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1.
Eur J Pharm Biopharm ; 163: 171-178, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33838263

RESUMO

Tuberculosis remains a leading cause of death, therapeutic failure being mainly due to non-compliance with prolonged treatments, often associated with severe side-effects. New therapeutic strategies are demanded and, considering that the lung is the primary site of infection, direct lung delivery of antibiotics is possibly an effective approach. Therapeutic success in this context depends on suitable carriers that reach the alveoli where Mycobacterium hosts (macrophages) reside, as well as on their ability to promote macrophage capture and intracellular accumulation of drugs. In this work, we propose inhalable polymeric microparticles produced from chondroitin sulfate, a polymer composed by moieties recognized by macrophage receptors. Spray-drying of chondroitin sulfate in combination with two first-line antitubercular drugs (isoniazid and rifabutin) yielded respirable microparticles that evidenced no cytotoxic effects on lung epithelial cells (A549) and macrophages (dTHP1 and J744A.1). The microparticles exhibited tendency for macrophage capture in a dose-dependent manner, which was validated through imaging. High content image analysis revealed that rifabutin induced a dose-dependent increase in phospholipid content of macrophages, which could be prevented by formulation in chondroitin sulfate microparticles. This work provides indications on the potential of chondroitin sulfate carriers to interact with macrophages, thus providing a platform for drug delivery in the context of macrophage intracellular diseases, namely tuberculosis.


Assuntos
Antituberculosos/administração & dosagem , Sulfatos de Condroitina/química , Portadores de Fármacos/química , Macrófagos Alveolares/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Administração por Inalação , Animais , Linhagem Celular , Humanos , Isoniazida/administração & dosagem , Macrófagos Alveolares/microbiologia , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifabutina/administração & dosagem , Tuberculose Pulmonar/microbiologia
2.
Adv Healthc Mater ; 10(4): e2001089, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32864903

RESUMO

The π-conjugated polymer poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b0]-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (PCPDTBT) with deep-red/near-infrared (NIR) absorption and emission has been investigated as a contrast agent for in vivo optical and photoacoustic imaging. PCPDTBT is encapsulated within poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG2kDa -PLGA4kDa or PEG5kDa -PLGA55kDa ) micelles or enveloped by the phospholipid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG2kDa -DPPE), to investigate the formulation effect on imaging performance, biodistribution, and biocompatibility. Nanoparticles that meet the quality requirements for parenteral administration are generated with similar physicochemical properties. Optical phantom imaging reveals that both PEG-PLGA systems exhibit a 30% higher signal-to-background ratio (SBR) than PEG2kDa -DPPE. This trend cannot be observed in a murine HeLa xenograft model following intravenous administration since dramatic differences in biodistribution are observed. PEG2kDa -PLGA4kDa systems accumulate more rapidly in the liver compared to other formulations and PEG2kDa -DPPE demonstrates a higher tumor localization. Protein content in the "hard" corona differs between formulations (PEG2kDa -DPPE < PEG2kDa -PLGA4kDa < PEG5kDa -PLGA55kDa ), although this observation alone does not explain biodistribution patterns. PEG2kDa -PLGA4kDa systems show the highest photoacoustic amplitude in a phantom, but also a lower signal in the tumor due to differences in biodistribution. This study demonstrates that formulations for conjugated polymer contrast agents can have significant impact on both imaging performance and biodistribution.


