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1.
Heliyon ; 10(8): e29198, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38644863

RESUMO

Objectives: To describe a bladder cuff excision method modified with ureteral catheterization to better visualize the ureteral orifice during robot-assisted nephroureterectomy (RANU). Methods: We retrospectively analyzed 66 patients with upper urinary tract urothelial carcinoma of the renal pelvis and/or upper-mid ureter treated between January 2020 and January 2023. Among them, 32 patients (group A) underwent RANU supported by ureteral catheterization, and the remaining patients (group B) received routine transperitoneal RANU. Postoperative cystoscopy was performed routinely to compare the rates of residual ureteral orifice between the two groups. Results: Surgeries were completed uneventfully in all 66 patients, without blood transfusion or conversion to open procedures. The operative time, estimated blood loss, and postoperative length of hospital stay were similar between both groups. However, the mean time required for BCE in group A was shorter than that in group B (9.5 min vs. 16.0 min, p = 0.006). Cystoscopy at postoperative three months showed no ipsilateral ureteral orifice in group A, but residual ureteral orifice was found in 23.5% of patients in group B. During a short follow-up period of 16 months, no patients in group A experienced bladder tumor recurrence. However, two patients (5.9%) in group B developed bladder tumor recurrence, with one experiencing local tumor recurrence at the level of the ureteral stump. Conclusions: Our novel technique enables complete ureteral retrieval, accurate and rapid bladder cuff excision, which makes the procedure less invasive and safely reproducible during robot-assisted nephroureterectomy.

2.
ACS Appl Mater Interfaces ; 16(3): 4071-4088, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38194589

RESUMO

Surgical resection remains the most common method of tumor treatment; however, the high recurrence and metastasis after surgery need to be solved urgently. Herein, we report an injectable zwitterionic hydrogel based on "thiol-ene" click chemistry containing doxorubicin (DOX) and a macrophage membrane (MM)-coated 1-methyl-tryptophan (1-MT)-loaded polyamide-amine dendrimer (P-DOX/1MT) for preventing the postoperative recurrence of tumors. The results indicated that P-DOX/1MT@MM exhibited enhanced recognition and uptake of the dendrimer by tumor cells and induced the immunogenic cell death. In the mice tumor model, the P-DOX/1MT@MM-Gel exhibited high therapeutic efficiency, which could significantly reduce the recurrence of the tumor, including suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. The mechanism analysis revealed that the hydrogel greatly reduces the side effects to normal tissues and significantly improves its therapeutic effect. 1MT in the hydrogel is released more rapidly, improving the tumor suppressor microenvironment and increasing the tumor cell sensitivity to DOX. Then, the DOX in the P-DOX/1MT@MM effectively eliminatedo the residual tumor cells and exerted enhanced toxicity. In conclusion, this novel injectable hydrogel that combines chemotherapy and immunotherapy has the property of sequential drug release and is a promising strategy for preventing the postoperative recurrence of tumors.


Assuntos
Dendrímeros , Neoplasias , Animais , Camundongos , Hidrogéis/química , Micelas , Dendrímeros/farmacologia , Dendrímeros/uso terapêutico , Neoplasias/tratamento farmacológico , Doxorrubicina/química , Imunoterapia , Linhagem Celular Tumoral , Microambiente Tumoral
3.
J Drug Target ; 32(2): 128-147, 2024 12.
Artigo em Inglês | MEDLINE | ID: mdl-38217526

RESUMO

Atherosclerosis is one of the major causes of death worldwide, and it is closely related to many cardiovascular diseases, such as stroke, myocardial infraction and angina. Although traditional surgical and pharmacological interventions can effectively retard or slow down the progression of atherosclerosis, it is very difficult to prevent or even reverse this disease. In recent years, with the rapid development of nanotechnology, various nanoagents have been designed and applied to different diseases including atherosclerosis. The unique atherosclerotic microenvironment with signature biological components allows nanoplatforms to distinguish atherosclerotic lesions from normal tissue and to approach plaques specifically. Based on the process of atherosclerotic plaque formation, this review summarises the nanodrug delivery strategies for atherosclerotic therapy, trying to provide help for researchers to understand the existing atherosclerosis management approaches as well as challenges and to reasonably design anti-atherosclerotic nanoplatforms.


