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BACKGROUND: Among heart transplant (HT) recipients who develop advanced graft dysfunction, cardiac re-transplantation may be considered. A smaller subset of patients will experience failure of their second allograft and undergo repeat re-transplantation. Outcomes among these individuals are not well-described. METHODS: Adult and pediatric patients in the United Network for Organ Sharing (UNOS) registry who received HT between January 1, 1990 and December 31, 2020 were included. RESULTS: Between 1990 and 2020, 90 individuals received a third HT and three underwent a fourth HT. Recipients were younger than those undergoing primary HT (mean age 32 years). Third HT was associated with significantly higher unadjusted rates of 1-year mortality (18% for third HT vs. 13% for second HT vs. 9% for primary HT, p < .001) and 10-year mortality (59% for third HT vs. 42% for second HT vs. 37% for primary HT, p < .001). Mortality was highest amongst recipients aged >60 years and those re-transplanted for acute graft failure. Long-term rates of CAV, rejection, chronic dialysis, and hospitalization for infection were also higher. CONCLUSIONS: Third HT is associated with higher morbidity and mortality than primary HT. Further consensus is needed regarding appropriate organ stewardship for this unique subgroup.
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Transplante de Coração , Adulto , Humanos , Criança , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Rejeição de Enxerto/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Since the 2018 allocation system change in heart transplantation (HT), ischemic times have increased, which may be associated with peri-operative and post-operative complications. This study aimed to compare ischemia reperfusion injury (IRI) in hearts preserved using ice-cold storage (ICS) and the Paragonix SherpaPak TM Cardiac Transport System (CTS). METHODS: From January 2021 to June 2022, consecutive endomyocardial biopsies from 90 HT recipients were analyzed by a cardiac pathologist in a single-blinded manner: 33 ICS and 57 CTS. Endomyocardial biopsies were performed at three-time intervals post-HT, and the severity of IRI manifesting histologically as coagulative myocyte necrosis (CMN) was evaluated, along with graft rejection and graft function. RESULTS: The incidence of IRI at weeks 1, 4, and 8 post-HT were similar between the ICS and CTS groups. There was a 59.3% statistically significant reduction in CMN from week 1 to 4 with CTS, but not with ICS. By week 8, there were significant reductions in CMN in both groups. Only 1 out of 33 (3%) patients in the ICS group had an ischemic time >240 mins, compared to 10 out of 52 (19%) patients in the CTS group. During the follow-up period of 8 weeks to 12 months, there were no significant differences in rejection rates, formation of de novo donor-specific antibodies and overall survival between the groups. CONCLUSION: The CTS preservation system had similar rates of IRI and clinical outcomes compared to ICS despite longer overall ischemic times. There is significantly more recovery of IRI in the early post operative period with CTS. This study supports CTS as a viable option for preservation from remote locations, expanding the donor pool.
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Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Coração , Preservação de Órgãos , Humanos , Transplante de Coração/efeitos adversos , Masculino , Feminino , Preservação de Órgãos/métodos , Pessoa de Meia-Idade , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Prognóstico , Adulto , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Criopreservação/métodos , Doadores de Tecidos/provisão & distribuição , Complicações Pós-Operatórias , Estudos RetrospectivosRESUMO
BACKGROUND: Leukopenia in the early period following heart transplantation (HT) is not well-studied. The aim of this study was to evaluate risk factors for the development of post-transplant leukopenia and its consequences for HT recipients. METHODS: Adult patients at a large-volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3 × 103 /µL) in the first 90-days following HT, individual risk factors, and its effect on 1-year outcomes were evaluated. RESULTS: Of 506 HT recipients, 184 (36%) developed leukopenia within 90-days. Median duration of the first leukopenia episode was 15.5 days (IQR 8-42.5 days). Individuals who developed leukopenia had lower pre-transplant WBC counts compared to those who did not (6.1 × 103 /µL vs. 6.9 × 103 /µL, p = .02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1-year (6.6% vs. 2.1%, p = .008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups. CONCLUSIONS: Leukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.
