria , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-AtividadeRESUMO
The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Nanopartículas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , gama-Ciclodextrinas/administração & dosagem , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Manose/química , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Compostos de Fenilureia/química , Piridinas/química , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , gama-Ciclodextrinas/químicaRESUMO
Canagliflozin (CG) was a highly effective, selective and reversible inhibitor of sodium-dependent glucose co-transporter 2 developed for the treatment of type 2 diabetes mellitus. The crystal structure of CG monohydrate (CG-H2O) was reported for the first time while CG hemihydrate (CG-Hemi) had been reported in our previous research. Solubility and dissolution rate results showed that the solubility of CG-Hemi was 1.4 times higher than that of CG-H2O in water and hydrochloric acid solution, and the dissolution rates of CG-Hemi were more than 3 folds than CG-H2O in both solutions. Hirshfeld surface analysis showed that CG-H2O had stronger intermolecular forces than CG-Hemi, and water molecules in CG-H2O participated three hydrogen bonds, forming hydrogen bond networks. These crystal structure features might make it more difficult for solvent molecules to dissolve CG-H2O than CG-Hemi. All these analyses might explain why the dissolution performance of CG-Hemi was better than CG-H2O. This work provided an approach to predict the dissolution performance of the drug based on its crystal structure.
Assuntos
Canagliflozina/química , Inibidores do Transportador 2 de Sódio-Glicose/química , Água/química , Cristalização , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , SolubilidadeRESUMO
Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]âEtOHâ(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics.
Assuntos
Química Farmacêutica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Isoflavonas/química , Prolina/química , Animais , Disponibilidade Biológica , Cristalização , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/patologia , Células HEK293 , Humanos , Isoflavonas/uso terapêutico , Medicina Tradicional Chinesa , Camundongos , Pós/química , Prolina/uso terapêutico , Solubilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Studies on neutrophil-based nanotherapeutic engineering have shown great potentials in treating infection and inflammation disorders. Conventional neutrophil labeling methods are time-consuming and often result in undesired contamination and activation since neutrophils are terminal-differentiated cells with a half-life span of only 7â h. A simple, fast, and biocompatible strategy to construct engineered neutrophils is highly desirable but remains difficult to achieve. In this study, we present an AIEgen-lipid conjugate, which can efficiently label harvested neutrophils in 30â s with no washing step required. This fast labeling method does not affect the activation and transmigration property of neutrophils, which has been successfully used to monitor neutrophil behaviors such as the chemotaxis process and migrating function towards inflammation sites both inâ vitro and inâ vivo, offering a tantalizing prospect for neutrophil-based nanotherapeutics studies.
Assuntos
Lipídeos/química , Neutrófilos/metabolismo , Animais , Quimiotaxia , Bicamadas Lipídicas/química , Lisofosfatidilcolinas/química , Camundongos , Nanopartículas/química , Neutrófilos/química , Neutrófilos/imunologia , Imagem Óptica , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Tenofovir alafenamide (TAF) is a prodrug of tenofovir as a potent nucleotide reverse transcriptase inhibitor. It serves as the key component of Genvoya® for the first-line treatment of human immunodeficiency virus infection (HIV) and is the active component of Vemlidy® for the treatment of chronic hepatitis B. Vemlidy® is also a monotherapeutic regimen formulated as TAF hemifumarate (1; TAF:fumarate = 2:1). In this work, we report for the first time the single-crystal structure of TAF fumarate hemihydrate (2, TAF:fumarate:H2O = 2:2:1). Compound 2 is initially documented as a salt in which one proton of the fumaric acid migrates to the amine group of the adenine moiety in TAF. It was recently proposed that ca. 20-30% proton is transferred to the N atom on the aromatic adenine backbone. We herein provide definitive single-crystal X-ray diffraction results to confirm that 2, though phase pure, is formed as a mixture of co-crystal (75%) and salt (25%). It features two pairs of TAF fumarates, wherein one of the four H atoms on the fumaric acid is transferred to the N atom of the adjacent adenine moiety while the other three carboxylates remain in their intrinsic acid form. Compound 2 is a metastable phase during the preparation of 1 and can be isolated by halting the reaction during the refluxing of TAF and fumaric acid in acetonitrile (MeCN). Our report complements the previous characterizations of TAF monofumarate, and its elusive structural patterns are finally deciphered.
Assuntos
Fumaratos/química , Modelos Moleculares , Tenofovir/química , Fármacos Anti-HIV/química , Técnicas de Química Sintética , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Sais , Análise Espectral , Tenofovir/síntese químicaRESUMO
As one of the most malignant primary cancers, hepatocellular carcinoma (HCC) still lacks an efficient therapeutic strategy to date. Here, we developed a polymer-based nanoplatform PEI-ßCD@Ad-CDM-PEG (PCACP) for functional microRNA (miRNA) therapy. PCACP exhibits excellent stability in physiological solutions, but sensitive PEG detachment and size transformation in an acidic tumor environment due to the breakdown of pH-responsive linkages, promoting tumor penetration and cellular uptake of nanoparticles, further facilitating transfection efficiency due to the proton sponge effect of polycations. We present a novel miRNA cocktail therapy by encapsulating miR-199a/b-3p mimics (miR199) and antimiR-10b (antimiR10b) into PCACP for eliminating HCC. Validated by qRT-PCR, immunoblotting and immunohistochemistry, compared with miR199 or antimiR10b delivered alone, miR-cocktail therapy substantially inhibits HCC cell proliferation and tumor growth by targeting mTOR, PAK4, RHOC and epithelial-mesenchymal transition (EMT) pathways both in vitro and in vivo (i.v. injection). Furthermore, we proposed personalized miR-cocktail therapy by adjusting the encapsulated miRNA formula according to the miRNA profiling of a patient's tumor sample. The personalized PCACP/miR-cocktail system exhibits significant tumor suppression and multitarget regulation on patient derived xenografts (PDXs), representing a notable effect improvement over conventional gene therapy. The tumor-acidity-cleavable PCACP/miR-cocktail system, with loaded miRNA controllability and high transfection efficiency, is a promising personalized therapeutic strategy for future HCC treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , MicroRNAs/genética , Medicina de Precisão , Quinases Ativadas por p21RESUMO
Developing ionic liquid (IL) drugs broaden new horizons in pharmaceuticals. The tunable nature endows ILs with capacity to delivery active ingredients. However, the tunability is limited to screen ionic components, and none realizes the kinetic tuning of drug release, which is a key challenge in the design of IL drugs. Here, a series of ILs are developed using biocompatible ionic components, which realizes absorption of gaseous NO to yield IL-NONOates. These IL-NONOates serve as HNO donors to release active ingredient. The release kinetics can be tuned through configuring the geometric construction of ILs (release half-lives, 4.2 to 1061 min). Mechanism research indicates that the tunability depends on the strength of intramolecular hydrogen bond. Furthermore, the IL-based HNO donors exert pharmacological potential to inhibit tumor progression by regulating intratumoral redox state. Coupled with biosafety, these IL-based HNO donors with facile preparation and tunable functionalization can be promising candidates for pharmaceutical application.