Assuntos
Aterosclerose , Placa Aterosclerótica , Humanos , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/patologia , Sistemas de Liberação de Medicamentos , Nanotecnologia
4.
Biomater Sci ; 12(2): 361-374, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-37982147

RESUMO

The eyes have a complicated microenvironment with many clearance mechanisms, making it challenging for effective drug delivery to the targeted areas of the eyes. Substrate transport mediated by active transporters is an important way to change drug metabolism in the ocular microenvironment. We designed multifunctional, dual-adaptive nanomicelles (GSCQ@NTB) which could overcome multiple physiological barriers by acting on both the efflux transporter and influx transporter to achieve deep delivery of the P-gp substrate in the cornea. Specifically, an effective "triple" antiangiogenic agent, nintedanib (NTB), was loaded into the biocompatible micelles. The expression of the efflux transporter was reversed by grafting quercetin. The peptide (glycylsarcosine, GS) was modified to target the influx transporter "Peptide Transporter-1" (PepT-1). Quercetin (QRT) and nintedanib (NTB) were transported to the cornea cooperatively, achieving long retention on the ocular surface and high compatibility. In a New Zealand rabbit model, within 8 hours after local administration, GSCQ@NTB was enriched in corneal stromal neovascularization and effectively inhibited the progress of neovascularization. Its effectiveness is slightly better than that in the first-line clinical application of steroids. In this study, we introduce the preparation of a dual adaptive nano-micelle system, which may provide an effective non-invasive treatment for corneal neovascularization.


Assuntos
Córnea , Quercetina , Animais , Coelhos , Córnea/metabolismo , Sistemas de Liberação de Medicamentos , Micelas , Transporte Biológico Ativo
5.
J Ethnopharmacol ; 322: 117612, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38135228

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisinin (ART) showed enhanced antimalarial potency in the herb Artemisia annua L. (A. annua), from which ART is isolated. Increased absorption of ART with inhibited metabolism in the plant matrix is an underlying mechanism. Several synergistic components have been reported based on a "bottom-up" approach, i.e., traditional isolation followed by pharmacokinetic and/or pharmacodynamic evaluation. AIM OF THE STUDY: In this study, we employed a "top-down" approach based on in vivo antimalarial and pharmacokinetic studies to identify synergistic components in A. annua. MATERIALS AND METHODS: Two A. annua extracts in different chemical composition were obtained by extraction using ethyl acetate (EA) and petroleum ether (PE). The synergistic antimalarial activity of ART in two extracts was compared both in vitro (Plasmodium falciparum) and in vivo (murine Plasmodium yoelii). For the PD-PK correlation analysis, the pharmacokinetic profiles of ART and its major metabolite (ART-M) were investigated in healthy rats after a single oral administration of pure ART (20 mg/kg) or equivalent ART in each A. annua extract. A liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS)-based analytical strategy was then applied for efficient component classification and structural characterization of the differential components in the targeted extract with a higher antimalarial potency. Major components isolated from the targeted extract were then evaluated for their synergistic effect in the same proportion. RESULTS: Compared with pure ART (ED50, 5.6 mg/kg), ART showed enhanced antimalarial potency in two extracts in vivo (ED50 of EA, 2.9 mg/kg; ED50 of PE, 1.6 mg/kg), but not in vitro (IC50, 15.0-20.0 nM). A significant increase (1.7-fold) in ART absorption (AUC0-t) was found in rats after a single oral dose of equivalent ART in PE but not in EA; however, no significant change in the metabolic capability (AUCART-M/AUCART) was found for ART in either extract. The differential component analysis of the two extracts showed a higher composition of sesquiterpene compounds, especially component AB (3.0% in PE vs. 0.9% in EA) and component AA (14.1% in PE vs. 5.1% in EA). Two target sesquiterpenes were isolated and identified as arteannuin B (AB) and artemisinic acid (AA). The synergism between ART and AB/AA in the same proportion with PE extract (20:1.6:7.6, mg/kg) was verified by a pharmacokinetic study in rats. CONCLUSIONS: A "top-down" strategy based on PD-PK studies was successfully employed to identify synergistic components for ART in A. annua. Two sesquiterpene compounds (arteannuin B and artemisinic acid) could enhance the antimalarial potency of ART by increasing its absorption.


