RESUMO
Mitochondrial DNA and nuclear DNA are essential genetic material which play an important role in maintaining normal metabolism, survival, and proliferation of cells. Constructing a mitochondria-targeting stimuli-responsive nano-drug delivery system releasing chemotherapeutic agents in a stepwise response manner and destroying mitochondrial DNA and nuclear DNA simultaneously is an effective way to improve the anti-tumor effect of chemotherapeutic agents. In this study, a new mitochondria-targeting pH/ROS dual-responsive block copolymer TPP-PEG2k-b-(BS-AA)n (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-b-(BS-AA)n (P2), pH single-responsive copolymer (mPEG2k-b-(AH-AA)n (P3), ROS single-responsive copolymer mPEG2k-b-(SA-TG)n (P4), and non-responsive copolymer mPEG-b-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Anticancer chemotherapeutic agent gemcitabine (GEM) or fluorescent substance Nile Red (NR) were loaded in the polymer micelles. Results of the mitochondrial colocalization experiment indicate that (5-carboxypentyl)(triphenyl)phosphonium bromide (TPP)-functionalized P1 micelles could be efficiently targeted and located in mitochondria. Results of the cellular uptake experiment showed that pH/ROS dual-responsive GEM-loaded P1 and P2 micelles have faster internalized and entry nucleus rates than single-responsive or non-responsive GEM-loaded micelles. The in vitro release experiment suggests pH/ROS dual-responsive GEM/P1 and GEM/P2 micelles have higher cumulative release than single-responsive GEM/P3 and GEM/P4 micelles. The in vitro cytotoxic experiment shows that the mitochondria-targeted dual-responsive GEM/P1 micelles had the lowest IC50 values, and the cytotoxic effect of dual-responsive GEM/P2 micelles was superior to the single-responsive and non-responsive drug-loaded micelles.
Assuntos
Antineoplásicos , Micelas , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Brometos/farmacologia , Prótons , Mitocôndrias/metabolismo , Antineoplásicos/química , Polietilenoglicóis/farmacologia , DNA Mitocondrial/metabolismo , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , GencitabinaRESUMO
Although nucleos(t)ide analog (NA) monotherapy is effective in hepatitis B virus suppression and fibrosis regression, serological response rates are not satisfactory. Studies assessing the benefits of combination therapy with NAs and peginterferon alpha (PegIFNα) in patients with chronic hepatitis B (CHB) have produced conflicting results and mainly focused on serological outcomes. Histological changes in response to combination therapy have not been evaluated in real-world practice. This study aimed to evaluate the histological changes in response to NA-PegIFNα combination therapy in CHB patients and to comprehensively compare the efficacy of NA-PegIFNα combination therapy and NA monotherapy. We conducted a retrospective analysis of data from 40 CHB patients who underwent either NA-PegIFNα combination therapy or NA monotherapy. Changes in histology at 48 weeks after treatment initiation were evaluated. Serological characteristics were also analysed and compared between the NA-PegIFNα combination therapy and NA monotherapy groups and between histological responders and nonresponders. Compared to baseline biopsies, both fibrosis staging and necroinflammatory grading scores were significantly lower in the second biopsies examined post-treatment in both groups. Nearly all patients experienced a reduction in inflammation (87.5% in both groups), but there was a subgroup of patients who exhibited either no significant improvement or fibrosis progression (33.3% and 31.2% in the NA monotherapy and NA-PegIFNα combination therapy groups, respectively). Nearly, all patients achieved ALT normalization and sustained virological response (SVR) after 48 weeks of antiviral treatment. Approximately one-third of individuals (36.8% and 30% in the two groups, respectively) achieved HBeAg loss at 48 weeks after treatment initiation. Although there were no significant differences in overall rates of histological, biochemical, virological and serological responses between the two groups, an earlier virological response and a higher cumulative SVR rate over time were observed during long-term follow-up in patients treated with NA-PegIFNα combination therapy (P = 0.0129). Trends of more rapid HBeAg loss and a higher cumulative HBeAg loss rate throughout long-term follow-up were also observed but were not statistically significant. The ALT normalization rates at 24 and 48 weeks after treatment initiation were associated with the histological response. Significant regression of fibrosis and resolution of necroinflammation were induced with either NA-PegIFNα combination therapy or NA monotherapy. Significant biochemical, virological and serological responses were observed in both groups, and the response rates at 48 weeks were similar in the two groups. Over time during long-term follow-up, the virological and serological responses were faster and superior following the combination regimen.