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1.
Nanoscale ; 13(30): 13000-13013, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477783

RESUMO

Inorganic nanoparticles are gaining increasing attention as drug carriers because they respond to external physical stimuli, allowing therapy to be combined with diagnosis. Their drawback is low drug loading capacity, which can be improved by proper and efficacious functionalization. In this computational study, we take TiO2 spherical nanoparticles as prototype photoresponsive inorganic nanoparticles and we fully decorate them with two different types of bifunctional ligands: TETTs and DOPACs, which present different surface anchoring groups (silanol or catechol) but the same drug tethering COOH group, although in different concentrations (3 vs. 1), thus causing different steric hindrances. Then, we put these two types of nanocarriers in bulk water and in the presence of several DOX molecules and let the systems evolve through molecular dynamics (MD) simulations, clearly observing drug loading on the nanocarriers. This comparative MD study allows the investigation of the loading mechanism, performance of a conformational analysis and establishment of the guiding interactions through an energy decomposition analysis. We learn that DOX mostly interacts with the functionalized NPs through electrostatics, as a consequence of the protonated amino group, although several H-bonds are also established both with the ligands and with the oxide surface. Different ligands induce a different electrostatic potential around the NP; therefore, those which lead to the formation of more negative hotspots (here TETTs) are found to favour DOX binding. The leading role of electrostatics can provide a rational explanation for a pH-dependent drug release mechanism that is often invoked for DOX when reaching diseased cells because under anomalous acidic conditions both the NP surface and the carboxylate groups of the ligands are expected to get protonated, which of course would weaken, if not totally quench, the interaction of the nanocarrier with protonated DOX.


Assuntos
Doxorrubicina , Nanopartículas , Portadores de Fármacos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular
2.
Mater Sci Eng C Mater Biol Appl ; 128: 112302, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474853

RESUMO

Localized delivery of chemotherapeutic agents allows extended drug exposure at the target site, thereby reducing systemic toxicity. We report the development of functionalized polymeric patch with unidirectional drug release to treat gastric cancer. The oxaliplatin-loaded patch was prepared by incorporating sodium carboxymethyl cellulose, hydroxypropyl cellulose and polyvinylpyrrolidone. The patch was functionalized by coating with transferrin-poly(lactic-co-glycolic acid) conjugate on one side of the patch for cancer targeting. The other side of the patch was coated with ethylcellulose (EC) to restrict the release of oxaliplatin. The physical and mechanical properties of oxaliplatin-loaded patches were characterized. Mucoadhesion studies using excised rat stomach tissue have shown that the functionalized side of the patch has significantly (p < 0.05) greater mucoadhesion strength compared with EC coated side of the patch. The in vitro and ex vivo (stomach sac and open-membrane model) studies revealed greater permeation of oxaliplatin across the stomach tissue when adhered to the functionalized and non-functionalized side of the patch compared with EC coated side. It was found that the growth inhibition with oxaliplatin solution was not significantly greater compared with corresponding concentrations of oxaliplatin-loaded patch in AGS and Caco-2 cell models. The in vivo studies were performed in mice, where indocyanine green-loaded patch encapsulated in a gelatin capsule was orally administered. The near-infrared (NIR) optical imaging revealed adherence of the patch on the mucosal side of the stomach tissue for up to 6 h. In conclusion, the functionalized polymeric patch loaded with oxaliplatin can be a potential localized delivery system to target gastric cancer.


Assuntos
Neoplasias Gástricas , Animais , Células CACO-2 , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Camundongos , Oxaliplatina , Polímeros , Ratos , Neoplasias Gástricas/tratamento farmacológico
3.
Mater Sci Eng C Mater Biol Appl ; 128: 112311, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474862

