RESUMO
Chemotherapy is the main method of treating malignant tumors in clinical treatment. However, the commonly used chemotherapeutic drugs have the disadvantages of high biological toxicity, poor water solubility, low targeting ability, and high side effects. Zwitterionic micelles assembled by amphiphilic dendrimers modified with zwitterionic groups and targeting ligand should largely overcome these shortcomings. Herein, the zwitterionic group and targeting peptide c(RGDfC) were modified on the surface of generation 2 poly(propylene imine) dendrimers (G2 PPI), which was conjugated with hydrophobic N-(2-mercaptoethyl) oleamide to form amphiphilic dendrimers (PPIMYRC). PPIMYRC self-assembled into micelles with doxorubicin (DOX) loaded in the interior of micelles to prepare DOX-loaded micelles (PPIMYRC-DOX micelles). The PPIMYRC-DOX micelles had great stability in fibrinogen and pH-responsive drug release. Furthermore, PPIMYRC-DOX micelles had higher cellular uptake rates than free DOX, resulting in higher cytotoxicity of PPIMYRC-DOX micelles than that of free DOX. More importantly, PPIMYRC-DOX micelles inhibited tumors much better than free DOX. The tumor inhibition rate of PPIMYRC-DOX micelles was as high as 93%. Taken together, PPIMYRC-DOX micelles were assembled by amphiphilic dendrimers with the zwitterionic and targeting groups, which enhanced the therapeutic effect of DOX and reduced its side effects. The prepared targeting nanodrug has great potential for further application in antitumor therapy.
Assuntos
Dendrímeros , Neoplasias , Humanos , Dendrímeros/química , Doxorrubicina , Portadores de Fármacos/toxicidade , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Micelas , Neoplasias/tratamento farmacológicoRESUMO
Much attention has been drawn to targeted nanodrug delivery systems due to their high therapeutic efficacy in cancer treatment. In this work, doxorubicin (DOX) was incorporated into a zwitterionic arginyl-glycyl-aspartic acid (RGD)-conjugated polypeptide by an emulsion solvent evaporation technique with high drug loading content (45%) and high drug loading efficiency (95%). This zwitterionic nanoformulation showed excellent colloidal stability at high dilution and in serum. The pH-induced disintegration and enzyme-induced degradation of the nanoformulation were confirmed by dynamic light scattering and gel permeation chromatography. Efficient internalization of DOX in the cells and high antitumor activity in vitro was observed. Compared with the free drug, this nanoformulation showed higher accumulation in tumor and lower systemic toxicity in vivo. The DOX-loaded zwitterionic RGD-conjugated polypeptide vesicles show potential application for targeted drug delivery in the clinic.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Peptídeos Cíclicos/química , Ácido Poliglutâmico/análogos & derivados , Polilisina/análogos & derivados , Linhagem Celular Tumoral , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Nanopartículas/química , Nanopartículas/toxicidade , Peptídeos Cíclicos/toxicidade , Ácido Poliglutâmico/química , Ácido Poliglutâmico/toxicidade , Polilisina/química , Polilisina/toxicidadeRESUMO
In this study, a versatile fabrication method for coating enzyme-based biosensors with ultrathin antifouling zwitterionic polymer films to meet the challenge of the long-time stability of sensors in vivo was developed. Electrochemically mediated atom transfer radical polymerization (eATRP) was applied to polymerize zwitterionic sulfobetaine methacrylate monomers on the rough enzyme-absorbed electrode surfaces; meanwhile, a refined overall bromination was developed to improve the coverage of polymers on the biosensor surfaces and to maintain the enzyme activity simultaneously for the first time. X-ray photoelectron spectroscopy and atomic force microscopy were used to characterize the properties of the polymer layers. The antifouling performance and long-time stability in 37 °C undiluted bovine serum in vitro were evaluated. The results showed that the polymer brush coatings diminished over 99% nonspecific protein adsorption and that the sensitivity of the evaluated sensor was maintained at 94% after 15 days. The overall sensitivity deviation of 7% was nearly 50% lower than that of the polyurethane-coated ones and also much smaller than the current commercially available glucose biosensors. The results suggested that this highly controllable electrodeposition procedure could be a promising method to develop implantable biosensors with long-time stability.
