RESUMO
Fludarabine (FA) is still considered as a first-line chemotherapy drug for hematological tumors related to B lymphocytes. However, it is worth noting that the non-specific distribution and non-different cytotoxicity of FA may lead to irreversible consequences such as central nervous system damage such as blindness, coma, and even death. Therefore, it is very important to develop a system to targeting delivery FA. In preliminary studies, it was found that B lymphoma cells would specific highly expressing the sialic acid-binding immunoglobulin-like lectin 2 (known as CD22). Inspired by the specific recognition of sialic acid residues and CD22, we have developed a supramolecular prodrug based on polysialic acid, an endogenous biomacromolecule, achieving targeted-therapy of B-cell non-Hodgkin's lymphoma (B-NHL). Specifically, the prepared hydrophobic reactive oxygen species-responsive FA dimeric prodrug (F2A) interacts with the TPSA, which polysialic acid were modified by the thymidine derivatives, through non-covalent intermolecular interactions similar to "Watson-Crick" base pairing, resulting in the formation of nanoscale supramolecular prodrug (F@TPSA). Cell experiments have confirmed that F@TPSA can be endocytosed by CD22+ B lymphoma cells including Raji and Ramos cells, and there is a significant difference of endocytosis in other leukocytes. Furthermore, in B-NHL mouse model, compared with FA, F@TPSA is determined to have a stronger tumor targeting and inhibitory effect. More importantly, the distribution of F@TPSA in vivo tends to be enriched in lymphoma tissue rather than nonspecific, thus reducing the leukopenia of FA. The targeted delivery system based on PSA provides a new prodrug modification strategy for targeted treatment of B-NHL.
Assuntos
Linfoma de Células B , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Camundongos , Humanos , Linhagem Celular Tumoral , Linfoma de Células B/tratamento farmacológico , Ácidos Siálicos/química , Ácidos Siálicos/farmacologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Antineoplásicos/farmacologia , Antineoplásicos/química , Nanopartículas/química , Medicina de Precisão/métodos , Sistemas de Liberação de Medicamentos/métodos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Linfoma não Hodgkin/tratamento farmacológicoRESUMO
Polysialic acid (PSA) is a straight-chain homoglycan linked by N-acetylneuraminic acid monomers via α-2, 8- or α-2, 9-glycosidic bonds. As a negatively charged non-glycosaminoglycan, PSA has the remarkable characteristics of non-immunogenicity and biodegradation. Although different in class, PSA is similar to poly(ethylene glycol), and was originally used to increase the stability of the delivery system in circulation to prolong the half-life. As research continues, PSA's application potential in the pharmaceutical field becomes increasingly prominent. It can be used as a biomaterial for protein polysialylation and tissue engineering, and it can be used alone or with other materials to develop multifunctional drug delivery systems. In this article, the results of the bioproduction and biofunction of PSA are introduced, the common strategies for chemical modification of PSA are summarized, and the application progress of PSA-based drug delivery systems is reviewed.
Assuntos
Sistemas de Liberação de Medicamentos , Ácidos Siálicos , Sistemas de Liberação de Medicamentos/métodos , Ácidos Siálicos/química , Ácido N-Acetilneuramínico , Meia-VidaRESUMO
Numerous cutting-edge studies have confirmed that the slow accumulation of cell cycle arrested and secretory cells, called senescent cells (SCs), in tissues is an important negative factor, or even the culprit, in age- associated diseases such as non-alcoholic fatty liver, Alzheimer's disease, type 2 diabetes, atherosclerosis, and malignant tumors. With further understanding of cellular senescence, SCs are important effective targets for the treatment of senescence-related diseases, called the Senotherapy. However, existing therapies, including Senolytics (which lyse SCs) and Senostatic (which regulate senescence-associated secretory phenotype), do not have the properties to target SCs, and side effects due to non-specific distribution are one of the hindrances to clinical use of Senotherapy. In the past few decades, targeted delivery has attracted much attention and been developed as a recognized diagnostic and therapeutic novel tool, due to the advantages of visualization of targets, more accurate drug/gene delivery, and ultimately "reduced toxicity and enhanced efficacy". Despite considerable advances in achieving targeted delivery, it has not yet been widely used in Senotherapy. In this review, we clarify the challenge for Senotherapy, then discuss how different targeted strategies contribute to imaging or therapy for SCs in terms of different biomarkers of SCs. Finally, the emerging nano-Senotherapy is prospected.
Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias , Humanos , Senoterapia , Senescência Celular , Neoplasias/patologiaRESUMO
B-cell lymphoma is one of the most common types of lymphoma, and chemotherapy is still the current first-line treatment. However, due to the systemic side effects caused by chemotherapy drugs, traditional regimens have limitations and are difficult to achieve ideal efficacy. Recent studies have found that CD22 (also known as Siglec-2), as a specific marker of B-cells, is significantly up-regulated on B-cell lymphomas. Inspired by the specific recognition and binding of sialic acid residues by CD22, a polysialic acid (PSA)-modified PLGA nanocarrier (SAPC NP) designed to target B-cell lymphoma was fabricated. Mitoxantrone (MTO) was further loaded into SAPC NP through hydrophobic interactions to obtain polysialylated immunogenic cell death (ICD) nanoinducer (MTO@SAPC NP). Cellular experiments confirmed that MTO@SAPC NP could be specifically taken up by two types of CD22+ B lymphoma cells including Raji and Ramos cells, unlike the poor endocytic performance in other lymphocytes or macrophages. MTO@SAPC NP was determined to enhance the ICD and show better apoptotic effect on CD22+ cells. In the mouse model of B-cell lymphoma, MTO@SAPC NP significantly reduced the systemic side effects of MTO through lymphoma targeting, then achieved enhanced anti-tumor immune response, better tumor suppressive effect, and improved survival rate. Therefore, the polysialylated ICD nanoinducer provides a new strategy for precise therapy of B-cell lymphoma. STATEMENT OF SIGNIFICANCE: ⢠Polysialic acid functionalized nanocarrier (SAPC NP) was designed and prepared. ⢠SAPC NP is specifically endocytosed by two CD22+ B lymphoma cells. ⢠Mitoxantrone-loaded nanoinducer (MTO@SAPC NP) promote immunogenic cell death and anti-tumor immune response. ⢠"Polysialylation" is a potential new approach for precision treatment of B-cell lymphoma.
Assuntos
Linfoma de Células B , Linfoma , Animais , Apoptose , Imunidade , Linfoma de Células B/tratamento farmacológico , Camundongos , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêuticoRESUMO
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by a complex and dysfunctional immune response. Currently, IBD is incurable, and patients with IBD often need to take drugs for life. However, as the traditional systemic treatment strategies for IBD do not target the site of inflammation, only limited efficacy can be obtained from them. Moreover, the possibility of serious side effects stemming from the systemic administration or redistribution of drugs in the body is high when conventional drug formulations are used. Therefore, a targeted drug-delivery system for IBD should be considered. Based on the pathological features related to IBD, the new targeted drug-delivery strategy can directly transfer the drug to the inflammatory site, thus enhancing the accumulation of the drugs and reducing side effects. This article reviews the pathological features of IBD and the application of the IBD-targeted delivery system based on different pathological features, and discusses the challenges and new prospects in this field.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Preparações FarmacêuticasRESUMO
Due to its complexity, diversity and heterogeneity, melanoma is a kind of malignant tumor. It has been proved that the enhancement of anti-tumor immune response such as immunogenic cell death (ICD) is an important therapeutic strategy. In previous studies, we confirmed that dermatan sulfate (DS) from skin tissue could specifically homing to melanoma B16F10 cells. In this study, we propose a nanoinducer (DOX/ADS NP) based on a functional DS for melanoma. This nanosystem is composed of DS as framework, aromatic thioketal derivative (ATK) as functional grafting unit and doxorubicin (DOX) designed as an ICD inducer. Through the intermolecular interaction between DOX and ATK, DOX/ADS NP with specific-homing, high-loading and ROS-triggering release was obtained via self-assemble. Compared with free DOX and non-functionalized nanomedicine, DOX/ADS NP could release DOX into B16F10 cells better, and strongly induce the translocation of calreticulin (CRT) to the cell membrane. CRT is a marker of ICD, also as a "eat me" signal to stimulate the maturation and antigen presentation of dendritic cells. Therefore, a series of subsequent immune responses were activated: maturation of dendritic cells, T cells proliferation, increased tumor-infiltrating CTLs and the ratio of CTLs to Tregs, and up-regulated cytotoxic cytokine expression. In conclusion, DOX/ADS NP promoted ICD-associated immune response through more specific targeting effect and sensitive responsive DOX release, achieving better inhibitory effect on melanoma than free DOX and other nanoformulation. This biomimetic ICD nanoinducer based on DS is expected to provide new strategies and references for the treatment of melanoma.
Assuntos
Antineoplásicos , Melanoma , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dermatan Sulfato/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Morte Celular Imunogênica , Melanoma/tratamento farmacológico , Melanoma/patologia , Espécies Reativas de OxigênioRESUMO
Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.
Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Neoplasias Associadas a Colite/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Budesonida/administração & dosagem , Budesonida/química , Budesonida/farmacologia , Linhagem Celular , Neoplasias Associadas a Colite/metabolismo , Neoplasias Associadas a Colite/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , GencitabinaRESUMO
Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H2O2- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.