RESUMO

Herein, we design a rGO-based magnetic nanocomposite by decorating rGO with citrate-coated magnetic nanoparticles (CMNP). The magnetic rGO (mrGO) was modified by phospholipid-polyethylene glycol to prepare PEGylated mrGO, for conjugating with gastrin-releasing peptide receptor (GRPR)-binding peptide (mrGOG). The anticancer drug doxorubicin (DOX) was bound to mrGO (mrGOG) by π-π stacking for drug delivery triggered by the low pH value in the endosome. The mrGOG showed enhanced photothermal effect under NIR irradiation, endorsing its role for dual targeted DOX delivery. With efficient DOX release in the endosomal environment and heat generation from light absorption in the NIR range, mrGOG/DOX could be used for combination chemo-photothermal therapy after intracellular uptake by cancer cells. We characterized the physico-chemical as well as biological properties of the synthesized nanocomposites. The mrGOG is stable in biological buffer solution, showing high biocompatibility and minimum hemolytic properties. Using U87 glioblastoma cells, we confirmed the magnetic drug targeting effect in vitro for selective cancer cell killing. The peptide ligand-mediated targeted delivery increases the efficiency of intracellular uptake of both nanocomposite and DOX up to ~3 times due to the over-expressed GRPR on U87 surface, leading to higher cytotoxicity. The increased cytotoxicity using mrGOG over mrGO was shown from a decreased IC50 value (0.70 to 0.48 µg/mL) and an increased cell apoptosis rate (19.8% to 47.1%). The IC50 and apoptosis rate changed further to 0.19 µg/mL and 76.8% in combination with NIR laser irradiation, with the photothermal effect supported from upregulation of heat shock protein HSP70 expression. Using U87 tumor xenograft model created in nude mice, we demonstrated that magnetic guidance after intravenous delivery of mrGOG/DOX could significantly reduce tumor size and prolong animal survival over free DOX and non-magnetic guided groups. Augmented with NIR laser treatment for 5 min, the anti-cancer efficacy significantly improves with elevated cell apoptosis and reduced cell proliferation. Together with safety profiles from hematological as well as major organ histological analysis of treated animals, the mrGOG nanocomposite is an effective nanomaterial for combination chemo-photothermal cancer therapy.


Assuntos
Hipertermia Induzida , Nanocompostos , Neoplasias , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Grafite , Fenômenos Magnéticos , Camundongos , Camundongos Nus , Fototerapia , Receptores da Bombesina
4.
Mater Sci Eng C Mater Biol Appl ; 128: 112317, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474868

RESUMO

Acid-triggered degradable polyprodrug P(DOX-AH) was designed for long-acting drug delivery with minimal leakage and enhanced antitumor efficacy. By facile polymerization of doxorubicin (DOX) and N-(tert-butoxycarbonyl)acryloylhydrazine (Boc-AH), P(DOX-AH) with drug as unique repeating unit was obtained, possessing an ultrahigh drug content. It was stable in the neutral media but could degrade completely into DOX-AH in the acidic media without any other by-product. The cleavage of the hydrazone linkage between the DOX-AH repeating units was revealed by the LC-MS/MS analysis. Furthermore, a slow solubility-controlled drug release performance was achieved in the acidic media because of the low solubility of the released DOX-AH. Even with the slow DOX-AH releasing, the enhanced antitumor efficacy was obtained than free DOX in the in vitro cellular experiments. These features demonstrated the promising potential of the proposed polyprodrug for long-acting drug delivery in future tumor chemotherapy.


Assuntos
Polímeros , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Micelas
5.
Mater Sci Eng C Mater Biol Appl ; 128: 112334, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474885

RESUMO

Surgical sutures are the most widely used medical device in any surgical procedure worldwide. In this study, modified electrospinning technique has been used as manufacturing technique to produce nanofiber bundles twisted simultaneously to obtain nanofiber yarns. Taking the advantage of nanofiber yarns in terms of biomimetic structure, mechanical strength and handling properties, the material is chosen. Curcumin, a natural compound is incorporated to the nanofiber yarns by blend electrospinning technique for its anti-inflammatory, antibiotic and wound healing properties. The synthesized nanofiber yarns were characterized by various characterization techniques such as XRD, FTIR, SEM, Tensile testing, stem cell interaction, hemocompatibility, bacterial response, drug release profiling and in vivo studies. Curcumin loaded nanofiber yarns demonstrated sustained release with improved antibacterial, antiplatelet, cell migration and stem cell interaction in vitro. The results from skin inflammation animal model revealed that curcumin laden nanofiber yarn suture manifested reduced inflammation and cellularity. The three dimensional structure, adequate mechanical strength and biological properties of the nanofiber yarn provide naive environment for wound healing with the balanced degradation of suture material in rat model.


