RESUMO
Herein novel multicompartment nanoparticles (MCNs) that combine high stability and cargo loading capacity are developed. The MCNs are fabricated by crystallization-driven self-assembly (CDSA) of a tailor-made 21 arm star polymer, poly(L-lactide)[poly(tert-butyl acrylate)-block-poly(ethylene glycol)]20 [PLLA(PtBA-b-PEG)20 ]. Platelet-like or spherical MCNs containing a crystalline PLLA core and hydrophobic PtBA subdomains are formed and stabilized by PEG. Hydrophobic cargos, such as Nile Red and chemotherapeutic drug doxorubicin, can be successfully encapsulated into the collapsed PtBA subdomains with loading capacity two orders of magnitude higher than traditional CDSA nanoparticles. Depolarized fluorescence measurements of the Nile Red loaded MCNs suggest that the free volume of the hydrophobic chains in the nanoparticles may be the key for regulating their drug loading capacity. In vitro study of the MCNs suggests excellent cytocompatibility of the blank nanoparticles as well as a dose-dependent cellular uptake and cytotoxicity of the drug-loaded MCNs.
Assuntos
Nanopartículas , Polímeros , Polímeros/química , Portadores de Fármacos/química , Cristalização , Polietilenoglicóis/química , Nanopartículas/química , MicelasRESUMO
BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.
Assuntos
Camptotecina , Neoplasias , Camptotecina/farmacologia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Micelas , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Receptor 7 Toll-Like , Microambiente TumoralRESUMO
Interactive materials that can respond to a trigger by changing their morphology, but that can also gradually degrade into a fully soluble state, are attractive building blocks for the next generation of biomaterials. Herein, we design such transiently responsive polymers that exhibit UCST behaviour while gradually losing this property in response to a hydrolysis reaction in the polymer side chains. The polymers operate within a physiologically relevant window in terms of temperature, pH, and ionic strength. Whereas such behaviour has been reported earlier for LCST systems, it is at present unexplored for UCST polymers. Furthermore, we demonstrate that, in contrast to LCST polymers, in aqueous medium the UCST polymer forms a coacervate phase below the UCST, which can entrap a hydrophilic model protein, as well as a hydrophobic dye. Because of their non-toxicity, we also provide inâ vivo proof of concept of the use of this coacervate as a protein depot, in view of sustained-release applications.
Assuntos
Materiais Biocompatíveis/química , Transição de Fase , Polímeros/química , Proteínas/química , Temperatura , Hidrólise , PolimerizaçãoRESUMO
Heterotelechelic, hydrophilic polymers with a primary amine and thiol group at the α- and ω-chain end, respectively, are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization in a straightforward and versatile way and subsequently used for the design of dual-responsive polymer/gold nanohybrids. Therefore, a phthalimido-containing chain transfer agent (CTA) is synthesized and used for the polymerization of the hydrophilic monomers N-isopropylacrylamide (NIPAM) and N,N-dimethylacrylamide (DMA). After polymerization, the trithiocarbonate functionality at the ω-chain end, originating from the CTA, is converted into a thiol upon aminolysis. In the next step, the phthalimido α-chain end is hydrolyzed into a primary amine, resulting in heterotelechelic, hydrophilic polymers. End-group conversions are monitored by (1)H NMR spectroscopy, MALDI-TOF MS analysis, and UV-Vis spectroscopy, confirming that quantitative modifications are obtained during each stage. The amino groups of these heterotelechelic polymer chains are modified with citraconic anhydride, after which the obtained polymers are grafted with the thiol group onto citrate-stabilized gold nanoparticles resulting in the creation of dual-temperature- and pH-responsive gold particles.
Assuntos
Resinas Acrílicas/síntese química , Acrilamidas/química , Resinas Acrílicas/química , Aminas/química , Ouro/química , Espectroscopia de Ressonância Magnética , Nanopartículas Metálicas/química , Polimerização , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Compostos de Sulfidrila/químicaRESUMO
Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.
Assuntos
Nanopartículas , Neoplasias , Adjuvantes Imunológicos , Linhagem Celular Tumoral , Ácido Fólico , Humanos , Morte Celular Imunogênica , Imunoterapia , Manose , Neoplasias/tratamento farmacológico , Oxaliplatina/farmacologia , Polímeros , Receptor 7 Toll-Like/agonistas , Microambiente TumoralRESUMO
Pulmonary drug delivery has become a promising route in the treatment of lung diseases because of better local retention and lower systemic penetration. In this study, etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres were designed with potential pulmonary delivery properties. The microspheres were prepared via improved emulsion-solvent evaporation method. Physicochemical characteristics, micromeritics properties and in vitro drug release behavior of the microspheres were then evaluated. Results showed that etoposide-loaded PLGA microspheres were spherical in shape with smooth surface with size (11.8 ± 1.25) µm. Particles remained stable without any changing in size and morphology after dried by the freeze-drying method. Etoposide was loaded into PLGA microspheres in an amorphous state with high drug loading ((7.7 ± 0.3)%) and encapsulation efficiency ((84.2 ± 2.9)%). Results of micromeritics properties also demonstrated that etoposide-loaded PLGA microspheres were very suitable for pulmonary delivery. In addition, in vitro drug release study indicated a sustained release profile fitted with the Ritger-Peppas equation for up to 20 days. In conclusion, the etoposide-loaded PLGA microspheres were promising for pulmonary delivery, and etoposide could be sustained released from the PLGA microspheres.