Assuntos
Nanopartículas , Técnicas Fotoacústicas , Animais , Meios de Contraste , Camundongos , Poliésteres , Polietilenoglicóis , Polímeros , Distribuição Tecidual
3.
J Control Release ; 328: 339-349, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-32827612

RESUMO

The aim of this study was to investigate the potential of human serum albumin (HSA) as a solubilising agent/drug delivery vehicle for pulmonary administration of antimycobacterial benzothiazinone (BTZ) compounds. The solubility of four novel BTZ compounds (IR 20, IF 274, FG 2, AR 112) was enhanced 2 to 140-fold by incubation with albumin (0.38-134 µg/mL). Tryptophan 213 residue quenching studies indicated moderate binding strength to Sudlow's site I. Nanoparticle manufacture achieved 37-60% encapsulation efficiency in HSA particles (169 nm, zeta potential -31 mV). Drug release was triggered by proteases with >50% released in 4 h. The antimycobacterial activity of IR 20 and FG 2 loaded in HSA nanoparticles was enhanced compared to DMSO/phosphate buffered saline (PBS) or albumin/PBS solutions in an in vitro M. tuberculosis-infected macrophage model. Intranasal instillation was used to achieve pulmonary delivery daily over 10 days to M. tuberculosis infected mice for FG2 HSA nanoparticles (0.4 mg/kg), FG 2 DMSO/saline (0.4 and 8 mg/kg) and a reference compound, BTZ043, DMSO/saline (0.4 and 8 mg/kg). A lower lung M. tuberculosis burden was apparent for all BTZ cohorts, but only significant for BTZ043 at both doses. In conclusion, mechanisms of HSA nanoparticle loading and release of BTZ compounds were demonstrated, enhanced antimycobacterial activity of the nanoparticle formulations was demonstrated in a biorelevant in vitro bioassay and the effectiveness of BTZ by pulmonary delivery in vivo was established with pilot evidence for effectiveness when delivered by HSA nanoparticles. Finally, the feasibility of developing an inhaled nanoparticle-in-microparticle powder formulation was ascertained.


Assuntos
Nanopartículas , Albumina Sérica Humana , Administração por Inalação , Animais , Antituberculosos , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Camundongos
4.
Eur J Pharm Biopharm ; 154: 297-308, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32707286

RESUMO

Conjugated polymer nanoparticles (CPNs) have emerged as highly photostable probes for optical and photoacoustic imaging. However, the aggregation of conjugated polymer (CP) molecules upon nanoparticle formation is associated with fluorescence quenching, poor yields and mutable particle sizes. This study investigated whether the CP encapsulation within the liquid midchain triglyceride (MCT) core of lipid nanocapsules (LNCs) may achieve reduced packing of CP chains leading to a stable system with enhanced optical features. The red- and near infrared-emitting CPs, CN-PPV and PCPDTBT, showed precipitation and aggregation-induced quenching with concentrations >~25 µg/mL in MCT alone. Despite this, CP encapsulation within LNCs abolished quenching at concentrations up to 1500 µg/mL. PCPDTBT-LNCs exhibited a quantum yield of 2.8% and a higher signal:background ratio in an optical imaging phantom compared to literature reports of PCPDTBT encapsulated in PEG-PLGA nanoparticles. In contrast, PCPDTBT-LNCs had slightly lower photoacoustic amplitudes than reported PEG-PLGA systems. CP-LNCs were also stable in size (32 ± 0.7 nm) and photoluminescence over 21 days at 4 °C, 25 °C and 37 °C. In summary, encapsulation of CP within the liquid core of lipid nanocapsules enhances the optical properties of fluorescent CP.


Assuntos
Corantes Fluorescentes/química , Nanocápsulas/química , Imagem Óptica/métodos , Polietilenoglicóis/química , Polímeros/química , Estearatos/química , Triglicerídeos/química , Animais , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/metabolismo , Humanos , Lipídeos , Camundongos , Nanocápsulas/administração & dosagem , Imagem Óptica/tendências , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Polímeros/administração & dosagem , Polímeros/metabolismo , Estearatos/administração & dosagem , Estearatos/metabolismo , Triglicerídeos/administração & dosagem , Triglicerídeos/metabolismo
5.
ACS Appl Mater Interfaces ; 11(50): 46525-46535, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31746180