Assuntos
Antimaláricos , Artemisia annua , Artemisininas , Sesquiterpenos , Ratos , Camundongos , Animais , Antimaláricos/química , Artemisia annua/química , Artemisininas/farmacocinética , Extratos Vegetais/farmacologia , Extratos Vegetais/química
6.
Asian J Pharm Sci ; 18(5): 100851, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37915760

RESUMO

Growing evidence suggests that the presence of cancer stem cells (CSCs) is a major challenge in current tumor treatments, especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis. Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy. In this work, we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid (ATRA) via biomineralization. This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters, which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration. With the help of CSC differentiation induced by ATRA, IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner. Furthermore, ATRA can boost immunogenic cell death induced by phototherapy, thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells. Taken together, this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation, improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.

7.
ACS Nano ; 17(24): 24883-24900, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-37883579

RESUMO

Surgical resection is the first-line therapy for breast cancer. However, residual tumor cells and the highly immunosuppressive tumor microenvironment (TME) continue to have a serious impact on tumor recurrence and metastasis postresection. Implantation of an in situ hydrogel system postresection has shown to be an effective treatment with great clinical potential. Herein, an injectable zwitterionic hydrogel system was developed for local drug delivery with enhanced immune activation and prevention of tumor recurrence. Driven by electrostatic interactions, poly(sulfobetaine methacrylate) (PSBMA) self-assembles into a hydrogel in saline, achieving low protein adsorption and tunable biodegradability. The chemotherapy drug doxorubicin (DOX) was loaded into copper peroxide nanoparticles (CuO2/DOX), which were coated with macrophage membranes to form tumor-targeting nanoparticles (M/CuO2/DOX). Next, M/CuO2/DOX and the stimulator of interferon genes (STING) agonist 2',3'-cGAMP were coloaded into PSBMA hydrogel (Gel@M/CuO2/DOX/STING). The hydrophilic STING agonist was first released by diffusion from hydrogel to activate the STING pathway and upregulate interferon (IFN) signaling related genes, remodeling the immunosuppressive TME. Then, M/CuO2/DOX targeted the residual tumor cells, combining with DOX-induced DNA damage, immunogenic tumor cell death, and copper death. Hence, this work combines chemodynamic therapy with STING pathway activation in TME, encouraging residual tumor cell death, promoting the maturation of dendritic cells, enhancing tumor-specific CD8+ T cell infiltration, and preventing postoperative recurrence and metastasis.


Assuntos
Hidrogéis , Nanopartículas , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Cobre , Neoplasia Residual/tratamento farmacológico , Microambiente Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Interferons , Linhagem Celular Tumoral
8.
Biomater Sci ; 11(18): 6325-6341, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37555273

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive cancers with an immunosuppressive microenvironment, and achieving a satisfactory effect from monotherapies, such as chemotherapy, photodynamic therapy (PDT) or immunotherapy, remains difficult. To solve this puzzle, a deepening synergistic therapy strategy of DNA damage and immunogenic cell death (ICD) stimuli was proposed. We engineered a doxorubicin (DOX) and 4-(hydroxymethyl) phenylboronic acid pinacol ester (PBAP) prodrug polymer, and encapsulated chlorin e6 (Ce6) to obtain the hyaluronidase (HAase) and H2O2 dual-sensitive responsive nanoparticles (Ce6/HDP NPs). The NPs displayed efficient intratumoral accumulation and cellular internalization properties due to the active targeting of the hyaluronic acid (HA). The dual DNA damage of the chemotherapy and ROS production directly caused tumor cell apoptosis. The strong ICD stimuli, which were induced by ROS production and GSH depletion, generated an amplified immunogenicity to activate tumor immunotherapy in vivo. In this manner, the NPs could significantly inhibit primary tumor, abscopal tumor, pulmonary metastasis and recurrent tumor in a subcutaneous 4T1 tumor model, with effective biosafety. This study has provided a promising deepening synergistic therapy strategy against TNBC.


Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio , Morte Celular Imunogênica , Porfirinas/farmacologia , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes , Microambiente Tumoral
9.
ACS Nano ; 17(12): 11537-11556, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37272777

RESUMO

Ferroptosis activation has been considered a mighty weapon for cancer treatment, and growing attention is being paid to reinforcing tumor cells' sensitivity to ferroptosis. However, the existence of certain ferroptosis resistance mechanisms, especially the abnormal metabolism of tumor cells, has long been underestimated. We propose an enhanced ferroptosis-activating pattern via regulating tumor cells' glycometabolism and construct a nanoplatform named PMVL, which is composed of lonidamine (LND)-loaded tannic acid coordinated vanadium oxides with the camouflage of PD-L1 inhibiting peptide-modified tumor cell membrane. This work reveals that the mixed valence of vanadium (VIV and VV) in PMVL triggers ferroptosis due to the self-cyclic valence alteration of V, the process of which generates •OH for lipid peroxide accumulation (VIV → VV) and depletes glutathione (GSH) for glutathione peroxidase (GPX4) deactivation (VV → VIV). Notably, LND strengthens ferroptosis by dual suppression of glycolysis (decreasing ATP supply) and the pentose phosphate pathway (decreasing NADPH production), causing anabatic GSH consumption. Besides, the inhibited glycolysis generates less intracellular lactic acid and alleviates the acidity of tumor microenvironment, preventing immunosuppressive M2 macrophage polarization. In vitro and in vivo data demonstrate the glycometabolism-intervention-enhanced ferroptosis and boosted immunity activation, potentially providing opportunities and possibilities for synergetic cancer therapy.


Assuntos
Neoplasias , Vanádio , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Morte Celular , Glutationa Peroxidase/metabolismo , Glucose , Linhagem Celular Tumoral , Microambiente Tumoral
10.
Int J Pharm ; 641: 123069, 2023 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-37225024

RESUMO

The application of variable novel drug delivery system has shown a flowering trend in recent years. Among them, the cell-based drug delivery system (DDS) utilizes the unique physiological function of cells to deliver drugs to the lesion area, which is the most complex and intelligent DDS at present. Compared with the traditional DDS, the cell-based DDS has the potential of prolonged circulation in body. Cellular DDS is expected to be the best carrier to realize multifunctional drug delivery. This paper introduces and analyzes common cellular DDSs such as blood cells, immune cells, stem cells, tumor cells and bacteria as well as relevant research examples in recent years. We hope that this review can provide a reference for future research on cell vectors and promote the innovative development and clinical transformation of cell-based DDS.


Assuntos
Sistemas de Liberação de Medicamentos
11.
Curr Drug Metab ; 24(2): 131-138, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36941813

RESUMO

BACKGROUND: Piperaquine (PQ) and its pharmacologically active metabolite PQ N-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMO enzymes. OBJECTIVES: The reductive metabolism of PM1 and its further N-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated. METHODS: The hepatic and microbial reduction metabolism of PM1 and PM2 was studied in vitro. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was evaluated in mice pretreated with antibiotics. The effect of the reduction metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. RESULTS: Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ N-oxide metabolites. In vitro physiologic and enzyme kinetic studies of both N-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after an oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling. CONCLUSION: Microbial NTRs and hepatic P450/FMO enzymes contributed to the reduction metabolism of PQ Noxide metabolites. The reduction metabolism by intestinal microflora did not affect PQ clearance, and the medical warning in patients with NTRs-related disease (e.g., hyperlipidemia) will not be clinically meaningful.