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Interferon-alfa/uso terapêutico , Nucleotídeos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Biópsia , Quimioterapia Combinada , Feminino , Hepatite B Crônica/virologia , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Nucleotídeos/administração & dosagem , Nucleotídeos/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Although long-term antiviral treatment with nucleos(t)ide analogs (NAs) can lead to histological improvement in patients with chronic hepatitis B (CHB), a substantial proportion of patients still fail to achieve regression of fibrosis. Here, we investigated whether peginterferon alpha (Peg-IFNαï¼ add-on therapy had benefits on fibrosis regression in patients with sustained severe fibrosis even after long-term NA treatment. We conducted a retrospective analysis of data from 50 patients with CHB receiving 48 weeks of Peg-IFNα add-on therapy. All enrolled patients had advanced fibrosis or cirrhosis (S score ≥ 3) at baseline and underwent NA treatment for at least 1 year before Peg-IFNα addition. Paired liver biopsies before and after Peg-IFNα add-on treatment and laboratory tests at baseline, 24 weeks of treatment, 48 weeks of treatment and long-term follow-up were analysed. Of the 50 patients enrolled in this study, 34 patients (68.0%) had significant regression of fibrosis, and 42 (84.0%) showed significant remission of inflammation after Peg-IFNα add-on treatment. Compared with nonresponders, patients with significant histological improvement showed faster hepatitis B surface antigen (HBsAg) decline and tended to have higher cumulative hepatitis B e antigen (HBeAg) and HBsAg loss rates during long-term follow-up. Peg-IFNα add-on therapy led to significant regression of fibrosis and resolution of inflammation in patients with advanced fibrosis after long-term NA treatment.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Interferon-alfa/uso terapêutico , Cirrose Hepática/patologia , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Idoso , Biomarcadores , Biópsia , DNA Viral , Quimioterapia Combinada , Feminino , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/etiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Due to the high oxidative stress of the tumor microenvironment, more and more researchers have been devoted to reactive oxygen species (ROS)-responsive nanodrug delivery systems for anticancer therapy. Herein, a ROS-responsive moiety, thioacetal, was synthesized, and cinnamaldehyde (CA) was introduced in the polymer chain to trigger the generation of ROS to expect the enhancement of the ROS-responsive effect. The poly(ester-thioacetal) mPEG2k - b-(NTA-HD)12 polymer, its self-assembled micelles, and the ROS-responsive behavior were characterized by 1H NMR and DLS. The anticancer drug doxorubicin (DOX) was adopted to prepare DOX-loaded poly(ester-thioacetal) micelles. The intracellular ROS detection indicated that the mPEG2k - b-(NTA-HD)12 polymer could degrade via the high concentration of ROS in cancer cells, and the released CA stimulated mitochondria to regenerate additional ROS. The flow cytometry results indicated that the ROS-responsive polymeric micelles showed faster cellular uptake compared to the control mPEG2k - b-PCL5k micelles. The ROS responsive DOX/mPEG2k - b-(NTA-HD)12 micelles exhibited much better anticancer efficiency on both 4T1 and HeLa cancer cells than DOX/mPEG2k - b-PCL5k micelles.
Assuntos
Antineoplásicos/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacologia , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Micelas , Nanopartículas/química , Poliésteres/química , Polímeros/química , Espécies Reativas de OxigênioRESUMO
With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 µg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL-PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 µg/mL) and in vivo anticancer activity tests revealed that the DOX-loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Transferência Ressonante de Energia de Fluorescência , Micelas , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Monitoramento de Medicamentos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis , Polímeros , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As the implications of reactive oxygen species (ROS) are elucidated in many diseases, ROS-responsive nanoparticles are attracting great interest from researchers. In this work, a ROS sensitive thioketal (TK) moiety with a π-conjugated structure was introduced into biodegradable methoxy poly(ethylene glycol)-thioketal-poly(ε-caprolactone)mPEG-TK-PCL micelles as a linker, which was designed to speed up the drug release and thus enhance the therapeutic efficacy. The micelle showed a high drug loading content of 12.8% and excellent stability under physiological conditions because of the evocation of π-π stacking and hydrophobic interactions with the anticancer drug doxorubicin (DOX). The polymeric micelle presented a better drug carrier capacity and higher in vitro anticancer efficacy towards cancer cells. The in vivo study showed that DOX-loaded mPEG-TK-PCL micelles displayed lower toxicity towards normal cells and remarkably enhanced antitumor efficacy. This research provides a way to design potential drug carriers for efficient cancer chemotherapy.