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Transplante de Coração , Transplante de Rim , Leucopenia , Adulto , Humanos , Transplante de Rim/efeitos adversos , Leucopenia/epidemiologia , Leucopenia/etiologia , Imunossupressores/efeitos adversos , Fatores de Risco , Transplante de Coração/efeitos adversos , Transplantados , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Estudos RetrospectivosRESUMO
Sorafenib, marketed under the brand name Nexavar®, is a multiple tyrosine kinase inhibitor drug that has been actively used in the clinical setting for the treatment of several cancers. However, the low solubility and bioavailability of sorafenib constitute a significant barrier to achieving a good therapeutic outcome. We developed a sorafenib-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation composed of capmul MCM, tween 80, and tetraglycol, and demonstrated that the SNEDDS formulation could improve drug solubility with excellent self-emulsification ability. Moreover, the sorafenib-loaded SNEDDS exhibited anticancer activity against Hep3B and KB cells, which are the most commonly used hepatocellular carcinoma and oral cancer cell lines, respectively. Subsequently, to improve the storage stability and to increase the possibility of commercialization, a solid SNEDDS for sorafenib was further developed through the spray drying method using Aerosil® 200 and PVP K 30. X-ray diffraction and differential scanning calorimeter data showed that the crystallinity of the drug was markedly reduced, and the dissolution rate of the drug was further improved in formulation in simulated gastric and intestinal fluid conditions. In vivo study, the bioavailability of the orally administered formulation increases dramatically compared to the free drug. Our results highlight the use of the solid-SNEDDS formulation to enhance sorafenib's bioavailability and outlines potential translational directions for oral drug development.
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In this study, functional twin liposomes (TLs) were designed by linking avidin-anchored single liposomes and biotin-anchored single liposomes via avidin-biotin interactions. Here, we first punched a hole on the liposome surface using the liposome magnetoporation method to prepare functional single liposomes, which were used for safely encapsulating quercetin (QER, as a model prodrug) or laccase (LAC, as a bioactive enzyme) inside the liposomes without the use of organic solvents; the pores were then plugged by pH-sensitive glycol chitosan grafted with 3-diethylaminopropylamine (GDEAP) and avidin (or biotin). As a result, single liposomes with QER and biotin-GDEAP were efficiently coupled with other liposomes with LAC and avidin-GDEAP. We demonstrated that the TLs could accelerate QER and LAC release at acidic pH (6.8), improving the LAC-mediated oxidization of QER and significantly elevating tumor cell death, suggesting that this strategy can be used as an efficient method for the programmed action of prodrugs.
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Avidina , Pró-Fármacos , Avidina/metabolismo , Biotina , Concentração de Íons de Hidrogênio , Lacase , Lipossomos , Pró-Fármacos/farmacologia , Quercetina/farmacologiaRESUMO
In this study, the strategy of transient generation of holes in the liposome surface has been shown to enable safe encapsulation of a high-molecular weight antibody (rituximab, Mw â¼140 kDa) within liposomes. These transient holes generated using our magnetoporation method allowed rituximab to safely enter the liposomes, and then the holes were plugged using hyaluronic acid grafted with 3-diethylaminopropylamine (DEAP). In the tumor microenvironment, the resulting liposomal rituximab was destabilized because of the ionization of the DEAP moiety at the acidic pH 6.5, resulting in extensive release of rituximab. Consequently, the rituximab released from the liposomes accumulated at high levels in tumors and bound to the CD20 receptors overexpressed on Burkitt lymphoma Ramos cells. This event led to significant enhancement in tumor cell ablation through rituximab-mediated complement-dependent cytotoxicity and Bcl-2 signaling inhibition-induced cell apoptosis.