Assuntos
Microbioma Gastrointestinal , Quinolinas , Humanos , Animais , Camundongos , Cinética , Óxidos , Quinolinas/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo
12.
Acta Biomater ; 157: 551-565, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36513248

RESUMO

Photodynamic therapy (PDT) is a minimally invasive and locally effective treatment method, which has been used in the clinical treatment of a variety of superficial tumors. In recent years, PDT has received extensive attention due to its induction of immunogenic cell death (ICD). However, the repair mechanism of tumor cells and low immune response limit the further development of PDT. To this end, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) is developed to co-deliver the photosensitizer Chlorin e6 (Ce6) and Olaparib (Ola) with the function of preventing DNA repair. The nanoplatform shows efficient tumor targeting and cellular internalization properties due to cell membrane camouflage, and Ce6 and Ola produce a significant synergistic anti-tumor effect under laser irradiation. Meanwhile, the nanoplatform can also activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-interferon gene stimulator signaling (cGAS-STING) pathway to produce cytokines. The damage-associated molecular patterns induced by ICD can work with these cytokines to recruit and stimulate the maturation of dendritic cells and induce the systemic anti-tumor immune response. Overall, this multifunctional biomimetic nanoplatform integrating PDT, chemotherapy, and immunotherapy is highlighted here to boost anti-tumor therapy. STATEMENT OF SIGNIFICANCE: Self-repair of DNA damage is the most important reason for the failure of primary tumor eradication and the formation of secondary and metastatic tumors. To address this issue, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) was developed to integrate a photosensitizer Chlorine a6 and a poly (ADP-ribose) polymerase inhibitor Olaparib. With tumor targeting ability and controlled release of drugs, the MPCO was expected to enhance tumor immunogenicity and facilitate antitumor immunity through the induction of immunogenic cell death as well as the activation of the cGAS-STING pathway. This study develops a promising combination strategy against tumors and has substantial implications for the prognosis of patients with breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanopartículas , Fotoquimioterapia , Porfirinas , Humanos , Feminino , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Fotoquimioterapia/métodos , Biomimética , Antineoplásicos/uso terapêutico , Porfirinas/farmacologia , Reparo do DNA , Citocinas , Linhagem Celular Tumoral , Nanopartículas/uso terapêutico
13.
J Drug Target ; 31(4): 335-353, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36543743

RESUMO

Extracellular vesicles (EVs) could be produced by most cells and play an important role in disease development. As a subtype of EVs, exosomes exhibit suitable size, rich surface markers and diverse contents, making them more appealing as potential drug carriers. Compared with traditional synthetic nanoparticles, exosomes possess superior biocompatibility and much lower immunogenicity. This work reviewed the most up-to-date research progress of exosomes as carriers for nucleic acids, proteins and small molecule drugs for cancer and inflammation management. The drug loading strategies and potential cellular uptake behaviour of exosomes are highlighted, trying to provide reference for future exosome design and application.


Exosomes are secreted by a variety of cells and play an important role in the process of inter-cell communication.This paper provides a comprehensive review focussing on the up-to-date applications of exosomes as carriers of nucleic acids, proteins and small molecule drugs for cancer and inflammation management.This paper briefly introduces the basic properties of exosomes, from definition, biogenesis to cellular uptake manners.Various strategies to enable exosomes to efficiently load cargoes are highlighted.Problems to be solved when using exosomes to deliver drugs are discussed.


Assuntos
Exossomos , Vesículas Extracelulares , Neoplasias , Humanos , Portadores de Fármacos/metabolismo , Exossomos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos
14.
Biomater Sci ; 10(22): 6583-6600, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36227002

