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Background: Development of an inhalable nanoformulation of dacomitinib (DMB) encapsulated in poly-(lactic-co-glycolic acid) nanoparticles (NPs) to improve solubility, facilitate direct lung delivery and overcome the systemic adverse effects. Methods: DMB-loaded poly-(lactic-co-glycolic acid) NPs were prepared using solvent evaporation and characterized for particle size, polydispersity index and zeta-potential. The NPs were evaluated for in vitro drug release, aerosolization performance and in vitro efficacy studies. Results: The NPs showed excellent particle characteristics and displayed a cumulative release of â¼40% in 5 days. The NPs demonstrated a mass median aerodynamic diameter of â¼3 µm and fine particle fraction of â¼80%. Further, in vitro cell culture studies showed improved cytotoxic potential of DMB-loaded NPs compared with free drug. Conclusion: The study underscores the potential of DMB-loaded NPs as a viable approach for non-small cell lung cancer treatment.
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Tuberculosis (TB) is an airborne bacterial infection caused by Mycobacterium tuberculosis (M. tb), resulting in approximately 1.3 million deaths in 2022 worldwide. Oral therapy with anti-TB drugs often fails to achieve therapeutic concentrations at the primary infection site (lungs). In this study, we developed a dry powder inhalable formulation (DPI) of clofazimine (CFZ) to provide localized drug delivery and minimize systemic adverse effects. Poly (lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) containing CFZ were developed through a single emulsion solvent evaporation technique. Clofazimine microparticles (CFZ MPs) displayed entrapment efficiency and drug loading of 66.40 ± 2.22 %w/w and 33.06 ± 1.45 µg/mg, respectively. To facilitate pulmonary administration, MPs suspension was spray-dried to yield a dry powder formulation (CFZ SD MPs). Spray drying had no influence on particle size (~1 µm), zeta potential (-31.42 mV), and entrapment efficiency. Solid state analysis (PXRD and DSC) of CFZ SD MPs studies demonstrated encapsulation of the drug in the polymer. The drug release studies showed a sustained drug release. The optimized formulation exhibited excellent aerosolization properties, suggesting effective deposition in the deeper lung region. The in vitro antibacterial studies against H37Ra revealed improved (eight-fold) efficacy of spray-dried formulation in comparison to free drug. Hence, clofazimine dry powder formulation presents immense potential for the treatment of tuberculosis with localized pulmonary delivery and improved patient compliance.
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The 2023-2024 American Association of Colleges of Pharmacy Research and Graduate Affairs Committee ("the Committee") was charged with developing programs focused on career and professional development for researchers, new faculty, and graduate students in colleges and schools of pharmacy. After reviewing exiting resources available to pharmacy faculty for grant writing, the Committee recognized a need for more comprehensive, diverse, and tailored resources for pharmacy faculty. The Committee, therefore, focused its effort on creating an intensive grant writing course intended for independent pharmacy researchers without previous major grant awards that would support writing for career development and research grant applications and cater to faculty in translational, clinical sciences, and pharmacy practice, along with fellows and residents. To implement this grant writing course and other programs to advance research progress by pharmacy faculty, the Committee proposes 3 recommendations for consideration by the American Association of Colleges of Pharmacy and 1 suggestion for consideration by colleges and schools of pharmacy.