Assuntos
Acetais/química , Portadores de Fármacos/química , Micelas , Polímeros/química , Animais , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Cetonas/química , CamundongosRESUMO
Chitosan is widely used in molecular imprinting technology (MIT) as a functional monomer or supporting matrix because of its low cost and high contents of amino and hydroxyl functional groups. The various excellent properties of chitosan, which include nontoxicity, biodegradability, biocompatibility, and attractive physical and mechanical performances, make chitosan a promising alternative to conventional functional monomers. Recently, chitosan molecularly-imprinted polymers have gained considerable attention and showed significant potential in many fields, such as curbing environmental pollution, medicine, protein separation and identification, and chiral-compound separation. These extensive applications are due to the polymers' desired selectivity, physical robustness, and thermal stability, as well as their low cost and easy preparation. Cross-linkers, which fix the functional groups of chitosan around imprinted molecules, play an important role in chitosan molecularly-imprinted polymers. This review summarizes the important cross-linkers of chitosan molecularly-imprinted polymers and illustrates the cross-linking mechanism of chitosan and cross-linkers based on the two glucosamine units. Finally, some significant attempts to further develop the application of chitosan in MIT are proposed.
Assuntos
Quitosana/química , Reagentes de Ligações Cruzadas/química , Impressão Molecular/métodos , Polímeros/químicaRESUMO
Modern baleen whales are unique as large-sized filter feeders, but their roles were replicated much earlier by diverse marine reptiles of the Mesozoic. Here, we investigate convergence in skull morphology between modern baleen whales and one of the earliest marine reptiles, the basal ichthyosauromorph Hupehsuchus nanchangensis, from the Early Triassic, a time of rapid recovery of life following profound mass extinction. Two new specimens reveal the skull morphology especially in dorsal view. The snout of Hupehsuchus is highly convergent with modern baleen whales, as shown in a morphometric analysis including 130 modern aquatic amniotes. Convergences in the snout include the unfused upper jaw, specialized intermediate space in the divided premaxilla and grooves around the labial margin. Hupehsuchus had enlarged its buccal cavity to enable efficient filter feeding and probably used soft tissues like baleen to expel the water from the oral cavity. Coordinated with the rigid trunk and pachyostotic ribs suggests low speeds of aquatic locomotion, Hupehsuchus probably employed continuous ram filter feeding as in extant bowhead and right whales. The Early Triassic palaeoenvironment of a restrictive lagoon with low productivity drove Hupehsuchus to feed on zooplankton, which facilitated ecosystem recovery in the Nanzhang-Yuan'an Fauna at the beginning of the Mesozoic.
Assuntos
Evolução Biológica , Baleia Franca , Animais , Filogenia , Ecossistema , Crânio , BocaRESUMO
The block polyethers PEO-PPO-ph-PPO-PEO (BPE) and PPO-PEO-ph-PEO-PPO (BEP) are synthesized by anionic polymerization using bisphenol A as initiator. Compared with Pluronic P123, the aggregation behaviors of BPE and BEP at an air/water interface are investigated by the surface tension and dilational viscoelasticity. The molecular construction can influence the efficiency and effectiveness of block polyethers in decreasing surface tension. BPE has the most efficient ability to decrease surface tension of water among the three block polyethers. The maximum surface excess concentration (Γ(max)) of BPE is larger than that of BEP or P123. Moreover, the dilational modulus of BPE is almost the same as that of P123, but much larger than that of BEP. The molecular dynamics simulation provides the conformational variations of block polyethers at the air/water interface.