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Antineoplásicos , Lipossomos , Anticorpos Monoclonais Murinos , Antígenos CD20/farmacologia , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Lipossomos/farmacologia , Rituximab/farmacologiaRESUMO
Lutein has been used as a dietary supplement for the treatment of eye diseases, especially age-related macular degeneration. For oral formulations, we investigated lutein stability in artificial set-ups mimicking different physiological conditions and found that lutein was degraded over time under acidic conditions. To enhance the stability of lutein upon oral intake, we developed enteric-coated lutein solid dispersions (SD) by applying a polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF), through a solvent-controlled precipitation method. The SD were characterized in crystallinity, morphology, and drug entrapment. In the dissolution profile of lutein SD, a F80 formulation showed resistance toward the acidic environment under simulated gastric conditions while exhibiting a bursting drug release under simulated intestinal conditions. Our results highlight the potential use of HPMCAS-LF as an effective matrix to enhance lutein bioavailability during oral delivery and to provide novel insights into the eye-care supplement industry, with direct benefits for the health of patients.
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Luteína/síntese química , Luteína/farmacocinética , Metilcelulose/análogos & derivados , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Metilcelulose/síntese química , Metilcelulose/farmacocinética , Polímeros/síntese química , Polímeros/farmacocinética , Solubilidade , Solventes , Difração de Raios X/métodosRESUMO
In this study, we developed an extremely small-sized water-soluble hyaluronate dot (dHA) conjugated with cyclic RGD (cRGD) and cleavable doxorubicin (DOX, as a model antitumor drug), named cRGD@dHA-c-DOX. This dot with HA moieties (as specific ligands to tumor CD44 receptors) and cRGD moieties (as specific ligands to tumor integrin αvß3) was designed to enable multivalent tumor targeting. In particular, the imine bonds, linking the DOX and dHA, can exhibit cleavage performance at endosomal pH, resulting in pH-triggered DOX release from cRGD@dHA-c-DOX. We demonstrated that cRGD@dHA-c-DOX resulted in highly improved cellular uptake and cell death in MDA-MB-231 tumor cells (CD44+, integrin αvß3+) compared to those in Huh7 tumor cells (CD44-, integrin αvß3-). In vivo studies using MDA-MB-231 tumor-bearing mice revealed that cRGD@dHA-c-DOX enhanced the tumor inhibition efficacy. These results suggest that cRGD@dHA-c-DOX can be utilized as a promising multivalent tumor-targeting drug carrier for highly efficient tumor treatment.
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Antineoplásicos , Doxorrubicina , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Camundongos , Peptídeos CíclicosRESUMO
The development of an oral formulation that ensures increased bioavailability of drugs is a great challenge for pharmaceutical scientists. Among many oral formulation systems, a drug delivery system employing superporous networks was developed to provide a prolonged gastro-retention time as well as improved bioavailability of drugs with a narrow absorption window in the gastrointestinal tract. Superporous networks (SPNs) were prepared from chitosan by crosslinking with glyoxal and poly(vinyl alcohol) (PVA). The SPNs showed less porosity and decreased water uptake with an increase in the crosslinking density and content of PVA. Gastro-retentive tablets (GRTs) were formulated using hydroxypropyl methylcellulose (HPMC, a hydrophilic polymer) and the prepared SPNs. Ascorbic acid (AA), which is mainly absorbed in the proximal part of the small intestine, was selected as a model drug. The formulated GRTs exhibited no floating lag time and stayed afloat until the end of the dissolution test. The in vitro drug release from the GRTs decreased with a decrease in the water uptake of the SPNs. The profile of drug release from the GRTs corresponded to the first-order and Higuchi drug-release models. Overall, floating tablets composed of the SPNs and HPMC have potential as a favorable platform to ensure sustained release and improved bioavailability of drugs that are absorbed in the proximal part of the small intestine.