RESUMO

Due to the complex bloodstream components, tumor microenvironment and tumor heterogeneity, traditional nanoparticles have a limited effect (low drug delivery efficiency and poor penetration to the deeper tumor) on eradicating tumors. To solve these challenges, novel platelet membrane-coated nanoparticles (PCDD NPs) were constructed for combined chemo-photodynamic- and immunotherapy of melanoma. The platelet membrane imparted the PCDD nanoparticles with an excellent long circulation effect and tumor targeting ability, which solved the issues of low drug delivery efficiency. After reaching the tumor cells, it releases the drug-loaded CDD micelles, becoming positively charged and facilitating the deep penetration of tumors. Cytotoxic and apoptosis experiments showed that PCDD nanoparticles have the strongest tumor cell killing ability. Based on the excellent results in vitro, PCDD was used to assess anti-tumor and distal tumor inhibition in rat models. The results revealed that the PCDD combined PDT, immunotherapy and chemotherapy could not only inhibit the primary tumor growth (inhibition rate: 92.0%) but also suppress the distant tumor growth (inhibition rate: 90.7%) and lung metastasis, which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, leading to excellent results in tumor suppression and lung metastasis. In conclusion, this novel multifunctional PCDD nanoparticle is a promising platform for tumor combined chemotherapy, photodynamic therapy (PDT) and immunotherapy.


Assuntos
Neoplasias Pulmonares , Nanopartículas , Fotoquimioterapia , Dibenzodioxinas Policloradas , Animais , Ratos , Espécies Reativas de Oxigênio , Biomimética , Linhagem Celular Tumoral , Fotoquimioterapia/métodos , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente Tumoral
15.
Biomaterials ; 290: 121832, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36228518

RESUMO

Photodynamic therapy (PDT) induces apoptosis of cancer cells by generating cytotoxic reactive oxygen species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform is fabricated for the precise delivery of photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, ferroptosis activation and CD47-SIRPα blockade. Hemin's catalase-mimetic activity alleviates TME hypoxia and enhances PDT. The nanoplatform activates ferroptosis via both classical (down-regulating glutathione peroxidase 4 pathway) and non-classical (inducing Fe2+ overload) modes. Besides the role of hemin in consuming glutathione and up-regulating heme oxygenase-1 expression, interestingly, we observe that Ce6 enhance ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity is reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 has been revealed for the first time to sensitize ferroptosis by down-regulating system Xc-. This work sheds new light on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and ferroptosis activation, laying the theoretical foundation for novel combinational modes of cancer treatment.


Assuntos
Clorofilídeos , Ferroptose , Fotoquimioterapia , Porfirinas , Humanos , Antígeno CD47 , Microambiente Tumoral , Oxigênio/farmacologia , Biomimética , Hemina/farmacologia , Clorofilídeos/farmacologia , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Hipóxia/tratamento farmacológico
16.
Oxid Med Cell Longev ; 2022: 4813571, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120591

RESUMO

Downregulated DSC2 involved in the metastasis of cancers. Unfortunately, its role on the development of gastric cancer (GC) and the potential mechanisms remain unclear. Bioinformatics analysis, Western blot, qRT-PCR, and immunohistochemistry were performed to detect the DSC2 levels of human GC and normal stomach tissues. The role of DSC2 and the downstream signaling in gastric carcinogenesis were explored by using GC specimens, GC cells with different DSC2 expression, inhibitors, and mouse metastasis models. We found that the level of DSC2 decreased significantly in GC tissues and cells. Recovered DSC2 inhibited the invasion and migration of GC cells both in culture and in xenografts. Mechanistically, DSC2 could not only decrease Snail level and nuclear BRD4 level by forming DSC2/BRD4, but also inhibit nuclear translocation of ß-catenin. We concluded that DSC2 inhibited the metastasis of GC, and the underlying mechanisms were closely related to the regulation on nuclear translocation of BRD4 and ß-catenin. Our results suggest that DSC2 may serve as a novel therapeutic target for GC.


Assuntos
Neoplasias Gástricas , beta Catenina , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Desmocolinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo
17.
Expert Opin Drug Deliv ; 19(3): 221-234, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35164610

RESUMO

INTRODUCTION: Compared with ordinary chemotherapeutic drugs, the variable-size nanoparticles (NPs) have better therapeutic effects and fewer side effects. AREAS COVERED: This review mainly summarizes the strategies used to construct smart, size-tunable nanocarriers based on characteristic factors of tumor microenvironment (TME) to dramatically increase the penetration and retention of drugs within tumors. EXPERT OPINION: Nanosystems with changeable sizes based on the TME have been extensively studied in the past decade, and their permeability and retention have been greatly improved, making them a very promising treatment for tumors.