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Docentes de Farmácia , Faculdades de Farmácia , Sociedades Farmacêuticas , Humanos , Estados Unidos , Educação em Farmácia , Pesquisa em Farmácia , Educação de Pós-Graduação em Farmácia , Redação , Estudantes de FarmáciaRESUMO
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) and is the second leading cause of death from an infectious disease globally. The disease mainly affects the lungs and forms granulomatous lesions that encapsulate the bacteria, making treating TB challenging. The current treatment includes oral administration of bedaquiline (BDQ) and pretomanid (PTD); however, patients suffer from severe systemic toxicities, low lung drug concentration, and non-adherence. In this study, we developed BDQ-PTD loaded nanoparticles as inhalable dry powders for pulmonary TB treatment using a Quality-by-Design (QbD) approach. The BDQ-PTD combination showed an additive/synergistic effect for M.tb inhibition in vitro, and the optimized drug ratio (1:4) was successfully loaded into polymeric nanoparticles (PLGA NPs). The QbD approach was implemented by identifying the quality target product profile (QTPPs), critical quality attributes (CQAs), and critical process parameters (CPPs) to develop efficient design space for dry powder preparation using spray drying. The three-factorial and three-level Box-Behnken Design was used to assess the effect of process parameters (CPPs) on product quality (CQAs). The Design of Experiments (DoE) analysis showed different regression models for product quality responses and helped optimize process parameters to meet QTPPs. The optimized dry powder showed excellent yield (72 ± 2 % w/w), high drug (BDQ-PTD) loading, low moisture content (<1% w/w), and spherical morphology. Further, aerosolization performance revealed the suitability of powder for deposition in the respiratory airways of the lungs (MMAD 2.4 µm and FPF > 75 %). In conclusion, the QbD approach helped optimize process parameters and develop dry powder with a suitable quality profile for inhalation delivery in TB patients.
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Diarilquinolinas , Nanopartículas , Nitroimidazóis , Tuberculose , Humanos , Pós , Aerossóis e Gotículas Respiratórios , Administração por Inalação , Inaladores de Pó Seco , Tamanho da Partícula , AerossóisRESUMO
Nisin ZP is an antimicrobial peptide (AMP) produced by the bacterium Lactococcus lactis, and we have previously demonstrated anticancer activity in NSCLC (A549) cells. In this study, we formulated a nisin ZP dry powder (NZSD) using a spray dryer to facilitate inhaled delivery for the treatment of NSCLC. Nisin ZP was spray-dried with mannitol, l-leucine, and trehalose in a ratio of 75:15:10 using Büchi mini spray-dryer B-290 in different drug loadings (10, 20, and 30% w/w). NZSD powder revealed a good powder yield of >55% w/w with ≤3 % w/w moisture content and high nisin ZP drug loading for all the peptide ratios. The NZSD powder particles were irregularly shaped with corrugated morphology. The presence of an endothermic peak in DSC thermograms and attenuated crystalline peaks in PXRD diffractograms confirmed the semi-crystalline powder nature of NZSD. The anticancer activity of nisin ZP was maintained after fabricating it into NZSD powder and showed a similar inhibitory concentration to free nisin ZP. Stability studies indicated that NZSD powders were stable for three months at 4 and 25 â with more than 90% drug content and semi-crystalline nature, as confirmed by DSC and PXRD. Aerosolization studies performed using NGI indicated an aerodynamic diameter (MMAD) within the desired range (1-5 µm) and a high fine particle fraction (FPF > 75%) for all peptide ratios, suggesting powder deposition in the lung's respiratory airways. In conclusion, a dry powder of nisin ZP was formulated using a spray dryer with enhanced storage stability and suitable for inhaled delivery.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nisina , Humanos , Administração por Inalação , Peptídeos Antimicrobianos , Pós/química , Aerossóis e Gotículas Respiratórios , Pulmão , Tamanho da Partícula , Inaladores de Pó SecoRESUMO
Tuberculosis (TB) is a contiguous airborne disease caused by Mycobacterium tuberculosis (M.tb), primarily affecting the human lungs. The progression of drug-susceptible TB to drug-resistant strains, MDR-TB and XDR-TB, has become a global challenge toward eradicating TB. Conventional TB treatment involves frequent dosing and prolonged treatment regimens predominantly by an oral or invasive route, leading to treatment-related systemic adverse effects and patient's noncompliance. Pulmonary delivery is an attractive option as we could reduce dose, limit systemic side-effects, and achieve rapid onset of action. Delamanid (DLD), an antituberculosis drug, has poor aqueous solubility, and in this study, we aim to improve its solubility using cyclodextrin complexation. We screened different cyclodextrins and found that HP-ß-CD resulted in a 54-fold increase in solubility compared to a 27-fold and 13-fold increase by SBE-ß-CD and HP-É£-CD, respectively. The stability constant (265 ± 15 M-1) and complexation efficiency (8.5 × 10-4) suggest the formation of a stable inclusion complex of DLD and HP-ß-CD in a 2:1 ratio. Solid-state characterization studies (DSC, PXRD, and NMR) further confirmed successful complexation of DLD in HP-ß-CD. The nebulized DLD-CD complex solution showed a mass median aerodynamic diameter of 4.42 ± 0.62 µm and fine particle fraction of 82.28 ± 2.79%, suggesting deposition in the respiratory airways. In bacterial studies, minimum inhibitory concentration of DLD-CD complex was significantly reduced (four-fold) compared to free DLD in M.tb (H37Ra strain). Furthermore, accelerated stability studies confirmed that the inclusion complex was stable for 4 weeks with 90%w/w drug content. In conclusion, we increased the aqueous solubility of DLD through cyclodextrin complexation and improved its efficacy in vitro.