Assuntos
Antineoplásicos Fitogênicos/química , Portadores de Fármacos , Etoposídeo/química , Ácido Láctico/química , Ácido Poliglicólico/química , Administração por Inalação , Antineoplásicos Fitogênicos/administração & dosagem , Química Farmacêutica , Preparações de Ação Retardada , Etoposídeo/administração & dosagem , Cinética , Microesferas , Modelos Químicos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Solubilidade , Propriedades de Superfície , Tecnologia Farmacêutica/métodosRESUMO
In recent years, the layer-by-layer (LbL) assembly based on hydrogen bonding interactions is gaining popularity for the preparation of thin film coatings, especially for biomedical purposes, based on the use of neutral, non-toxic building blocks. The use of tannic acid (TA) as hydrogen bonding donor is especially interesting as it results in LbL films that are stable under physiological conditions. In this work, investigations on the LbL thin film preparation of TA with poly(2-oxazoline)s with varying hydrophilicity, namely poly(2-methyl-2-oxazoline) (PMeOx), poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2-n-propyl-2-oxazoline) (PnPropOx), are reported. The LbL assembly process is investigated by quartz crystal microbalance and UV-vis spectroscopy revealing linear growth of the film thickness. Furthermore, isothermal titration calorimetry demonstrates the LbL assembly of TA, and PMeOx is found to be mostly enthalpy driven while the LbL assembly of TA with PEtOx and PnPropOx is mostly entropy driven. Finally, scanning electron microscopy and ellipsometry demonstrate the formation of smooth thin films for LbL assembly of TA with all three polymers. Such poly(2-oxazoline) coatings have high potential for use as anti-biofouling coatings.
Assuntos
Materiais Biocompatíveis/química , Oxazóis/química , Taninos/química , Ligação de Hidrogênio , Teste de MateriaisRESUMO
The aim of this study was to investigate the joint tissue distribution and pharmacodynamics of Lornoxicam (Lnxc) following intra-articular injection of either Lnxc suspensions or sustained release Lnxc-loaded PLGA microspheres (Lnxc-MS), as well as the biocompatibility of PLGA microspheres with or without drugs. In this study, Lnxc suspensions or Lnxc-loaded PLGA microspheres was injected into the knee joint cavity of rats. Blood samples were taken at predetermined times from the jugular vein and the joint tissue (cartilage and synovial membrane) were removed from the rats. Biocompatibility and pharmacodynamics were evaluated by observing the swelling of the joints of the rats and histological analysis following the injection of the microspheres. The plasma drug concentration decreased in rats and retention time increased in rats' joint with intra-articular injections of microspheres, revealing good targeting efficiency and decreased systemic toxicity. After 30 days of intra-articular injection with Lnxc-loaded or blank microspheres, the filtration liquid accumulation, blood vessels and fibrous proliferation were not detected, showing their good compatibility. Furthermore, the articular cartilage damage by papain could also be repaired by the Lnxc-loaded PLGA microspheres. In conclusion, intra-articular Lnxc-MS have considerable potential for creating a sustained release Lnxc delivery system and providing effective healing to Osteoarthritis.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Ácido Láctico/administração & dosagem , Microesferas , Osteoartrite/tratamento farmacológico , Piroxicam/análogos & derivados , Ácido Poliglicólico/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Artrite/tratamento farmacológico , Materiais Biocompatíveis/administração & dosagem , Preparações de Ação Retardada , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Injeções Intra-Articulares , Articulação do Joelho/efeitos dos fármacos , Masculino , Piroxicam/administração & dosagem , Piroxicam/farmacologia , Piroxicam/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Wistar , Suspensões , Membrana Sinovial/efeitos dos fármacos , Distribuição TecidualRESUMO
Owing to its rationale of targeting the drug to the site of action and minimizing systemic toxic effects of the drug, intra-articular drug delivery system has gained growing interests. In this study, emphasis was placed on intra-articular Lornoxicam-loaded PLGA microspheres (Lnxc-PLGA-MS) preparation and improving the targeting of lornoxicam (Lnxc) in knee joint. The microspheres were prepared by a process involving solid-in-oil-in-water(S/O/W) emulsion, and evaluated for physicochemical properties. Joint cavity's drug leakage into systemic circulation in rabbits was examined to define the drug stagnation. Meanwhile, drug retention in synovial fluid in rats was investigated to further validate the drug targeting. The microspheres were spherical as evidenced by the SEM photographs with mean size of 7.47 µm, and encapsulation efficiency was observed 82.22% along with drug loading 12.17%. DSC revealed that the drug in the microspheres existed in the phase of uncrystallization. The formulated microspheres could prolong the drug release up to 32 days in vitro. Comparing with animals injected with lornoxicam solution, the plasma drug concentration decreased in rabbits and retention time increased in rats' synovial fluid with intra-articular injections of microspheres, revealing good targeting efficiency. In conclusion, PLGA microspheres could be used to deliver lornoxicam following intra-articular administration for enhancing targeting efficiency.