Assuntos
Nanofibras , Animais , Antibacterianos/farmacologia , Liberação Controlada de Fármacos , Ratos , Suturas , Cicatrização
6.
Anal Chem ; 93(34): 11751-11757, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34398599

RESUMO

Developing nanoplatforms that simultaneously integrate diagnostic imaging and therapy functions has been a promising but challenging task for cancer theranostics. Herein, we report the rational design of a smart nucleic acid-gated covalent organic framework (COF) nanosystem for cancer-specific imaging and microenvironment-responsive drug release. Cy5 dye-labeled single-stranded DNA (ssDNA) for mRNA recognition was adsorbed on the surface of doxorubicin (Dox)-loaded COF nanoparticles (NPs). Dox loaded in the pores of COF NPs could strengthen the interactions between ssDNA and COF and enhance the fluorescence quenching effect toward Cy5, while the densely coated ssDNA could prevent the leakage of Dox from COF NPs. The obtained nanosystem exhibited low fluorescence signal and Dox release in normal cells; however, the ssDNA could be released by the overexpressed TK1 mRNA in cancer cells to recover the intense fluorescence signal of Cy5, and the loaded Dox could be further released for chemotherapy. Therefore, cancer cell-specific diagnostic imaging and drug release were realized with the rationally developed nanosystem. This work offers a universal nanoplatform for cancer theranostics and a promising strategy for regulating the interaction between COFs and biomolecules.


Assuntos
Estruturas Metalorgânicas , Nanopartículas , Neoplasias , Ácidos Nucleicos , Diagnóstico por Imagem , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
7.
ACS Appl Mater Interfaces ; 13(33): 38979-38989, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433249

RESUMO

Chronic infections caused by Pseudomonas aeruginosa pose severe threats to human health. Traditional antibiotic therapy has lost its total supremacy in this battle. Here, nanoplatforms activated by the clinical microenvironment are developed to treat P. aeruginosa infection on the basis of dynamic borate ester bonds. In this design, the nanoplatforms expose targeted groups for bacterial capture after activation by an acidic infection microenvironment, resulting in directional transport delivery of the payload to bacteria. Subsequently, the production of hyperpyrexia and reactive oxygen species enhances antibacterial efficacy without systemic toxicity. Such a formulation with a diameter less than 200 nm can eliminate biofilm up to 75%, downregulate the level of cytokines, and finally promote lung repair. Collectively, the biomimetic design with phototherapy killing capability has the potential to be an alternative strategy against chronic infections caused by P. aeruginosa.


Assuntos
Antibacterianos/química , Verde de Indocianina/química , Nanocápsulas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/radioterapia , Células A549 , Animais , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Verde de Indocianina/farmacologia , Raios Infravermelhos , Masculino , Metacrilatos/química , Camundongos Endogâmicos BALB C , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Pseudomonas aeruginosa/efeitos dos fármacos
8.
ACS Appl Mater Interfaces ; 13(33): 39003-39017, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433253

RESUMO

Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a small-molecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.


Assuntos
Acetamidas/química , Aminopiridinas/química , Antineoplásicos/farmacologia , Benzamidas/química , Portadores de Fármacos/química , Inibidores de Checkpoint Imunológico/química , Piridinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Acetamidas/farmacologia , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Terapia Combinada/métodos , Liberação Controlada de Fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Distribuição Tecidual , Resultado do Tratamento
9.
Nat Commun ; 12(1): 4755, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362890