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Ciclodextrinas , Tuberculose Pulmonar , Tuberculose , Humanos , Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Solubilidade , Pulmão , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Non-small cell lung cancer (NSCLC) is a major cause of global cancer mortalities and accounts for approximately 80-85% of reported lung cancer cases. Conventional chemotherapeutics show limited application because of poor tumor selectivity and acquired drug resistance. Antimicrobial peptides (AMPs) have gained much attention as potential anticancer therapeutics owing to their high potency and high target selectivity and specificity with limited scope for drug resistance. In this study, D-LAK (D-LAK-120A), a cationic AMP, was evaluated for its anticancer efficacy in various NSCLC cell lines. D-LAK peptide demonstrated enhanced cytotoxicity in A549, H358, H1975, and HCC827 cell lines with inhibitory concentrations between 4.0 and 5.5 µM. An increase in the lactate dehydrogenase (LDH) levels and propidium iodide (PI) uptake across compromised membrane suggested membranolytic activity as an inhibition pathway. In addition, we found D-LAK induced lung cancer cell apoptosis and arrested cells in the S phase (DNA synthesis) of cell cycle. Moreover, a decreased mitochondrial membrane potential and elevated ROS levels were observed after D-LAK treatment, suggesting induction of mitochondria-mediated apoptosis. Additionally, D-LAK inhibited single cell proliferation and cancer cell migration in vitro. The tumor reduction observed in the 3D spheroid assay further suggests the potential use of D-LAK as an anticancer agent for NSCLC treatment. Our results postulate innovative insights on the anticancer mechanism of D-LAK, which may contribute to its further development into preclinical studies and a potential therapeutic.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Peptídeos Antimicrobianos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA , Lactato Desidrogenases , Neoplasias Pulmonares/genética , Propídio/farmacologia , Propídio/uso terapêutico , Espécies Reativas de OxigênioRESUMO
Lung cancer is the leading cause of cancer deaths globally with most of the reported cases (> 85%) associated with non-small cell lung cancer (NSCLC). Current therapies have enhanced the overall survival rate of patients but treatment-related adverse effects and increase in drug-resistance limit the success of these treatment options. Antimicrobial peptides (AMPs) have gained interest as anticancer agents as they selectively target cancer cells and decrease the possibility of resistance. Nisin ZP is a polycyclic antimicrobial peptide produced by the Gram-positive bacterium, Lactococcus lactis and is commonly used as a food preservative. Nisin ZP has recently demonstrated anticancer activity in melanoma, head and neck squamous cell carcinoma, hepatic, colon, and blood cancer. In this study, we evaluated the anticancer potential of nisin ZP and assessed the underlying mechanisms in NSCLC cells. The results revealed that nisin ZP induced selective toxicity in cancer (A549 and H1299) cells compared to healthy (HEK293) cells after 48 h of treatment. Nisin ZP exposure induced apoptosis and cell cycle arrest (G0/G1 phase) in NSCLC cells irrespective of tumor protein p53 expression. The cancer cell proliferation was inhibited via non-membranolytic pathways by mitochondrial membrane depolarization and elevation in reactive oxygen species (ROS) generation. Furthermore, nisin ZP decreased cancer cells' clonal expansion and migration, demonstrating potential use against highly metastatic NSCLC. The 3D spheroid growth and cell viability of the A549 cells were significantly inhibited by nisin ZP compared to control. Overall, the