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Preparações de Ação Retardada/administração & dosagem , Sistemas de Liberação de Medicamentos , Porosidade , Comprimidos , Disponibilidade Biológica , Liberação Controlada de Fármacos , Derivados da Hipromelose , PolímerosRESUMO
The purpose of this research was to develop a novel revaprazan-loaded surface-modified solid dispersion (SMSD) with improved drug solubility and oral bioavailability. The impact of carriers on aqueous solubility of revaprazan was investigated. HPMC and Cremophor A25 were selected as an appropriate polymer and surfactant, respectively, due to their high drug solubility. Numerous SMSDs were prepared with various concentrations of carriers, using distilled water, and the drug solubility of each was assessed. Moreover, the physicochemical properties, dissolution and pharmacokinetics of selected SMSD in rats were assessed in comparison to revaprazan powder. Of the SMSDs assessed, the SMSD composed of revaprazan/HPMC/Cremophor A25 at the weight ratio of 1:0.28:1.12 had the most enhanced drug solubility (â¼6000-fold). It was characterized by particles with a relatively rough surface, suggesting that the carriers were attached onto the surface of the unchanged crystalline revaprazan powder. It had a significantly higher dissolution rate, AUC and Cmax, and a faster Tmax value in comparison to revaprazan powder, with a 5.3-fold improvement in oral bioavailability of revaprazan. Therefore, from an environmental perspective, this SMSD system prepared with water, and without organic solvents, should be recommended as a revaprazan-loaded oral pharmaceutical alternative.
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Portadores de Fármacos/química , Derivados da Hipromelose/química , Polietilenoglicóis/química , Inibidores da Bomba de Prótons/química , Pirimidinonas/química , Tensoativos/química , Tetra-Hidroisoquinolinas/química , Administração Oral , Cristalização , Inibidores da Bomba de Prótons/administração & dosagem , ATPases Translocadoras de Prótons/antagonistas & inibidores , Pirimidinonas/administração & dosagem , Solubilidade , Tetra-Hidroisoquinolinas/administração & dosagemRESUMO
To develop a novel revaprazan-loaded gelatine microsphere with enhanced solubility and oral bioavailability, numerous gelatine microspheres were prepared using a spray-drying technique. The impact of gelatine amount on drug solubility in the gelatine microspheres was investigated. The physicochemical properties of the selected gelatine microsphere, such as shape, particle size and crystallinity, were evaluated. Moreover, its dissolution and pharmacokinetics in rats were assessed in comparison with revaprazan powder. Amongst the gelatine microspheres tested, the gelatine microsphere consisting of revaprazan and gelatine (1:2, w/w), which gave about 150-fold increased solubility, had the most enhanced drug solubility. It provided a spherical shape, amorphous drug and reduced particle size. Furthermore, it gave a higher dissolution rate and plasma concentration than did revaprazan powder. Particularly, it gave about 2.3-fold improved oral bioavailability in comparison with revaprazan powder. Therefore, this novel gelatine microsphere system is recommended as an oral pharmaceutical product of poorly water-soluble revaprazan.
Assuntos
Portadores de Fármacos/química , Gelatina/química , Pirimidinonas/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Composição de Medicamentos , Masculino , Tamanho da Partícula , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacocinéticaRESUMO
To develop a novel celecoxib (CXB)-loaded drug delivery system, numerous nanosuspensions were prepared with various polymers and surfactants using a wet media milling process, and their particle sizes were subsequently determined. A 24 full factorial design was used to identify the most appropriate preparation conditions. Pharmacokinetics of the selected nanosuspension were performed in rats and compared with those of a drug powder and a commercial CXB-loaded product. Among the carriers investigated, copovidone and sodium lauryl sulphate gave the smallest particle size of the drug in the nanosuspension. In particular, the nanosuspension prepared with 5% CXB, 4% copovidone, and 0.1% sodium lauryl sulphate, under the appropriate conditions, showed a particle size of approximately 190 nm, which was physically stable for at least 8 weeks. This nanosuspension provided a significantly higher plasma concentration and AUC in rats as compared with the drug powder and the commercial product. Thus, this novel CXB-loaded nanosuspension is a promising candidate with excellent stability and enhanced oral bioavailability.