Assuntos
Nanopartículas , Neoplasias , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Microambiente Tumoral
18.
Colloids Surf B Biointerfaces ; 212: 112345, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35074639

RESUMO

Despite its high antitumor activity, the clinical application of chemotherapy is greatly impeded by lacking of specific accumulation and poor solubility. To address the above challenges, we designed a AS1411 aptamer modified nanoparticles based on molecular recognition of nucleobases. Firstly, a redox sensitive Paclitaxel-SS-Zidovudine (PZ) prodrug was synthesized. Then PZ/ß-lapachone/AS1411/DSPE-PEG nanoparticles were prepared and AS1411 aptamer was connected through molecular recognition between the nucleoside analogue Zidovudine (ZDV) and the thymine on aptamer. DSPE-PEG (DP) was incorporated into nanoparticles to prolong the residence time of nanoparticles in the blood circulation. Furthermore, to realize the combination treatment, ß-lapachone (LAP) has been incorporated into nanoparticles with high drug loading efficiency through the interaction of π-π stacking force and H-bonding between LAP and Paclitaxel (PTX). LAP can generate abundant exogenous reactive oxygen species (ROS) via the bioactivation of NAD(P)H: quinone oxidoreductase-1 (NQO1). Moreover, the connection of Zidovudine (ZDV) and AS1411 through molecular recognition of nucleobases further optimized the nanoparticles with high affinity to nucleolin which overexpressed on tumor cell membrane, thereby inducing the specific accumulation of nanoparticles in tumor sites. In vivo and in vitro studies showed that the obtained nanoparticles of PZ/LAP/AS1411/DP exhibited better tumor growth inhibition and lower systemic side effects. Herein, we have rationally conducted a novel self-codelivery system for effectively synergistic antitumor treatment.


Assuntos
Nanopartículas Multifuncionais , Nanopartículas , Pró-Fármacos , Aptâmeros de Nucleotídeos , Linhagem Celular Tumoral , Naftoquinonas , Nucleosídeos , Oligodesoxirribonucleotídeos , Oxirredução , Paclitaxel , Pró-Fármacos/farmacologia
19.
J Med Chem ; 65(5): 4218-4237, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35084182

RESUMO

Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower compared with that of lesinurad. Moreover, 23 exhibited stronger URAT1 inhibition activity (IC50 = 1.36 µM) than lesinurad (IC50 = 5.54 µM). Additionally, 23 showed favorable safety profiles, and no obvious acute toxicity was observed in Kunming mice under a single dose of 1000 mg·kg-1. 23 also achieved excellent pharmacokinetic properties with the oral bioavailability of 59.3%. Overall, all the results indicated that 23 is a promising drug candidate in the treatment of hyperuricemia and gout.


Assuntos
Gota , Hiperuricemia , Transportadores de Ânions Orgânicos , Animais , Gota/tratamento farmacológico , Humanos , Hiperuricemia/tratamento farmacológico , Camundongos , Proteínas de Transporte de Cátions Orgânicos , Ácido Úrico/uso terapêutico
20.
J Drug Target ; 30(2): 166-187, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34319838

RESUMO

Autophagy is a multi-step lysosomal degradation process, which regulates energy and material metabolism and has been used to maintain homeostasis. Autophagy has been shown to be involved in the regulation of health and disease. But at present, there is no consensus on the relationship between autophagy and tumour, and we consider that it plays a dual role in the occurrence and development of tumour. That is to say, under certain conditions, it can inhibit the occurrence of tumour, but it can also promote the process of tumour. Therefore, autophagy could be used as a target for tumour treatment. The regulation of autophagy plays a synergistic role in the radiotherapy, chemotherapy, phototherapy and immunotherapy of tumour, and nano drug delivery system provides a promising strategy for improving the efficacy of autophagy regulation. This review summarised the progress in the regulatory pathways and factors of autophagy as well as nanoformulations as carriers for the delivery of autophagy modulators.


Assuntos
Autofagia , Neoplasias , Autofagia/fisiologia , Homeostase , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
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