results suggest an excellent antitumor potential in vitro and, thus, can further be developed as a novel therapeutic for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nisina , Humanos , Peptídeos Antimicrobianos , Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Técnicas de Cultura de Células em Três Dimensões , Linhagem Celular Tumoral , Proliferação de Células , Células HEK293 , Neoplasias Pulmonares/patologia , Nisina/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Osimertinib (OB) is a third-generation irreversible tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), overexpressed in non-small cell lung cancer. Systemic administration of drug often results in poor drug levels at the primary tumor in the lungs and is associated with systemic side effects. In this study, we developed inhalable OB liposomes that can locally accumulate at the tumor site thereby limiting systemic toxicity. OB was loaded into liposomes via active and passive loading methods. The OB active liposomes achieved a higher encapsulation (78%) compared to passive liposomes (25%). The liposomes (passive and active) exhibited excellent aerosolization performance with an aerodynamic diameter of 4 µm and fine particle fraction of 82%. In H1975 cells, OB active and passive liposomes reduced IC50 by 2.2 and 1.2-fold, respectively, compared to free drug. As the OB active liposomes demonstrated higher cytotoxicity compared to OB passive liposomes, they were further investigated for in vitro anti-cancer activity. The OB active liposomes inhibited tumor cell migration and colonization as determined by the scratch assay and clonogenic assay, respectively. Furthermore, the 3D spheroid studies showed that the liposomes were successful in inhibiting tumor growth. These results highlight the potential of OB liposomes to suppress lung cancer. Owing to these attributes, the inhalable OB liposomes can potentially promote better therapeutic outcomes with limited systemic toxicity.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Indóis , Lipossomos/uso terapêutico , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , PirimidinasRESUMO
Pulmonary drug delivery is governed by several biophysical parameters of delivery carriers, such as particle size, shape, density, charge, and surface modifications. Although much attention has been given to other parameters, particle shape effects have rarely been explored. In this work, we assess the influence of particle shape of inhaled delivery carriers on their aerodynamic properties and macrophage uptake by using polymeric microparticles of different geometries ranging in various sizes. Doxorubicin was conjugated to the polymer particles and the bioconjugates were characterized. Interestingly, the results of in-vitro lung deposition, performed using a next generation impactor, demonstrated a significant improvement in the aerodynamic properties of the rod-shaped particles with a high aspect ratio as compared to spherical particles with the same equivalent volume. The results of a macrophage uptake experiment demonstrate that the high aspect ratio particles were phagocytosed less than spherical particles. Furthermore, the cytotoxicity of these doxorubicin-conjugated particles was determined against murine macrophages, resulting in reduced toxicity when treated with high aspect ratio particles as compared to spherical particles. This project provides valuable insights into the influence of particle shape on aerodynamic properties and primary defense mechanisms in the peripheral lungs, while using polymeric microparticles of various sizes and geometries. Further systematic development can help translate these findings to preclinical and clinical studies for designing efficient inhalable delivery carriers.