Assuntos
Celecoxib/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Celecoxib/química , Celecoxib/farmacocinética , Química Farmacêutica/métodos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Estabilidade de Medicamentos , Masculino , Tamanho da Partícula , Polímeros/química , Pós , Ratos , Ratos Sprague-Dawley , Tensoativos/química , SuspensõesRESUMO
The aim of this study was to develop a novel fluticasone propionate (FP) and salmeterol xinafoate (SX)-loaded dry powder inhaler (DPI) system, which was composed of powder formulation and performance. The air flow resistances were determined with various types of DPI device, showing that the modified RS01 device gave the specific resistance similar to the commercial DPI device. The particle properties of FP, SX, and inhalation grade lactose particles, such as particle size, size distribution, and fine content, were assessed. Subsequently, the aerodynamic behaviors of the DPI powder formulations were evaluated by the in vitro deposition of drugs in the DPI products using Andersen cascade impactor. Amongst the DPI powder formulations tested, the formulation composed of FP, SX, Respitose® SV003, Respitose® SV010, and Respitose® ML006 at the weight ratio of 0.5/0.145/19/19/2 gave depositions, emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter of drugs similar to the commercial product, suggesting that they had similar aerodynamic behaviors. Furthermore, it gave excellent content uniformity. Thus, this DPI using the modified RS01 device would be recommended as a candidate for FP and SX-loaded pharmaceutical DPI products.
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Cápsulas/química , Fluticasona/química , Pós/química , Xinafoato de Salmeterol/química , Administração por Inalação , Aerossóis/química , Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Lactose/química , Tamanho da PartículaRESUMO
Tacrolimus (Tac) is an immunosuppressant that inhibits translocation of nuclear factor of activated T cells and has therapeutic potential for pulmonary fibrosis. Here, we investigated the therapeutic efficacy of a sustained-release type inhaled Tac formulation for treating bleomycin-induced pulmonary fibrosis. Inhalation has many meaningful advantages over injections, such as improved patient compliance, safety, and therapeutic effect. To this end, we fabricated inhalable albumin nanoparticles with bound Tac (Tac Alb-NPs) at a daily therapeutic dose (60 µg/mouse) using a high-pressure homogenizer via nanoparticle albumin-bound technology. The Tac Alb-NPs were spherical, â¼ 182.1 ± 28.5 nm in size, with a zeta potential of -34.5 ± 0.3 mV, and the Tac incorporation efficiency was as high as â¼ 85.3%. The bound tacrolimus was released gradually from Tac Alb-NPs for â¼ 24 h, which was sufficient time for pulmonary delivery. Most of all, the inhaled Tac Alb-NPs displayed remarkable anti-fibrotic efficacy in mice with bleomycin-induced pulmonary fibrosis, which was much better than the efficacy resulting from intraperitoneal administration of Tac (60 µg/mouse) based on histopathological results (hematoxylin and eosin and Masson's trichrome staining). Furthermore, the inhaled Cy5.5-labelled Tac Alb-NPs were visualized throughout the lungs of mice for â¼ 48 h, indicating direct exposure to fibrotic tissues in lung lesions. In conclusion, Tac Alb-NPs offer great potential as an inhalation delivery formulation for treating pulmonary fibrosis. Additionally, these NPs would be particularly useful as an effective and safe prototype for delivering practically insoluble therapeutic agents into the lungs.
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Albuminas/química , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Nanopartículas , Fibrose Pulmonar/tratamento farmacológico , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Administração por Inalação , Animais , Antimetabólitos , Bleomicina , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Hidroxiprolina/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologiaRESUMO
Albumin conjugation is viewed as an effective means of protracting short in vivo lifespans of proteins and targeting rheumatoid arthritis (RA). In this study, we present a human serum albumin (HSA) conjugate linked with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a bifunctional PEG derivative (HSA-TRAIL). Prepared HSA-TRAIL was found to have a larger molecular size (â¼240 kDa, 15.4 nm) than TRAIL (â¼66 kDa, 6.2 nm), and its bioactivity (apoptosis, cytotoxicity, and antiproliferation) was well preserved in Mia Paca-2 cells and mouse splenocytes. The enhanced therapeutic efficacy of HSA-TRAIL was demonstrated in collagen-induced arthritis (CIA) mice. The incidence and clinical scores, expressed as degree of erythema and swelling in HSA-TRAIL-treated mice, were remarkably lower than those of TRAIL-treated mice. The serum levels of pro-inflammatory cytokines IFN-γ, TNF-α, IL-1ß, and IL-2 in HSA-TRAIL-treated mice were significantly lower than those of TRAIL-treated mice. Furthermore, HSA-TRAIL accumulated in the hind paws of CIA mice, not in naïve TRAIL mice. Pharmacokinetic profiles of HSA-TRAIL were greatly improved in comparison to those of TRAIL (AUCinf: 844.1 ± 130.0 vs 36.0 ± 1.2 ng·h/mL; t1/2: 6.20 ± 0.72 vs 0.23 ± 0.01 h, respectively). The HSA-TRAIL conjugate, which presents clear advantages of targeting RA and long systemic circulation by HSA and unique anti-inflammatory efficacy by TRAIL, has potential as a novel treatment for rheumatoid arthritis.