Assuntos
Ar , Simulação de Dinâmica Molecular , Polietilenoglicóis/síntese química , Água/química , Compostos Benzidrílicos/química , Fenóis/química , Poloxaleno/química , Polietilenoglicóis/química , Polimerização , Tensão SuperficialRESUMO
More and more industries demand environmental friendliness. Silkworm pupae oil (SPO), extracted from the desilked silkworm pupae, can serve as a promising substrate alternative to use in plasticization. This study aimed to prepare epoxidized silkworm pupae oil (ESPO) and investigate their effects on the thermal stability and plasticization of polyvinyl chloride (PVC) films. A chemo-enzymatic method of ESPO was developed in the presence of Lipase SMG1-F278N and H2O2 in natural deep eutectic solvents (DESs). Lipase SMG1-F278N could initiate the epoxidation reaction effectively at room temperature with a negligible loss of activities 10 batches. A maximum oxirane value of 6.94% was obtained. The formation of oxirane ring in ESPO was confirmed by FTIR and 13C NMR spectra. Moreover, ESPO showed a better thermal stability and lower freezing point than epoxidized soybean oil (ESO). It was demonstrated that ESPO had a good frost resistance. In addition, ESPO showed a significantly improved plasticizing effect on flexible polyvinyl chloride (PVC). Compared with ESO, ESPO could increase the tensile elongation at break effectively. A significantly lower migration rate of plasticizer was observed in PVC plasticized with ESPO.
Assuntos
Cloreto de PolivinilaRESUMO
It has been confirmed that endogenous glycopeptide plays an important role in a variety of pathological and physiological processes. However, direct analysis of endogenous glycopeptide is still a great challenge owing to the low abundance of endogenous glycopeptides and the presence of a large number of interfering substances such as large-sized proteins and heteropeptides in complex biological sample. Herein, we reported a novel bowl-like mesoporous polydopamine nanoparticle modified by carrageenan (denoted as MPDA@PEI@CA) with strong hydrophilicity and size-exclusion effect for high specificity enrichment of endogenous glycopeptides. Thanks to the suitable pore channel structure as well as strong hydrophilic surface, the as-prepared MPDA@PEI@CA nanoparticles exhibited prominent performance in enrichment of N-linked glycopeptide with ultrahigh selectivity (1:5000 M ratio of horseradish peroxidase (HRP) digests/bovine serum albumin (BSA) digests), low detection limit (5 fmol µL-1), outstanding size-exclusion ability (1:1000 mass of HRP/BSA), and unique reusability (five times). 125 N-glycosylation sites of 134 glycopeptides from 65 glycoproteins were identified from 2 µL sample of human serum treated with the MPDA@PEI@CA nanoparticles, which manifested the ability to enrich endogenous N-linked glycopeptides from complex biological samples. These results indicated that the bowl-like MPDA@PEI@CA nanoparticles with novel structure prepared in this work had great potential for glycopeptidome analysis.
Assuntos
Glicopeptídeos , Indóis , Peroxidase do Rábano Silvestre , Humanos , Interações Hidrofóbicas e Hidrofílicas , PolímerosRESUMO
OBJECTIVES: The current study was focused on preparing curcumin (CUR) supersaturated self-nano-emulsion (PI-CUR-SNEDDS) using hydrophilic polymer and to study the influence of polymer precipitation inhibitor on the physicochemical and biopharmaceutical properties of the PI-CUR-SNEDDS. METHODS: PI-CUR-SNEDDS were prepared using hydrophilic polymer in order to maintain the supersaturation of CUR in nano-emulsion solution, artificial gastrointestinal fluid (AGF), and the precipitates formed, and characterised by in vitro dispersion tests, in vitro intestinal absorption and in vivo pharmacokinetic and compared with CUR-SNEDDS. KEY FINDINGS: PI-CUR-SNEDDS prepared with 2% hydroxypropyl methylcellulose 55-60 (HPMC55-60) as precipitation inhibitor (PI) significantly improved the viscosity, physical stability and CUR's equilibrium solubility of nanoemulsion. HPMC55-60 and CUR interact in AGF through intermolecular interactions, form hydrogen bonds, and produce amorphous precipitates. Compared with CUR-SNEDDS, the proportion of CUR in the hydrophilic phase increased by about 3-fold, and apparent permeability coefficient (Papp) in duodenum, jejunum, ileum, and colon increased by 2.30, 3.65, 1.54 and 2.08-fold, respectively, and the area under the plasma concentration-time curve0-12h of PI-CUR-SNEDDS also increased by 3.50-fold. CONCLUSIONS: Our results suggested that HPMC55-60 maintained the CUR supersaturation state by forming hydrogen bonds with CUR, increasing the solution's viscosity and drug solubilisation, thus improving the absorption and bioavailability of CUR.