RESUMO

Borylated poly(fluorene-benzothiadiazoles) (PF8-BT) are π-conjugated polymers (CPs) with deep-red/near-infrared (NIR) absorption and emission profiles suitable for in vivo optical imaging. A fully borylated PF8-BT derivative (P4) was encapsulated in pegylated poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles and compared with a reference NIR-emitting CP (PCPDTBT) or indocyanine green (ICG). All formulations satisfied quality requirements for parenterally administered diagnostics. P4 nanoparticles had higher quantum yield (2.3%) than PCPCDTBT (0.01%) or ICG nanoparticles (1.1%). The signal/background ratios (SBRs) of CP systems P4 and PCPDTBT in a phantom mouse (λem = 820 nm) increased linearly with fluorophore mass (12.5-100 µg/mL), while the SBRs of ICG decreased above 25 µg/mL. P4 nanoparticles experienced <10% photobleaching over 10 irradiations (PCPDTBT: ∼25% and ICG: >44%). In a mouse tumor xenograft model, P4 nanoparticles showed a 5-fold higher SBR than PCPDTBT particles with fluorophore accumulation in the liver > spleen > tumor. Blood chemistry and tissue histology showed no abnormalities compared to untreated animals after a single administration.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Tiadiazóis/farmacologia , Animais , Fluorenos/química , Fluorenos/farmacologia , Corantes Fluorescentes/química , Xenoenxertos , Humanos , Verde de Indocianina/química , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Camundongos , Nanopartículas/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotodegradação/efeitos dos fármacos , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Baço/diagnóstico por imagem , Baço/efeitos dos fármacos , Tiadiazóis/efeitos adversos , Tiadiazóis/química
6.
J Mater Chem B ; 7(33): 5115-5124, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31363720

RESUMO

The near-infrared absorbing conjugated polymer poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (PCPDTBT) has been investigated as a contrast agent for optical and photoacoustic imaging. Lipophilic π-conjugated polymers can be efficiently encapsulated within self-assembling diblock copolymer poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles, although the effect of variations in PEG and PLGA chain lengths on nanoparticle properties, performance and biocompatibility have not yet been investigated. In this study, PEG-PLGA with different block lengths (PEG2kDa-PLGA4kDa, PEG2kDa-PLGA15kDa and PEG5kDa-PLGA55kDa) were used to encapsulate PCPDTBT. Nanoparticle sizes were smallest (<100 nm) when using PEG2kDa-PLGA4kDa, with <5% PCPDTBT content and a reduction in the total solids concentration of the organic phase. All PEG-PLGA nanoparticles were colloidally stable in water and serum-supplemented cell culture medium over 24 h at 37 °C, with slight evidence of protein surface adsorption. PEG2kDa-PLGA4kDa systems showed a threefold lower cytotoxicity (IC50 value) than the other two systems. Haemolytic activity was <2.5% for all systems and no platelet aggregation or inhibition of ADP-induced platelet aggregation was observed. Encapsulation of PCPDTBT within a PEG-PLGA matrix shifted fluorescence emission towards red wavelengths (760 nm in THF vs. 840 nm in nanoparticles) and reduced the quantum yield by 30-70-fold compared to THF. Nonetheless, PCPDTBT:PEG2kDa-PLGA4kDa systems had a marginally higher quantum yield and signal-to-background ratio in a phantom mouse compared with PEG2kDa-PLGA15kDa and PEG5kDa-PLGA55kDa systems. As a photoacoustic imaging probe, PCPDTBT:PEG2kDa-PLGA4kDa systems also showed a higher photoacoustic amplitude compared to higher molecular weight PEG-PLGA systems. Overall, the low molecular weight PEG2kDa-PLGA4kDa nanoparticle systems conferred the benefits of smaller sizes, reduced cytotoxicity and enhanced imaging performance compared to higher molecular weight matrix polymers.


Assuntos
Materiais Biocompatíveis/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Animais , Materiais Biocompatíveis/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Peso Molecular , Nanopartículas/toxicidade , Tamanho da Partícula , Agregação Plaquetária/efeitos dos fármacos , Polímeros/química , Tiadiazóis/química , Imagem Corporal Total
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