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Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Albumina Sérica/química , Ligante Indutor de Apoptose Relacionado a TNF/química , Animais , Antirreumáticos/farmacocinética , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/metabolismo , Colágeno/toxicidade , Citocinas/metabolismo , Humanos , Masculino , Camundongos Endogâmicos DBA , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacocinética , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Distribuição TecidualRESUMO
Addressing disorders related to the central nervous system (CNS) remains a complex challenge because of the presence of the blood-brain barrier (BBB), which restricts the entry of external substances into the brain tissue. Consequently, finding ways to overcome the limited therapeutic effect imposed by the BBB has become a central goal in advancing delivery systems targeted to the brain. In this context, the intranasal route has emerged as a promising solution for delivering treatments directly from the nose to the brain through the olfactory and trigeminal nerve pathways and thus, bypassing the BBB. The use of lipid-based nanoparticles, including nano/microemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, has shown promise in enhancing the efficiency of nose-to-brain delivery. These nanoparticles facilitate drug absorption from the nasal membrane. Additionally, the in situ gel (ISG) system has gained attention owing to its ability to extend the retention time of administered formulations within the nasal cavity. When combined with lipid-based nanoparticles, the ISG system creates a synergistic effect, further enhancing the overall effectiveness of brain-targeted delivery strategies. This comprehensive review provides a thorough investigation of intranasal administration. It delves into the strengths and limitations of this specific delivery route by considering the anatomical complexities and influential factors that play a role during dosing. Furthermore, this study introduces strategic approaches for incorporating nanoparticles and ISG delivery within the framework of intranasal applications. Finally, the review provides recent information on approved products and the clinical trial status of products related to intranasal administration, along with the inclusion of quality-by-design-related insights.
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Lipossomos , Nanopartículas , Administração Intranasal , Barreira Hematoencefálica , Encéfalo , Sistemas de Liberação de Medicamentos , Lipídeos , Lipossomos/farmacologia , Mucosa Nasal/metabolismoRESUMO
A novel nanoparticle screening technique was established to mostly enhance the aqueous solubility and oral bioavailability of aceclofenac using nanoparticle systems. Among the polymers investigated, sodium carboxymethylcellulose (Na-CMC) showed the greatest increase in drug solubility. Utilizing spray-drying technique, the solvent-evaporated solid dispersion (SESD), surface-attached solid dispersion (SASD), and solvent-wetted solid dispersion (SWSD) were prepared using aceclofenac and Na-CMC at a weight ratio of 1:1 in 50 % ethanol, distilled water, and ethanol, respectively. Using Na-CMC as a solid carrier, an aceclofenac-loaded liquid self-emulsifying drug delivery system was spray-dried and fluid-bed granulated together with microcrystalline cellulose, producing a solid self-nanoemulsifying drug delivery system (SNEDDS) and solid self-nanoemulsifying granule system (SNEGS), respectively. Their physicochemical properties and preclinical assessments in rats were performed. All nanoparticles exhibited very different properties, including morphology, crystallinity, and size. As a result, they significantly enhanced the solubility, dissolution, and oral bioavailability in the following order: SNEDDS ≥ SNEGS > SESD ≥ SASD ≥ SWSD. Based on our screening technique, the SNEDDS was selected as the optimal nanoparticle with the highest bioavailability of aceclofenac. Thus, our nanoparticle screening technique should be an excellent guideline for solubilization research to improve the solubility and bioavailability of many poorly water-soluble bioactive materials.