RESUMO

Some specific chemotherapeutic drugs are able to enhance tumor immunogenicity and facilitate antitumor immunity by inducing immunogenic cell death (ICD). However, tumor immunosuppression induced by the adenosine pathway hampers this effect. In this study, E-selectin-modified thermal-sensitive micelles are designed to co-deliver a chemotherapeutic drug (doxorubicin, DOX) and an A2A adenosine receptor antagonist (SCH 58261), which simultaneously exhibit chemo-immunotherapeutic effects when applied with microwave irradiation. After intravenous injection, the fabricated micelles effectively adhere to the surface of leukocytes in peripheral blood mediated by E-selectin, and thereby hitchhiking with leukocytes to achieve a higher accumulation at the tumor site. Further, local microwave irradiation is applied to induce hyperthermia and accelerates the release rate of drugs from micelles. Rapidly released DOX induces tumor ICD and elicits tumor-specific immunity, while SCH 58261 alleviates immunosuppression caused by the adenosine pathway, further enhancing DOX-induced antitumor immunity. In conclusion, this study presents a strategy to increase the tumor accumulation of drugs by hitchhiking with leukocytes, and the synergistic strategy of chemo-immunotherapy not only effectively arrested primary tumor growth, but also exhibited superior effects in terms of antimetastasis, antirecurrence and antirechallenge.


Assuntos
Tratamento Farmacológico , Imunoterapia , Leucócitos/efeitos dos fármacos , Micelas , Neoplasias/terapia , Animais , Doxorrubicina/farmacologia , Portadores de Fármacos/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Hipertermia/terapia , Imunidade , Camundongos , Camundongos Endogâmicos BALB C , Micro-Ondas/uso terapêutico , Fototerapia
10.
Anal Chem ; 93(32): 11208-11214, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34339178

RESUMO

Biocompatible hydrogels for tissue regeneration/replacement and drug release with specific architectures can be obtained by three-dimensional bioprinting techniques. The preservation of the higher order structure of the proteins embedded in the hydrogels as drugs or modulators is critical for their biological activity. Solution nuclear magnetic resonance (NMR) experiments are currently used to investigate the higher order structure of biotherapeutics in comparability, similarity, and stability studies. However, the size of pores in the gel, protein-matrix interactions, and the size of the embedded proteins often prevent the use of this methodology. The recent advancements of solid-state NMR allow for the comparison of the higher order structure of the matrix-embedded and free isotopically enriched proteins, allowing for the evaluation of the functionality of the material in several steps of hydrogel development. Moreover, the structural information at atomic detail on the matrix-protein interactions paves the way for a structure-based design of these biomaterials.


Assuntos
Bioimpressão , Liberação Controlada de Fármacos , Hidrogéis , Impressão Tridimensional , Engenharia Tecidual , Tecidos Suporte
11.
Molecules ; 26(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34361646

RESUMO

Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10-30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion.


Assuntos
Liberação Controlada de Fármacos , Naproxeno/química , Impressão Tridimensional , Comprimidos/química , Tecnologia Farmacêutica/métodos , Excipientes/química , Solubilidade , Temperatura
12.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361725

RESUMO

This study investigated supercritical solvent impregnation of polyamide microfiltration membranes with carvacrol and the potential application of the modified membranes in ventilation of open surgical wounds. The impregnation process was conducted in batch mode at a temperature of 40 °C under pressures of 10, 15, and 20 MPa for contact times from 1 to 6 h. FTIR was applied to confirm the presence of carvacrol on the membrane surface. In the next step, the impact of the modification on the membrane structure was studied using scanning electron and ion beam microscopy and cross-filtration tests. Further, the release of carvacrol in carbon dioxide was determined, and finally, an open thoracic cavity model was applied to evaluate the efficiency of carvacrol-loaded membranes in contamination prevention. Carvacrol loadings of up to 43 wt.% were obtained under the selected operating conditions. The swelling effect was detectable. However, its impact on membrane functionality was minor. An average of 18.3 µg of carvacrol was released from membranes per liter of carbon dioxide for the flow of interest. Membranes with 30-34 wt.% carvacrol were efficient in the open thoracic cavity model applied, reducing the contamination levels by 27% compared to insufflation with standard membranes.