Assuntos
Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Animais , Betaína/análogos & derivados , Betaína/química , Incrustação Biológica , Técnicas Biossensoriais/instrumentação , Bovinos , Técnicas Eletroquímicas/instrumentação , Enzimas Imobilizadas/química , Glucose/análise , Glucose Oxidase/química , Halogenação , Teste de Materiais , Metacrilatos/química , Microscopia de Força Atômica , Espectroscopia Fotoeletrônica , Polimerização , Proteínas/química , Soro/químicaRESUMO
Blood stability, active targeting, and controlled drug release are the most important features to design desirable drug carriers. Here, we demonstrate a zwitterionic biodegradable cross-linked micelle based on a penta-block copolymer, which utilizes poly(carboxybetaine methacrylate) as hydrophilic segment, poly(ε-caprolactone) as biodegradable hydrophobic segment, poly(S-2-hydroxyethyl-O-ethyl dithiocarbonate methacrylate) (PSODMA) block as thiol protecting segment for cross-linking, and cyclic Arg-Gly-Asp-d-Tyr-Lys [c(RGDyK)] as targeting ligand. As a result, this micelle possessed excellent colloidal stability at high dilution and in 50% fetal bovine serum. In vitro drug release experiment showed no burst release under physiological conditions but accelerated drug release in mimicking tumor tissue environment. In vivo tests showed that the drug-loaded micelles had prolonged half-life in bloodstream, enhanced therapeutic efficiency, and reduced cardiac toxicity and biotoxicity compared with free drug formulation. Taken together, the reported c(RGDyK)-modified zwitterionic interfacially cross-linked micelle has emerged as an appealing platform for cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Materiais Biocompatíveis/química , Reagentes de Ligações Cruzadas/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Peptídeos Cíclicos/química , Polímeros/química , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Doxorrubicina/sangue , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Camundongos , Camundongos Nus , Micelas , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Polymer-drug conjugates are commonly used as nano drug vehicles (NDVs) to delivery anticancer drugs. Zwitterionic polymers are ideal candidates to conjugate drugs because they show higher resistance to nonspecific protein adsorption in complex media than that of nonionic water-soluble polymers, such as poly(ethylene glycol). However, the charge balance characteristics of zwitterionic polymers used as NDVs will be broken from the inclusion of additional charged groups brought by conjugated drugs or functional groups, leading to the loss of resistance to protein adsorption. Consequently, the nonspecific protein adsorption on drug carriers will cause fast clearance from the blood system, an immune response, or even severe systemic toxicity. To overcome this drawback, a model zwitterionic polymer, poly(carboxybetaine methacrylate) (pCBMA), was modified by the introduction of a negatively charged component, to neutralize the positive charge provided by the model drug, doxorubicin (DOX). A DOX-conjugated NDV which possesses excellent resistance to nonspecific protein adsorption was achieved by the formation of a strongly hydrated pCBMA shell with a slightly negative surface charge. This kind of DOX-conjugated NDV exhibited reduced cytotoxicity and prolonged circulation time, and it accelerated DOX release under mild acid conditions. In tumor-bearing mouse studies a 55% tumor-inhibition rate was achieved without causing any body weight loss. These results indicate the importance of charge tuning in zwitterionic polymer-based NDVs.
Assuntos
Antineoplásicos/farmacocinética , Betaína/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/síntese química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Adsorção , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células COS , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacocinética , Feminino , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Eletricidade Estática , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The homeostasis of IgG is maintained by the neonatal Fc receptor, FcRn. Consequently, antagonism of FcRn to reduce endogenous IgG levels is an emerging strategy for treating antibody-mediated autoimmune disorders using either FcRn-specific antibodies or an engineered Fc fragment. For certain FcRn-specific antibodies, this approach has resulted in reductions in the levels of serum albumin, the other major ligand transported by FcRn. Cellular and molecular analyses of a panel of FcRn antagonists have been carried out to elucidate the mechanisms leading to their differential effects on albumin homeostasis. These analyses have identified 2 processes underlying decreases in albumin levels during FcRn blockade: increased degradation of FcRn and competition between antagonist and albumin for FcRn binding. These findings have potential implications for the design of drugs to modulate FcRn function.