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Lipid drug conjugates (LDCs) have attracted considerable attention in the fields of drug delivery and pharmacology due to their ability to target specific cells, increase drug solubility, reduce toxicity, and improve therapeutic efficacy. These unique features make LDCs promising candidates for the treatment cancer, inflammation, and infectious diseases. In fact, by choosing specific linkers between the lipid and drug molecules, stimuli-responsive LDCs can be designed to target cancer cells based on the unique properties of the tumor microenvironment. Despite the fact that many reviews have described LDCs, few articles have focused on tumor microenvironmental stimuli-responsive LDCs for cancer treatment. Therefore, the key elements of these types of LDCs in cancer treatment will be outlined and discussed in this paper. Our paper goes into detail on the concepts and benefits of LDCs, the various types of tumor microenvironment stimuli-responsive LDCs (such as pH, redox, enzyme, or reactive oxygen species-responsive LDCs), and the current status of LDCs in clinical trials.
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Neoplasias , Pró-Fármacos , Humanos , Microambiente Tumoral , Sistemas de Liberação de Medicamentos , Pró-Fármacos/química , Neoplasias/tratamento farmacológico , Lipídeos/químicaRESUMO
As an emerging anticancer strategy, ferroptosis has recently been developed in combination with current therapeutic modalities to overcome the existing limitations of conventional therapies. Herein, an ultraviolet (UV) upconversion luminescence-fueled nanoreactor is explored to combine ferroptosis and apoptosis through the UV-catalyzed Fenton reaction of an iron supplement (ferric ammonium citrate) loaded in a mesoporous silica layer in addition to the support of a chemotherapeutic agent (cisplatin) attached on the functionalized silica surface for the treatment of triple negative breast cancer (TNBC). The nanoplatform can circumvent the low penetration depth typical of UV light by upconverting near-infrared irradiation and emitting UV photons that convert Fe3+ to Fe2+ to boost the generation of hydroxyl radicals (·OH), causing devastating lipid peroxidation. Apart from DNA damage-induced apoptosis, cisplatin can also catalyze Fenton-based therapy by its abundant production of hydrogen peroxide (H2O2). As a bioinspired lipid membrane, the folate receptor-targeted liposome as the coating layer offers high biocompatibility and colloidal stability for the upconversion nanoparticles, in addition to prevention of the premature release of encapsulated hydrophilic compounds, before driving the nanoformulation to the target tumor site. As a result, superior antitumor efficacy has been observed in a 4T1 tumor-bearing mouse model with negligible side effects, suggesting that such a nanoformulation could play a pivotal role in effective apoptosis-strengthened ferroptosis TNBC therapy.
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Ferroptose , Nanopartículas , Neoplasias , Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Cisplatino/farmacologia , Luminescência , Peróxido de Hidrogênio/farmacologia , Apoptose , Neoplasias/tratamento farmacológico , Nanopartículas/uso terapêutico , Estresse Oxidativo , Nanotecnologia , Dióxido de Silício/farmacologia , Linhagem Celular TumoralRESUMO
Introduction: Ligand-conjugated liposomes are promising for the treatment of specific receptor-overexpressing cancers. However, previous studies have shown inconsistent results because of the varying properties of the ligand, presence of a polyethylene glycol (PEG) coating on the liposome, length of the linker, and density of the ligand. Methods: Here, we prepared PEGylated liposomes using PEG-linkers of various lengths conjugated with folate and evaluated the effect of the PEG-linker length on the nanoparticle distribution and pharmacological efficacy of the encapsulated drug both in vitro and in vivo. Results: When folate was conjugated to the liposome surface, the cellular uptake efficiency in folate receptor overexpressed KB cells dramatically increased compared to that of the normal liposome. However, when comparing the effect of the PEG-linker length in vitro, no significant difference between the formulations was observed. In contrast, the level of tumor accumulation of particles in vivo significantly increased when the length of the PEG-linker was increased. The tumor size was reduced by >40% in the Dox/FL-10K-treated group compared to that in the Dox/FL-2K- or 5K-treated groups. Discussion: Our study suggests that as the length of PEG-linker increases, the tumor-targeting ability can be enhanced under in vivo conditions, which can lead to an increase in the antitumor activity of the encapsulated drug.