Assuntos
Antibacterianos/farmacologia , Cimenos/farmacologia , Nylons/química , Agentes Molhantes/farmacologia , Antibacterianos/química , Bandagens/microbiologia , Dióxido de Carbono/química , Cimenos/química , Liberação Controlada de Fármacos , Humanos , Insuflação , Cinética , Manequins , Membranas Artificiais , Ferida Cirúrgica/reabilitação , Molhabilidade , Agentes Molhantes/química
13.
Molecules ; 26(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34443357

RESUMO

In this work, we propose the utilization of scCO2 to impregnate ibuprofen into the mcl-PHA matrix produced by Pseudomonas chlororaphis subs. aurantiaca (DSM 19603). The biopolymer has adhesive properties, is biocompatible and has a melting temperature of 45 °C. Several conditions, namely, pressure (15 and 20 MPa) and impregnation time (30 min, 1 h and 3 h) were tested. The highest ibuprofen content (90.8 ± 6.5 mg of ibuprofen/gPHA) was obtained at 20 MPa and 40 °C, for 1 h, with an impregnation rate of 89 mg/(g·h). The processed mcl-PHA samples suffered a plasticization, as shown by the decrease of 6.5 °C in the Tg, at 20 MPa. The polymer's crystallinity was also affected concomitantly with the matrices' ibuprofen content. For all the impregnation conditions tested the release of ibuprofen from the biopolymer followed a type II release profile. This study has demonstrated that the mcl-PHA produced by P. chlororaphis has a great potential for the development of novel topical drug delivery systems.


Assuntos
Dióxido de Carbono/química , Portadores de Fármacos/química , Ibuprofeno/química , Poli-Hidroxialcanoatos/química , Adesividade , Liberação Controlada de Fármacos , Temperatura
14.
ACS Appl Mater Interfaces ; 13(33): 38959-38968, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34379404

RESUMO

Chemotherapy continues to be the most commonly applied strategy for cancer. Despite the impressive clinical success obtained with several drugs, increasing numbers of (multi)drug-resistant tumors are reported. To overcome this shortcoming, novel drug candidates and delivery systems are urgently needed. Herein, a therapeutic copper polypyridine complex encapsulated in natural nanocarrier apoferritin is reported. The generated nanoparticles showed higher cytotoxicity toward various (drug-resistant) cancer cell lines than noncancerous cells. The study of the mechanism revealed that the compound triggers cell autophagy-dependent apoptosis. Promisingly, upon injection of the nanodrug conjugate into the bloodstream of a mouse model bearing a multidrug-resistant colon tumor, a strong tumor growth inhibition effect was observed. To date, this is the first study describing the encapsulation of a copper complex in apoferritin that acts by autophagy-dependent apoptosis.


Assuntos
Antineoplásicos/química , Apoferritinas/química , Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/química , Cobre/química , Nanocápsulas/química , Animais , Antineoplásicos/farmacologia , Apoferritinas/metabolismo , Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Complexos de Coordenação/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais
15.
Biomater Sci ; 9(17): 5977-5987, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34338256

RESUMO

Nanodrug delivery systems have been used extensively to improve the tumor-targeting ability and reduce the side effects of anticancer drugs. In this study, nanomicelles responsive to dual stimuli were designed and developed as drug carriers for delivering doxorubicin (DOX). The hydrophobic group of the nanomicelles was composed of the photosensitizer protoporphyrin IX (PpIX) and the disulfide bond-containing alpha-lipoic acid (LA); the hydrophilic group was made up of the nuclear localization signal (NLS, CGGGPKKKRKVGG) peptide with a lysine linker. Furthermore, anionic cyclo-γ-polyglutamic acid (cyclo-γ-PGA) was coated on the surface of the cationic micelles to construct a multifunctional drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA). Cyclo-γ-PGA, as a biological coating material, notably improved the stability of the cationic micelles by reducing nonspecific reactions with anionic groups. Additionally, the cyclo-γ-PGA coating mediated active tumor targeting and enhanced the cellular uptake of micelles via the γ-glutamyl transpeptidase (GGT) pathway. The integrated micelles not only achieved photochemical internalization (PCI) and photodynamic therapy (PDT) via light-activated reactive oxygen species (ROS) but also realized controlled intracellular drug release via the glutathione (GSH)-responsive disulfide-bond cleavage. As a result, NLS-LA-PpIX-DOX@cyclo-γ-PGA exhibited excellent synergistic chemo-photodynamic antitumor activity and fewer side effects than other therapies both in vitro and in vivo. In conclusion, this new dual-responsive drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA) with improved stability and enhanced tumor-targeting ability may facilitate the development of high-efficiency and low-toxicity nanotherapeutic approaches.