Assuntos
Antígenos de Histocompatibilidade Classe I , Receptores Fc , Receptores Fc/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunoglobulina G/metabolismo , Animais , Transporte Proteico/efeitos dos fármacos , Albumina Sérica/metabolismo , Camundongos , Ligação ProteicaRESUMO
The surface primary amines of generation five poly(amido amine) (G5 PAMAM) dendrimer were modified by different amounts of carboxybetaine acrylamide (CBAA). As a result, the fully modified molecules (CBAA-PAMAM-20, obtained from the 20:1 molar ratio of CBAA molecules to amino groups in modification solution) show excellent compatibility with protein and cells. CBAA-PAMAM-20 and fibrinogen (Fg) could coexist in solution without forming aggregation, indicating very weak interaction force between CBAA-PAMAM-20 and fibrinogen. CBAA-PAMAM-20 exhibits almost undetectable hemolytic activity, while other partially modified ones cause severe hemolysis and fibrinogen aggregation. Furthermore, the membrane of human umbilical vascular endothelial cell (HUVEC) remains intact after 24 h incubation with CBAA-PAMAM-20. The cytotoxicity assay of HUVEC cells and KB cells also showed that the CBAA-PAMAM-20 was not cytotoxic up to a 2 mg/mL concentration (>90% cell viability). In short, a thin compact layer of zwitterionic carboxybetaine could reduce the cytotoxicity of PAMAM through minimizing the interaction with protein and cell membranes, which suggest that the carboxybetaine-coated PAMAM could be a useful platform for biocompatible carriers to load contrast agents and drugs.
Assuntos
Betaína/análogos & derivados , Betaína/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Dendrímeros/química , Dendrímeros/toxicidade , Materiais Biocompatíveis/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/metabolismo , Hemólise/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Modelos Moleculares , Conformação Molecular , Proteínas/metabolismo , Relação Estrutura-AtividadeRESUMO
Immune checkpoint blockade (ICB) therapy for cancer has achieved great success both in clinical results and on the market. At the same time, success drives more attention from scientists to improve it. However, only a small portion of patients are responsive to this therapy, and it comes with a unique spectrum of side effects termed immune-related adverse events (irAEs). The use of nanotechnology could improve ICBs' delivery to the tumor, assist them in penetrating deeper into tumor tissues and alleviate their irAEs. Liposomal nanomedicine has been investigated and used for decades, and is well-recognized as the most successful nano-drug delivery system. The successful combination of ICB with liposomal nanomedicine could help improve the efficacy of ICB therapy. In this review, we highlighted recent studies using liposomal nanomedicine (including new emerging exosomes and their inspired nano-vesicles) in associating ICB therapy.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Nanomedicina , Neoplasias/tratamento farmacológico , ImunoterapiaRESUMO
Hydroquinone poses a major threat to human health and is refractory to degradation, so it is important to establish a convenient detection method. In this paper, we present a novel colorimetric method for the detection of hydroquinone based on a peroxidase-like Pd nanozyme. The vancomycin-stabilized palladium nanoparticles (Van-Pdn NPs, n = 0.5, 1, 2) were prepared using vancomycin as a biological template. The successful synthesis of Van-Pdn NPs (n = 0.5, 1, 2) was demonstrated by UV-vis spectrophotometry, transmission electron microscopy, and X-ray diffraction. The sizes of Pd nanoparticles inside Van-Pd0.5 NPs, Van-Pd1 NPs, and Van-Pd2 NPs were 2.6 ± 0.5 nm, 2.9 ± 0.6 nm, and 4.3 ± 0.5 nm, respectively. Furthermore, Van-Pd2 NPs exhibited excellent biocompatibility based on the MTT assay. More importantly, Van-Pd2 NPs had good peroxidase-like activity. A reliable hydroquinone detection method was established based on the peroxidase-like activity of Van-Pd2 NPs, and the detection limit was as low as 0.323 µM. Therefore, vancomycin improved the peroxidase-like activity and biocompatibility of Van-Pd2 NPs. Van-Pd2 NPs have good application prospects in the colorimetric detection of hydroquinone.