Assuntos
Ácidos Borônicos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Pró-Fármacos/farmacologia , Animais , Linhagem Celular Tumoral , Microambiente Celular , Liberação Controlada de Fármacos , Camundongos , Nanopartículas/químicaRESUMO
Melanoma is a malignant tumor of melanocytes that is a serious threat to human health. Dermatan sulfate (DS) is a natural glycosaminoglycan. Inspired by the origin of DS, we report a DS-functionalized biomimetic chitosan nanocarrier (DCNP) for melanoma targeted chemotherapy. DS can anchor to the surface of the chitosan nanocarrier (CNP) by forming amide bond. The SN38/DCNP can rapidly release the anti-tumor drug under acidic conditions. The functionalization of DS not only promoted the specific uptake behavior of melanoma cells, but also up-regulated cleaved caspase-3 and PARP promote tumor cell apoptosis. In vivo model, DCNP reduced the non-specific distribution of SN38 in the circulation and other tissues, while shows superior tumor targeting ability. SN38/DCNP significantly inhibit tumor growth and improved the survival rate. Moreover, SN38/DCNP has a milder myelosuppressive effect. The above results indicated that DS could be used as an excellent targeting unit for the treatment of melanoma.
Assuntos
Materiais Biomiméticos/química , Camptotecina/farmacologia , Dermatan Sulfato/química , Melanoma/tratamento farmacológico , Nanopartículas/química , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Materiais Biomiméticos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Dermatan Sulfato/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Estrutura Molecular , Nanopartículas/administração & dosagem , Tamanho da Partícula , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG2K. The morphology of B-ATK-T NP (approximate 100-120nm) was confirmed to be regular spherical by transmission electron microscope. B-ATK-T NP was endowed high drug loading content with 41.23% for Bud and 15.55% for Tem. The rapid drug release from B-ATK-T NP proceeded in an extensive reactive oxygen species (ROS)-dependent manner. More than 98% of Bud and Tem in B-ATK-T NP could release in the mimic inflammation microenvironment or phorbol-12-myristate-13-acetate (PMA)-stimulated macrophages within short time. The release of drugs in a simultaneous and proportional manner ensures that B-ATK-T NP can increase the combined efficacy of anti-inflammation and anti-oxidation. It is worth noting that B-ATK-T NP could be passively accumulated and dramatically increasing the maximum drugs concentration in the inflamed colon of mice with inflammatory bowel disease (IBD) by oral route, and avoiding potential systemic side effects. B-ATK-T NP could not only relieve colitis via inhibiting the expression of oxidative and proinflammatory mediators more than combination of free drugs, but also significantly reduce colitis-caused death. Taken together, the self-assembled, Janus-prodrug B-ATK-T NP is a promising candidate therapies for IBD, even for other inflammatory diseases.
Assuntos
Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Budesonida/farmacologia , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Pró-Fármacos , Células RAW 264.7 , Marcadores de SpinRESUMO
Colitis-associated colon cancer (CAC) is a widely recognized cancer, while treatment with the existing chemotherapeutic drugs affords limited clinical benefits. Herein we proposed a site-specific, combination nanotherapy strategy for targeted treatment of CAC by the oral route. Methods: A reactive oxygen species (ROS)-responsive and hydrogen peroxide-eliminating material OCD was synthesized, which was further produced into a functional nanoparticle (OCD NP). The antioxidative stress and anti-inflammatory effects of OCD NP were examined by in vitro and in vivo experiments. By packaging an anticancer drug camptothecin-11 (CPT-11) into OCD NP, a ROS-responsive nanotherapy CPT-11/OCD NP was obtained, and its antitumor activity was evaluated by both in vitro and in vivo studies. Preliminary safety studies were also performed for CPT-11/OCD NP in mice. Results: OCD NP significantly attenuated oxidative stress and inhibited inflammatory response in different cells and mice with induced colitis. CPT-11/OCD NP could selectively release drug molecules under intestinal pH conditions and at high levels of ROS. In C26 murine colon carcinoma cells, this nanotherapy showed significantly higher antitumor activity compared to free CPT-11 and a non-responsive CPT-11 nanotherapy. Correspondingly, oral delivery of CPT-11/OCD NP notably inhibited tumorigenesis and tumor growth in mice with induced CAC. By combination therapy with the nanovehicle OCD NP in the inflammatory phase, more desirable therapeutic effects were achieved. Furthermore, CPT-11/OCD NP displayed excellent safety profile for oral administration at a dose that is 87.3-fold higher than that employed in therapeutic studies. Conclusions: Anticancer nanotherapies derived from intrinsic anti-inflammatory nanocarriers are promising for targeted combination treatment of inflammation-associated tumors by simultaneously shaping pro-inflammatory microenvironment toward a relatively normal niche sensitive to chemotherapy.
Assuntos
Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Nanopartículas Multifuncionais/química , Microambiente Tumoral , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Colite/complicações , Neoplasias do Colo/etiologia , Progressão da Doença , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/química , Hidrólise , Inflamação/patologia , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
The flavonoid-metal complexes showed obviously stronger bioactivities such as antibiosis, antivirus, anti-inflammatory, anti-tumor and anti-free-radical, possibly because of the stronger binding force caused by the change in complex structure and accessibility to target spots, or the synergy effect between flavonoids and metallic ions. This essay summarizes studies on bioactivity and mechanism of flavonoid-metal complexes, in order to provide reference for in-depth study and development on effective constituents contained in flavonoid traditional Chinese medicines.