Assuntos
Fotoquimioterapia , Ácido Poliglutâmico , Doxorrubicina/farmacologia , Portadores de Fármacos , Liberação Controlada de Fármacos , Micelas , Ácido Poliglutâmico/análogos & derivados
16.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445465

RESUMO

Cordyline terminalis leaf extract (aqCT) possesses abundant polyphenols and other bioactive compounds, which are encapsulated in gelatin-polyethylene glycol-tyramine (GPT)/alpha-cyclodextrin (α-CD) gels to form the additional functional materials for biomedical applications. In this study, the gel compositions are optimized, and the GPT/α-CD ratios equal to or less than one half for solidification are found. The gelation time varies from 40.7 min to 5.0 h depending on the increase in GPT/α-CD ratios and aqCT amount. The aqCT extract disturbs the hydrogen bonding and host-guest inclusion of GPT/α-CD gel networks, postponing the gelation. Scanning electron microscope observation shows that all gels with or without aqCT possess a microarchitecture and porosity. GPT/α-CD/aqCT gels could release polyphenols from 110 to 350 nmol/mL at the first hour and sustainably from 5.5 to 20.2 nmol/mL for the following hours, which is controlled by feeding the aqCT amount and gel properties. GPT/α-CD/aqCT gels achieved significant antioxidant activity through a 100% scavenging DPPH radical. In addition, all gels are non-cytotoxic with a cell viability more than 85%. Especially, the GPT3.75α-CD10.5aqCT gels with aqCT amount of 3.1-12.5 mg/mL immensely enhanced the cell proliferation of GPT3.75α-CD10.5 gel without extract. These results suggest that the inherent bioactivities of aqCT endowed the resulting GPT/α-CD/aqCT gels with effective antioxidant and high biocompatibility, and natural polyphenols sustainably release a unique platform for a drug delivery system or other biomedical applications.


Assuntos
Cordyline/química , Derme/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Géis/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Polifenóis/farmacologia , Células Cultivadas , Liberação Controlada de Fármacos , Géis/administração & dosagem , Humanos
17.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445466

RESUMO

To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core-shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core-shell microparticles were of spherical appearance, with an average size of 14.65 µm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core-shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Microesferas , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Camundongos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443457

RESUMO

Curcumin extracted from the rhizome of Curcuma Longa has been used in therapeutic preparations for centuries in different parts of the world. However, its bioactivity is limited by chemical instability, water insolubility, low bioavailability, and extensive metabolism. In this study, the coaxial electrospinning technique was used to produce both poly (ε-caprolactone) (PCL)-curcumin and core-shell nanofibers composed of PCL and curcumin in the core and poly (lactic acid) (PLA) in the shell. Morphology and physical properties, as well as the release of curcumin were studied and compared with neat PCL, showing the formation of randomly oriented, defect-free cylindrical fibers with a narrow distribution of the dimensions. The antibacterial and antibiofilm potential, including the capacity to interfere with the quorum-sensing mechanism, was evaluated on Pseudomonas aeruginosa PAO1, and Streptococcus mutans, two opportunistic pathogenic bacteria frequently associated with infections. The reported results demonstrated the ability of the Curcumin-loading membranes to inhibit both PAO1 and S. mutans biofilm growth and activity, thus representing a promising solution for the prevention of biofilm-associated infections. Moreover, the high biocompatibility and the ability to control the oxidative stress of damaged tissue, make the synthesized membranes useful as scaffolds in tissue engineering regeneration, helping to accelerate the healing process.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes , Curcumina/farmacologia , Infecções/microbiologia , Nanofibras/química , Engenharia Tecidual , Biofilmes/efeitos dos fármacos , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Liberação Controlada de Fármacos , Sequestradores de Radicais Livres/farmacologia , Humanos , Cinética , Testes de Sensibilidade Microbiana , Picratos/química , Poliésteres/química , Percepção de Quorum/efeitos dos fármacos , Termogravimetria
19.
Chemistry ; 27(52): 13203-13210, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34346527