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Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Administração por Inalação , Animais , Portadores de Fármacos , Pulmão , Camundongos , Tamanho da PartículaRESUMO
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths globally. Treatment-related adverse effects and development of drug resistance limit the available treatment options for most patients. Therefore, newer drug candidates and drug delivery systems that have limited adverse effects with significant anti-cancer efficacy are needed. For NSCLC treatment, delivering drugs via inhalation is highly beneficial as it requires lower doses and limits systemic toxicity. Bedaquiline (BQ), an FDA-approved anti-tuberculosis drug has previously shown excellent anti-cancer efficacy. However, poor aqueous solubility limits its delivery via the lungs. In this project, we developed inhalable BQ-loaded cubosome (BQLC) nanocarriers against NSCLC. The BQLC were prepared using a solvent evaporation technique with the cubosomal nanocarriers exhibiting a particle size of 150.2 ± 5.1 nm, zeta potential of (+) 35.4 ± 2.3 mV, and encapsulation efficiency of 51.85 ± 4.83%. The solid-state characterization (DSC and XRD) confirmed drug encapsulation and in an amorphous form within the cubosomes. The BQLC nanocarriers showed excellent aerodynamic properties after nebulization (MMAD of 4.21 ± 0.53 µm and FPF > 75%). The BQLC displayed enhanced cellular internalization and cytotoxicity with a ~ 3-fold reduction in IC50 compared to free BQ in NSCLC (A549) cells, after 48 h treatment. The BQLC suppressed cell proliferation via apoptotic pathway, further inhibited colony formation, and cancer metastasis in vitro. Additionally, 3D-tumor simulation studies established the anti-cancer efficacy of cubosomal nanocarriers as compared to free BQ. This is the first study exploring the potential of cubosomes as inhalation therapy of repurposed drug, BQ and the results suggest that BQLC may be a promising NSCLC therapy due to excellent aerosolization performance and enhanced anti-cancer activity.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Diarilquinolinas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Tamanho da PartículaRESUMO
Three prophylactic vaccines are approved to protect against HPV infections. These vaccines are highly immunogenic. The most recent HPV vaccine, Gardasil-9, protects against HPV types associated with ~90% of cervical cancer (worldwide). Thus, ~10% of HPV-associated cancers are not protected by Gardasil-9. Although this is not a large percentage overall, the HPV types associated with 10% of cervical cancer not protected by the current vaccine are significantly important, especially in HIV/AIDS patients who are infected with multiple HPV types. To broaden the spectrum of protection against HPV infections, we developed mixed MS2-L2 VLPs (MS2-31L2/16L2 VLPs and MS2-consL2 (69-86) VLPs) in a previous study. Immunization with the VLPs neutralized/protected mice against infection with eleven high-risk HPV types associated with ~95% of cervical cancer and against one low-risk HPV type associated with ~36% of genital warts & up to 32% of recurrent respiratory papillomatosis. Here, we report that the mixed MS2-L2 VLPs can protect mice from three additional HPV types: HPV51, which is associated with ~0.8% of cervical cancer; HPV6, which is associated with up to 60% of genital warts; HPV5, which is associated with skin cancers in patients with epidermodysplasia verruciformis (EV). Overall, mixed MS2-L2 VLPs can protect against twelve HPV types associated with ~95.8% of cervical cancers and against two HPV types associated with ~90% of genital warts and >90% recurrent respiratory papillomatosis. Additionally, the VLPs protect against one of two HPV types associated with ~90% of HPV-associated skin cancers in patients with EV. More importantly, we observed that mixed MS2-L2 VLPs elicit protective antibodies that last over 9 months. Furthermore, a spray-freeze-dried formulation of the VLPs is stable, immunogenic, and protective at room temperature and 37 °C.
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Anticorpos Antivirais/sangue , Bacteriófagos/imunologia , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Condiloma Acuminado/prevenção & controle , Proteção Cruzada/imunologia , Feminino , Humanos , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Papillomaviridae/classificação , Papillomaviridae/patogenicidade , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Vacinas de Partículas Semelhantes a Vírus/administração & dosagemRESUMO
EXECUTIVE SUMMARY The 2020-2021 AACP Research and Graduate Affairs Committee (RGAC) continued the work begun by the 2019-2020 RGAC to increase awareness of and capacity for implementation research to advance practice transformation in academic pharmacy. AACP President Anne Lin charged the RGAC with developing resources and programs for training faculty and graduate students in implementation science. The committee was further charged with developing a mechanism to pair pharmacy faculty and implementation experts on practice advancement projects. In its work, the committee focused on generating near-term opportunities for pharmacy practice faculty to pursue projects while developing programs that would support ongoing career development and future implementation practice and research by pharmacy faculty and trainees.