RESUMO
The development of efficient, reliable, and sensitive dopamine detection methods has attracted much attention. In this paper, vancomycin-stabilized platinum nanoparticles (Van-Ptn NPs, n = 0.5, 1, 2) were prepared by the biological template method, where n represented the molar ratio of vancomycin to Pt. The results show that Van-Pt2 NPs had oxidase-like activity and peroxidase-like activity, and the mechanism was due to the generation of reactive oxygen 1O2 and OH. Van-Pt2 NPs exhibited good temperature stability, storage stability, and salt solution stability. Furthermore, Van-Pt2 NPs had almost no cytotoxicity to A549 cells. More importantly, the colorimetric detection of DA in human serum samples was performed based on the oxidase-like activity of Van-Pt2 NPs. The linear range of DA detection was 10-700 µM, and the detection limit was 0.854 µM. This study establishes a rapid and reliable method for the detection of dopamine and extends the application of biosynthetic nanoparticles in the field of biosensing.
RESUMO
Many diseases in the human body are related to the level of L-cysteine. Therefore, it is crucial to establish an efficient, simple and sensitive platform for L-cysteine detection. In this work, we synthesized platinum palladium bimetallic nanoparticles (Van-Ptm/Pdn NPs) using vancomycin hydrochloride (Van) as a stabilizer, which exhibited high oxidase-like catalytic activity. In addition, the catalytic kinetics of the Van-Pt1/Pd1 NPs followed the typical Michaelis-Menten equation, exhibiting a strong affinity for 3,3',5,5'-tetramethylbenzidine substrates. More importantly, we developed a simple and effective strategy for the sensitive colorimetric detection of L-cysteine using biocompatible Van-Pt1/Pd1 NPs. The detection limit was low, at 0.07 µM, which was lower than the values for many previously reported enzyme-like detection systems. The colorimetric method of the L-cysteine assay had good selectivity. The established method for the detection of L-cysteine showed promise for biomedical analysis.
Assuntos
Colorimetria , Vancomicina , Humanos , Cisteína , Paládio , PlatinaRESUMO
Nonfouling materials have attracted increasing interest for their excellent biocompatibility and low immunogenicity. Strong hydration is believed to be the key reason for their resisting capability to nonspecific protein adsorption. However, little attention has been paid to quantifying their strong water binding capacity. In this study, we synthesized four zwitterionic polymers, including poly(sulfobetaine methacrylate) (pSBMA), poly(carboxybetaine methacrylate) (pCBMA), poly(carboxybetaine acrylamide) (pCBAA) and poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC), and compared non-freezing water of these zwitterionic polymers with typical antifouling polymer poly(ethylene glycol) (PEG) using differential scanning calorimetry (DSC). Non-freezing water of their monomers was also investigated. The non-freezing water of the polymers (per unit) is pMPC (10.7 ± 1.4) ≈ pCBAA (10.8 ± 1.5) > pCBMA (9.0 ± 0.6) > pSBMA (6.6 ± 0.4) > PEG20000 (0.60 ± 0.04). Similar trend is observed for their monomers. For all studied zwitterionic materials, they showed higher binding capacity than PEG. We attribute the stronger hydration of zwitterionic polymers to their strong electrostatic interactions.