Assuntos
Curcumina/administração & dosagem , Curcumina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Emulsões/química , Interações Hidrofóbicas e Hidrofílicas , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/farmacologia , Absorção Intestinal , Tamanho da Partícula , Polímeros/administração & dosagem , Polímeros/farmacologia , Ratos Sprague-Dawley , SolubilidadeRESUMO
Targeted gene delivery offers immense potential for clinical applications. Liposomes decorated with targeting ligands have been extensively used for both in vitro and in vivo gene delivery. Lipoplexes with high cholesterol content that result in cholesterol domain formation within the complexes have been shown to exhibit enhanced transfection in vitro and resistance to serum-induced aggregation. In the present study, folate was employed as a targeting ligand that was conjugated with either cholesterol or a diacyl lipid (DSPE), and these conjugates were incorporated into lipoplexes formulated with DOTAP/cholesterol (wt/wt: 31/69) that are known to possess cholesterol nanodomains. Cellular uptake and transfection of these lipoplexes in the presence of 50% serum were examined when the ligand was located within or excluded from the cholesterol nanodomain. Lipoplexes with folate-cholesterol exhibited a 50-fold increase in transfection compared to those with folate-DSPE, while the cellular uptake level is only 40% of that with folate-DSPE. These results indicate that the presence of the ligand within the cholesterol domain promotes more productive transfection in cultured cells, and intracellular trafficking of the lipoplexes after entry into cells plays a crucial role in gene delivery.
Assuntos
Colesterol/química , Técnicas de Transferência de Genes , Lipossomos/química , Lipossomos/metabolismo , Varredura Diferencial de Calorimetria , Linhagem Celular Tumoral , Ácidos Graxos Monoinsaturados/química , Citometria de Fluxo , Ácido Fólico/química , Humanos , Fosfatidiletanolaminas/química , Compostos de Amônio Quaternário/química , Espalhamento de RadiaçãoRESUMO
The interaction between the cationic lipid DOTAP and cholesterol is examined in high cholesterol formulations by differential scanning calorimetry (DSC). Preparation of liposomes above 66 mol% cholesterol results in formulations that exhibit a calorimetric transition for anhydrous cholesterol at 38-40 degrees C. The enthalpy of this transition progressively increases at higher cholesterol contents, and is not detected below 66 mol% cholesterol. Furthermore, the enthalpy changes indicate that the composition of the non-domain forming portion containing DOTAP saturated with cholesterol is relatively constant above 66 mol% cholesterol. Greater transfection efficiency in the presence of 50% serum is observed at the formulations with high cholesterol contents where anhydrous cholesterol domains are detected by DSC. Although formulations possessing higher cholesterol exhibited a greater resistance to serum-induced aggregation, maintenance of small particle size does not appear to be responsible for the enhanced transfection efficiency. Additional studies quantifying albumin binding suggest that cholesterol domains in the lipid/DNA complex do not bind protein, and this may enable these moieties to enhance transfection by facilitating membrane fusion.
Assuntos
Colesterol/química , DNA/química , Lipídeos/química , Transfecção/métodos , Varredura Diferencial de Calorimetria , Linhagem Celular , Ácidos Graxos Monoinsaturados/química , Corantes Fluorescentes/química , Humanos , Lipossomos/química , Compostos de Amônio Quaternário/químicaRESUMO
Thioketal and thioether are moieties used to fabricate reactive oxygen species (ROS)-responsive polymers for drug delivery. In this paper, three amphiphilic copolymers of mPEG-poly(ester-thioether), mPEG-poly(thioketal-ester) and mPEG-poly(thioketal-ester-thioether) were synthesized. The ROS-responsive behaviors of the three copolymers nanoparticles as drug carriers were investigated. The ROS-sensitivity was demonstrated by NMR, DLS, and SEM. mPEG-poly(ester-thioether) nanoparticles exhibited the fastest drug release rate, which possessed the best ROS sensitivity. The in vitro anticancer activity of the DOX-loaded nanoparticles was studied, the results revealed that the mPEG-poly(ester-thioether) nanoparticles showed the most efficient anticancer activity. Notably, all the three ROS-responsive copolymers nanoparticles showed enhanced cellular uptake and anticancer efficacy comparing to the control mPEG-b-PCL nanoparticles.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/síntese química , Doxorrubicina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Micelas , Estrutura MolecularRESUMO
Combining photodynamic therapy (PDT) and chemotherapy can improve anti-cancer efficacy. In this study, a novel copolymer PTPP combining thioketal and protoporphyrin was synthesized and tested for antitumor activity. Self-assembled PTPP micelles loaded with doxorubicin (DOX) showed uniform size, narrow particle size distribution and greater antitumor activity in vivo and in vivo than DOX-loaded micelles made from the commonly used material mPEG-PCL. Under laser irradiation, the photosensitizing protoporphyrin of DOX/PTPP produces abundant reactive oxygen species (ROS) that directly kill tumor cells as well as destroy the micelles themselves, leading to drug release. The ROS and DOX then act synergistically against the tumors. These ROS-responsive, laser-sensitive polymeric micelles may be useful for combining PDT and chemotherapy.