RESUMO

This article describes the fabrication of new pH-responsive hybrid gel beads combining the polymer gelator calcium alginate with two different low-molecular-weight gelators (LMWGs) based on 1,3 : 2,4-dibenzylidene-d-sorbitol: pH-responsive DBS-COOH and thermally responsive DBS-CONHNH2 , thus clearly demonstrating that different classes of LMWG can be fabricated into gel beads by using this approach. We also demonstrate that self-assembled multicomponent gel beads can be formed by using different combinations of these gelators. The different gel bead formulations exhibit different responsiveness - the DBS-COOH network can disassemble within those beads in which it is present upon raising the pH. To exemplify preliminary data for a potential application for these hybrid gel beads, we explored aspects of the delivery of the lipid-lowering active pharmaceutical ingredient (API) rosuvastatin. The release profile of this statin from the hybrid gel beads is pH-dependent, with greater release at pH 7.4 than at pH 4.0 - primary control of this process results from the pKa of the API. The extent of pH-mediated API release is also significantly further modified according to gel bead composition. The DBS-COOH/alginate beads show rapid, highly effective drug release at pH 7.4, whereas the three-component DBS-COOH/DBS-CONHNH2 /alginate system shows controlled slow release of the API under the same conditions. These initial results indicate that such gel beads constitute a promising, versatile and easily tuned platform suitable for further development for controlled drug-delivery applications.


Assuntos
Alginatos , Polímeros , Liberação Controlada de Fármacos , Géis , Concentração de Íons de Hidrogênio , Rosuvastatina Cálcica
20.
ACS Appl Mater Interfaces ; 13(33): 39066-39075, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34387079

RESUMO

A controlled release formulation based on silica microcapsules is an ideal selection to improve both the effective utilization and duration of pesticides to decrease ecological damage. Herein, a simple and green method for preparing double-shelled microcapsules was developed using a newly prepared quaternary ammonium ionic liquid (IL) as the functional additive to entrap avermectin (Ave) in mesoporous silica nanospheres (MSNs) and tannic acid-Cu (TA-Cu) complex as the sealing agent to form the core-shell structure (Ave-IL@MSN@TA-Cu). The obtained microcapsules with an average size of 538 nm had pH-responsive release property and good stability in soil. The half-life of microcapsules (34.66 days) was 3 times that of Ave emulsifiable concentrate (EC) (11.55 days) in a test soil, which illustrated that microcapsules could protect Ave from rapid degradation by microorganisms by releasing TA, copper, and quaternary ammonium in the soil. Ave-IL@MSN@TA-Cu microcapsules had better nematicidal activity and antibacterial activity than Ave EC due to the synergistic effect of Ave, IL, and copper incorporated in the microcapsules. Pot experiments showed that the control efficacy of microcapsules was 87.10% against Meloidogyne incognita, which is better than that of Ave EC (41.94%) at the concentration of 1.0 mg/plant by the root-irrigation method after 60 days of treatment owing to the extended duration of Ave in microcapsules. The simple and green method for the preparation of double-shelled microcapsules based on natural quaternary ammonium IL would have tremendous potential for the extensive development of controlled release pesticide formulations.


Assuntos
Cápsulas/química , Preparações de Ação Retardada/química , Controle de Pragas/métodos , Praguicidas/química , Dióxido de Silício/química , Tylenchoidea/efeitos dos fármacos , Animais , Complexos de Coordenação/química , Cobre/química , Preparações de Ação Retardada/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Química Verde , Concentração de Íons de Hidrogênio , Líquidos Iônicos/química , Ivermectina/análogos & derivados , Ivermectina/química , Ivermectina/farmacologia , Praguicidas/farmacologia , Porosidade , Compostos de Amônio Quaternário/química , Solubilidade , Taninos/química , Fatores de Tempo
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