Assuntos
Polímeros , Água , Adsorção , Varredura Diferencial de Calorimetria , Polietilenoglicóis/química , Polímeros/química , Água/químicaRESUMO
The development of nanozymes with enhanced catalytic activity has been drawing great interest. Lentinan with special structure may be used to prepare bimetallic nanomaterials to enhance their catalytic activity. Herein, lentinan stabilized PdPt3 dendritic nanoparticles (PdPt3-LNT NDs) were prepared through reduction of Na2PdCl4 and K2PtCl4 with a molar ratio of 1:3 using lentinan as a biological template. PdPt3-LNT NDs had dendritic shape with size of 10.76 ± 1.82 nm. PdPt3-LNT NDs had the hydrodynamic size about 25.7 nm and the zeta potential between -1.4 mV and - 4.9 mV at different pH. Furthermore, PdPt3-LNT NDs catalyzed 3,3',5,5'-tetramethylbenzidine (TMB) to produce oxidized TMB, suggesting their oxidase-like property. The catalytic activity of PdPt3-LNT NDs was the highest when pH was 4 and the temperature was 40 °C. The catalytic mechanism was the generation of reactive oxygen species- from O2 catalyzed by PdPt3-LNT NDs. More importantly, L-cysteine detection method was set up based on the oxidase-like property of PdPt3-LNT NDs. This method had wide linear range for 0-200 µM and low detection limit for 3.099 µM. Taken together, PdPt3-LNT NDs have good potential applications in bio-related detection in the future.
Assuntos
Lentinano , Nanopartículas , Cisteína , Lentinano/química , Oxirredutases , Espécies Reativas de OxigênioRESUMO
Herein, three kinds of molecules were used to modify the surface of platinum nanoparticles (Pt NPs) to tune their surface charge. Zwitterionic thiol-functionalized sulfobetaine (SH-SB) stabilized Pt NPs (SH-SB/Pt NPs) had the highest oxidase activity and peroxidase activity in the prepared platinum nanozymes due to the generation of reactive oxygen species. In addition, a colorimetric dopamine detection method was established based on the peroxidase activity of SH-SB/Pt NPs. This method had a wide range (0-120 µM), a low detection limit (0.244 µM), and high specificity. More importantly, SH-SB/Pt NPs displayed little hemolysis and good stability in the presence of proteins. SH-SB/Pt NPs demonstrated high cytotoxicity in vitro and good antitumor ability in vivo, which was attributed to the photothermal conversion ability of SH-SB/Pt NPs and the generation of reactive oxygen species in the acidic environment. The surface modification of nanozymes using zwitterionic molecules opens a new method to improve the catalytic activity and antitumor ability of nanozymes.
Assuntos
Nanopartículas Metálicas , Platina , Dopamina , Espécies Reativas de Oxigênio , Compostos de Sulfidrila , PeroxidasesRESUMO
Silver nanoparticles as photothermal agents have the problems of low stability and low photothermal conversion efficiency. Amphiphilic daptomycin can improve the stability of silver nanoparticles, thereby improving their photothermal conversion efficiency. Herein, daptomycin-biomineralized silver nanoparticles (Dap-AgNPs) were prepared by reducing silver nitrate with sodium borohydride in the presence of daptomycin as a stabilizer and biomineralizer. The Dap-AgNPs had good solution stability and peroxidase-like activity. Furthermore, the photothermal conversion efficiency of the Dap-AgNPs was as high as 36.8%. The Dap-AgNPs displayed good photothermal stability under irradiation. More importantly, the Dap-AgNPs showed good cell compatibility with HeLa cells and HT-29 cells without irradiation by 808-nanometer near-infrared light at a concentration of 0.5 mM, and the cell viability was greater than 85.0%. However, the Dap-AgNPs displayed significant anti-tumor ability with irradiation by 808-nanometer near-infrared light, which was due to the increasing temperature of the culture medium caused by the Dap-AgNPs. In conclusion, Dap-AgNPs have potential applications as photothermal agents in the treatment of tumors.