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Educação em Farmácia , Farmácia , Docentes de Farmácia , Humanos , Ciência da Implementação , Faculdades de FarmáciaRESUMO
Aim: To formulate an aerosolized nanoliposomal carrier for remdesivir (AL-Rem) against coronavirus disease 2019. Methods: AL-Rem was prepared using modified hydration technique. Cytotoxicity in lung adenocarcinoma cells, stability and aerodynamic characteristics of developed liposomes were evaluated. Results: AL-Rem showed high encapsulation efficiency of 99.79%, with hydrodynamic diameter of 71.46 ± 1.35 nm and surface charge of -32 mV. AL-Rem demonstrated minimal cytotoxicity in A549 cells and retained monolayer integrity of Calu-3 cells. AL-Rem showed sustained release, with complete drug release obtained within 50 h in simulated lung fluid. Long-term stability indicated >90% drug recovery at 4°C. Desirable aerosol performance, with mass median aerodynamic diameter of 4.56 ± 0.55 and fine particle fraction of 74.40 ± 2.96%, confirmed successful nebulization of AL-Rem. Conclusion: AL-Rem represents an effective alternative for coronavirus disease 2019 treatment.
Lay abstract Remdesivir is one of the first drugs approved for the treatment of coronavirus disease 2019. Currently, it is administered via an injection into the bloodstream. This means that the drug circulates around the entire body and only a limited amount reaches the diseased site the lungs. Frequent dosing is therefore required, which needs expert personnel and multiple hospital visits and can result in serious side effects. In this study, the authors developed specialized, nanosized particles containing the drug remdesivir that can be administered directly into the lungs. This could drastically minimize side effects, enhance efficacy and allow easy self-administration at home. The results of the study are promising but require additional investigation.
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Tratamento Farmacológico da COVID-19 , Portadores de Fármacos , Células A549 , Monofosfato de Adenosina/administração & dosagem , Administração por Inalação , Aerossóis , Alanina/administração & dosagem , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Humanos , Lipossomos , Nanopartículas , Tamanho da PartículaRESUMO
There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer activity in non-small cell lung cancer (NSCLC). A sulfobutyl ether derivative of ß-cyclodextrin (SBE-ß-CD) was selected based on phase solubility studies and molecular modeling to prepare an inclusion complex of BDQ and cyclodextrin. Aqueous solubility of BDQ was increased by 2.8 × 103-fold after complexation with SBE-ß-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-ß-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 ± 0.6 µm (<5 µm) and fine particle fraction: 83.3 ± 3.8%) of BDQ-CD complex. Accelerated stability studies showed BDQ-CD complex to be stable up to 3 weeks. From cytotoxicity studies, a slight enhancement in the anti-cancer efficacy was observed with BDQ-cyclodextrin complex, compared to BDQ alone in H1299 cell line. The IC50 values for BDQ and BDQ-CD complex were found to be ~40 µM in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 µM in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment.
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Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diarilquinolinas/administração & dosagem , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , beta-Ciclodextrinas/química , Células A549 , Administração por Inalação , Antibióticos Antineoplásicos/farmacologia , Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Linhagem Celular Tumoral , Diarilquinolinas/farmacologia , Reposicionamento de Medicamentos , Humanos , Modelos MolecularesRESUMO
The development of vaccines is one of the most significant medical accomplishments which has helped to eradicate a large number of diseases. It has undergone an evolutionary process from live attenuated pathogen vaccine to killed whole organisms or inactivated toxins (toxoids), each of them having its own advantages and disadvantages. The crucial parameters in vaccination are the generation of memory response and protection against infection, while an important aspect is the effective delivery of antigen in an intelligent manner to evoke a robust immune response. In this regard, nanotechnology is greatly contributing to developing efficient vaccine adjuvants and delivery systems. These can protect the encapsulated antigen from the host's in-vivo environment and releasing it in a sustained manner to induce a long-lasting immunostimulatory effect. In view of this, the present review article summarizes nanoscale-based adjuvants and delivery vehicles such as viral vectors, virus-like particles and virosomes; non-viral vectors namely nanoemulsions, lipid nanocarriers, biodegradable and non-degradable nanoparticles, calcium phosphate nanoparticles, colloidally stable nanoparticles, proteosomes; and pattern recognition receptors covering c-type lectin receptors and toll-like receptors.