Assuntos
Espécies Reativas de Oxigênio/química , Doxorrubicina , Liberação Controlada de Fármacos , Micelas , Fotoquimioterapia , PolímerosRESUMO
BACKGROUND: Lumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects. METHODS AND RESULTS: Here, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(ε-benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied. CONCLUSION: We propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits.
Assuntos
Albuminas/uso terapêutico , Endopeptidases/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Albuminas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina B1/metabolismo , Portadores de Fármacos/química , Endopeptidases/sangue , Endopeptidases/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lisina/análogos & derivados , Lisina/síntese química , Lisina/química , Masculino , Microvasos/patologia , Peso Molecular , Paclitaxel/sangue , Paclitaxel/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polilisina/análogos & derivados , Polilisina/síntese química , Polilisina/química , Ratos Sprague-Dawley , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologiaRESUMO
Polymeric micelles are important carriers for anticancer drug delivery. However, rare papers focused on the dynamic of drug in the core of micelles. In this paper, we used fluorescence resonance energy transfer (FRET) technique to investigate the dynamic diffusion of drug from polymeric micelles. mPEG-PCL diblock copolymers were used as carriers. A pair of fluorescence molecules Cy3 and Cy5 was selected to evoke the FRET phenomenon. Cy5 was immobilized on the terminal group of PCL segments, Cy3 was encapsulated in the Cy5 modified polymeric micelles as the model drug. The drug loaded polymeric micelles were incubated with 4T1 breast cancer cells. The FRET was observed to explore the dynamic of Cy3 in the micelles. The results showed that the Cy3 loaded micelles were stable in aqueous solution as the energy-transfer efficiency (ETE, I660/I565) rarely decreased even when the time was as long as 120 h. The ETE increased with the content of encapsulated Cy3. The FRET spectra showed that the ETE of the Cy3 loaded polymeric micelles lowered with the release of Cy3 in PBS. The intracellular tracking of the Cy3 loaded micelles found more than 60% loaded drug was release within 12 h with the calculation of ETE in FRET spectra and it was same to confocal laser scanning and flow cytometry results.
Assuntos
Transferência Ressonante de Energia de Fluorescência , Micelas , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Polietilenoglicóis , PolímerosRESUMO
A method based on high-resolution size-exclusion chromatography (SEC) was established to analyze the solid products from the depolymerization of poly(trimethylene terephthalate) (PTT) in supercritical methanol. In the qualitative analysis, four factors (chromatographic retention time, qualitative multi-wavelength ultraviolet spectra, linear internal-insert SEC and qualitative IR spectra) were considered. The main solid products from the process were dimethyl terephthalate (DMT), methyl-(2-hydroxypropyl) terephthalate (MHPT), bis(2-hydroxypropyl) terephthalate (BHPT), methyl-(2-hydroxyethyl) terephthalate (MHET), bis(2-hydroxyethyl) terephthalate (BHET), and hydroxyethyl-(2-hydroxypropyl) terephthalate (HEHPT). It is found that the method is of a high resolution among the solid products and has a fine repeatability. In addition, the solid products from the de-polymerization of poly(ethylene terephthalate) (PET) in similar process were also analyzed by this method. Furthermore, the effects of supercritical conditions on the distribution of the products were also discussed.