RESUMO
The green synthesis of silver nanoparticles (Ag NPs) for catalysis and biological applications has gained great interest. Natural elm pods are a type of food that possesses anti-inflammatory and pain-relieving effects. In this study, elm pod polysaccharide (EPP) was extracted from elm pods using hot water extraction for the first time. Biocompatible EPP-stabilized silver nanoparticles (EPP-Agn NPs) were prepared by using a green synthesis method. The EPP-Ag25 NPs had a hydrodynamic size of 40.9 nm and a highly negative surface charge of -27.4 mV. Furthermore, EPP-Ag25 NPs exhibited high catalytic activity for the reduction of 4-nitrophenol, and the catalytic reaction followed a pseudo-first order kinetic equation. More importantly, the inhibition rate of EPP-Ag25 NPs on Escherichia coli was 71 % when samples were treated with an 808 nm laser. Besides, EPP-Agn NPs effectively inhibited the proliferation of tumor cells irradiated by an 808 nm laser. The improved performance of EPP-Agn NPs was due to the good stability of EPP. Taken together, EPP-Agn NPs had good stability, catalytic activity, antibacterial and antitumor ability under laser irradiation. EPP is a good stabilizer for many nanoparticles which have broad applications in the field of catalysis and biomedicine in the future.
Assuntos
Nanopartículas Metálicas , Prata , Antibacterianos/farmacologia , Catálise , Escherichia coli , Testes de Sensibilidade Microbiana , Polissacarídeos/farmacologia , Prata/farmacologiaRESUMO
L-377,202 prodrug consists of doxorubicin (Dox) conjugated to a prostate-specific antigen (PSA) peptide substrate that can be cleaved by enzymatically active PSA at the tumor site. Despite the initial promise in phase I trial, further testing of L-377,202 (herein called Dox-PSA) was ceased due to some degree of non-specific activation and toxicity concerns. To improve safety of Dox-PSA, we encapsulated it into low temperature-sensitive liposomes (LTSL) to bypass systemic activation, while maintaining its biological activity upon controlled release in response to mild hyperthermia (HT). A time-dependent accumulation of activated prodrug in the nuclei of PSA-expressing cells exposed to mild HT was observed, showing that Dox-PSA was efficiently released from the LTSL, cleaved by PSA and entering the cell nucleus as free Dox. Furthermore, we have shown that Dox-PSA loading in LTSL can block its biological activity at 37°C, while the combination with mild HT resulted in augmented cytotoxicity in both 2D and 3D PC models compared to the free Dox-PSA. More importantly, Dox-PSA encapsulation in LTSL prolonged its blood circulation and reduced Dox accumulation in the heart of C4-2B tumor-bearing mice over the free Dox-PSA, thus significantly improving Dox-PSA therapeutic window. Finally, Dox-PSA-loaded LTSL combined with HT significantly delayed tumor growth at a similar rate as mice treated with free Dox-PSA in both solid and metastatic PC tumor models. This indicates this strategy could block the systemic cleavage of Dox-PSA without reducing its efficacy in vivo, which could represent a safer option to treat patients with locally advanced PC. STATEMENT OF SIGNIFICANCE: This study investigates a new tactic to tackle non-specific cleavage of doxorubicin PSA-activatable prodrug (L-377,202) to treat advanced prostate cancer. In the present study, we report a nanoparticle-based approach to overcome the non-specific activation of L-377,202 in the systemic circulation. This includes encapsulating Dox-PSA in low temperature-sensitive liposomes to prevent its premature hydrolysis and non-specific cleavage. This class of liposomes offers payload protection against degradation in plasma, improved pharmacokinetics and tumor targeting, and an efficient and controlled drug release triggered by mild hyperthermia (HT) (â¼42°C). We believe that this strategy holds great promise in bypassing any systemic toxicity concerns that could arise from the premature activation of the prodrug whilst simultaneously being able to control the spatiotemporal context of Dox-PSA cleavage and metabolism.