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In this study, PGA-co-PDL nanoparticles (NPs) encapsulating model antigen, bovine serum albumin (BSA), were prepared via double emulsion solvent evaporation. In addition, chitosan hydrochloride (CHL) was incorporated into the external phase of the emulsion solvent method, which resulted in surface adsorption onto the NPs to form hybrid cationic CHL NPs. The BSA encapsulated CHL NPs were encompassed into nanocomposite microcarriers (NCMPs) composed of l-leucine to produce CHL NPs/NCMPs via spray drying. The CHL NPs/NCMPs were investigated for in vitro aerosolization, release study, cell viability and uptake, and stability of protein structure. Hybrid cationic CHL NPs (CHL: 10 mg/mL) of particle size (480.2 ± 32.2 nm), charge (+14.2 ± 0.72 mV), and BSA loading (7.28 ± 1.3 µg/mg) were produced. The adsorption pattern was determined to follow the Freundlich model. Aerosolization of CHL NPs/NCMPs indicated fine particle fraction (FPF: 46.79 ± 11.21%) and mass median aerodynamic diameter (MMAD: 1.49 ± 0.29 µm). The BSA α-helical structure was maintained, after release from the CHL NPs/NCMPs, as indicated by circular dichroism. Furthermore, dendritic cells (DCs) and A549 cells showed good viability (≥70% at 2.5 mg/mL after 4-24 h exposure, respectively). Confocal microscopy and flow cytometry data showed hybrid cationic CHL NPs were successfully taken up by DCs within 1 h of incubation. The upregulation of CD40, CD86, and MHC-II cell surface markers indicated that the DCs were successfully activated by the hybrid cationic CHL NPs. These results suggest that the CHL NPs/NCMPs technology platform could potentially be used for the delivery of proteins to the lungs for immunostimulatory applications such as vaccines.
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Afatinib (AFA) is a potent aniline-quinazoline derivative, approved by the Food and Drug Administration (FDA) in 2013, as a first-line treatment for metastatic non-small cell lung cancer (NSCLC). However, its clinical application is highly limited by its poor solubility, and consequently low bioavailability. We hypothesize that loading of AFA into biodegradable PLGA nanoparticles for localized inhalational drug delivery will be instrumental in improving therapeutic outcomes in NSCLC patients. Formulated AFA nanoparticles (AFA-NP) were evaluated for physicochemical properties (particle size: 180.2 ± 15.6 nm, zeta potential: - 23.1 ± 0.2 mV, % entrapment efficiency: 34.4 ± 2.3%), formulation stability, in-vitro aerosol deposition behavior, and anticancer efficacy. Stability studies revealed the physicochemical stability of AFA-NP. Moreover, AFA-NP exhibited excellent inhalable properties (mass median aerodynamic diameter (MMAD): 4.7 ± 0.1 µm; fine particle fraction (FPF): 77.8 ± 4.3%), indicating efficient particle deposition in deep lung regions. With respect to in-vitro drug release, AFA-NP showed sustained drug release with cumulative release of 56.8 ± 6.4% after 48 h. Cytotoxic studies revealed that encapsulation of AFA into PLGA nanoparticles significantly enhanced its cytotoxic potential in KRAS-mutated NSCLC cell lines (A549, H460). Cellular uptake studies revealed enhanced internalization of coumarin-loaded nanoparticles compared to plain coumarin in A549. In addition, 3D tumor spheroid studies demonstrated superior efficacy of AFA-NP in tumor penetration and growth inhibition. To conclude, we have established in-vitro efficacy of afatinib-loaded PLGA nanoparticles as inhalable NSCLC therapy, which will be of great significance when designing preclinical and clinical studies. Graphical abstract.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Afatinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Nanopartículas/química , Tamanho da PartículaRESUMO
Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.