Assuntos
Pró-Fármacos , Neoplasias da Próstata , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Temperatura Alta , Humanos , Lipossomos , Masculino , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológicoRESUMO
The development of stealth and effective antitumor nanodrugs has been drawing great attention. Herein, generation five poly(amide amine) dendrimer (G5 PAMAM) was modified by zwitterionic material carboxybetaine methacrylamide (CBMAA) on its surface to prepare zwitterionic dendrimer (G5-CBMAAn). The results showed that G5-CBMAA30 had the longest blood circulation time due to its thickest zwitterionic layer, and its residual rate after injection into mice at 2 and 12 h was as high as 47.22 % and 14.37 %, respectively. Nanodrug G5-CBMAA30-ICG was prepared by containing indocyanine green (ICG) in the cavity of G5-CBMAA30. G5-CBMAA30-ICG had better tumor targeting ability and antitumor effect than free ICG in mice after laser irradiation, and the tumor inhibition rate was 96.6 % after 14 days' treatment. The prepared G5-CBMAA30-ICG has great potential applications in the field of antitumor by phototherapy.
Assuntos
Dendrímeros , Nanopartículas , Neoplasias , Animais , Verde de Indocianina , Camundongos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fototerapia/métodosRESUMO
Prostate cancer (PC) is second-leading cancer in men, with limited treatment options available for men with advanced and metastatic PC. Prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) have been exploited as therapeutic targets in PC due to their upregulation in the advanced stages of the disease. To date, several PSA- and PSMA-activatable prodrugs have been developed to reduce the systemic toxicity of existing chemotherapeutics. Bioinspired nanovesicles have been exploited in drug delivery, offering prolonged drug blood circulation and higher tumour accumulation. For the first time, this study describes the engineering of dually targeted PSA/PSMA nanovesicles for advanced PC. PSMA-targeted bioinspired hybrids were prepared by hydrating a lipid film with anti-PSMA-U937 cell membranes and DOX-PSA prodrug, followed by extrusion. The bioinspired hybrids were characterised using dynamic light scattering, transmission electron microscopy, Dot blot, flow cytometry and Western blot. Cellular binding and toxicity studies in PC cancer cell lines were carried out using flow cytometry, confocal microscopy, and resazurin assay. Finally, tumour targeting and therapeutic efficacy studies were performed in solid and metastatic C4-2B-tumor-bearing mice. Interestingly, our PSMA-targeted hybrids demonstrated high cell uptake in PSMA-expressing cells with significant accumulation in solid and metastatic C4-2B tumour tissues following intravenous administration. More promisingly, our dually targeted PSA/PSMA hybrid significantly slowed down the C4-2B tumour growth in vivo, compared to free DOX-PSA and non-targeted PSA-hybrid. Our PSA/PSMA bioinspired hybrid could offer a highly selective treatment for advanced PC with lower side effects. STATEMENT OF SIGNIFICANCE: This study investigates a new approach to treat prostate cancer using dually targeted bioinspired nanovesicle . Our bioinspired vesicles are made mainly of a human blood cell membrane with a ligand recognising a specific marker (PSMA) on the surface of the prostate cancer cells. The present work describes the successful loading of a doxorubicin prodrug linked to a PSA- activatable peptide into these targeted bioinspired nanovesicle , where the active PSA enzyme presents in these cells converts the drug to its active form. Our dually targeted PSA/PSMA hybrid vesicles has successfully improved site-specific prodrug delivery to tackle advanced prostate cancer, offering a novel and effective prostate cancer treatment.
Assuntos
Pró-Fármacos , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Antígeno Prostático Específico , Neoplasias da Próstata/tratamento farmacológico , Células U937RESUMO
The present work describes the engineering of anti-PSMA peptide-decorated exosome mimetics (EMs) targeting advanced prostate cancer (PC). The targeted EMs were produced from anti-PSMA peptide, WQPDTAHHWATL, expressing U937 monoblastic cells, followed by successive extrusion cycles. The engineered EMs were nanosized, produced at a high yield, and displayed the anti-PSMA peptide, exosomal markers and monocytes proteins on their surface. As anticipated, PSMA-EMs showed increased cellular internalization in PSMA positive PC cell lines (LNCaP and C4-2B), compared to unmodified EMs. Most importantly, higher tumour targeting was observed in solid C4-2B tumours, following intravenous administration, confirming their targeting ability in vivo. Overall, our study indicates that the engineered anti-PSMA peptide-targeted EMs can be a promising drug delivery system for advanced PC.