RESUMO
Cell membrane-derived nanoparticles (NPs) have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells, impeding systemic clearance, and altering foreign body responses. Besides NP technology, adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy. In this research, we developed a biomimetic drug carrier based on chimeric antigen receptor (CAR) transduced T-cell membranes. For that purpose, anti-HER2 CAR-T cells were engineered via lentiviral transduction of anti-HER2 CAR coding lentiviral plasmids. Anti-HER2 CAR-T cells were characterized by their specific activities against the HER2 antigen and used for cell membrane extraction. Anti-cancer drug Cisplatin-loaded poly (D, l-lactide-co-glycolic acid) (PLGA) NPs were coated with anti-human epidermal growth factor receptor 2 (HER2)-specific CAR engineered T-cell membranes. Anti-HER2 CAR-T-cell membrane-coated PLGA NPs (CAR-T-MNPs) were characterized and confirmed via fluorescent microscopy and flow cytometry. Membrane-coated NPs showed a sustained drug release over the course of 21 days in physiological conditions. Cisplatin-loaded CAR-T-MNPs also inhibited the growth of multiple HER2+ cancer cells in vitro. In addition, in vitro uptake studies revealed that CAR-T-MNPs showed an increased uptake by A549 cells. These results were also confirmed via in vivo biodistribution and therapeutic studies using a subcutaneous lung cancer model in nude mice. CAR-T-MNPs localized preferentially at tumor areas compared to those of other studied groups and consisted of a significant reduction in tumor growth in tumor-bearing mice. In Conclusion, the new CAR modified cell membrane-coated NP drug-delivery platform has demonstrated its efficacy both in vitro and in vivo. Therefore, CAR engineered membrane-coated NP system could be a promising cell-mimicking drug carrier that could improve therapeutic outcomes of lung cancer treatments.
RESUMO
Toxoplasmosis is a major health problem and socioeconomic burden, affecting around 30-50% of the global population. Poly(dicarboxylatophenoxy)phosphazene (PCPP) polymer was chosen as adjuvant for the immunogenic peptide antigen. Peptide-loaded PCPP microparticles were synthesized via the coacervation method and the characterization studies of microparticles were conducted to determine their size, charge, morphology, encapsulation efficacy, and loading capacity. To evaluate in vivo efficacy of the vaccine candidate, Balb/c mice were immunized with the formulations. Brain and spleen tissues were isolated from animals to investigate cytokine levels, lymphocyte proliferation, and brain cyst formation. As a result, antibody and cytokine responses in groups immunized with peptide-loaded PCPP microparticles were found to be significantly higher when compared to the control group. In conclusion, our novel multi-epitope peptide-loaded PCPP microparticle-based vaccine formulation demonstrated considerable humoral and cellular immune responses against T. gondii and protected mice against T. gondii infection during Toxoplasmosis.
Assuntos
Vacinas Protozoárias , Toxoplasma , Toxoplasmose Animal , Toxoplasmose , Animais , Camundongos , Epitopos , Antígenos de Protozoários , Proteínas de Protozoários , Toxoplasmose/prevenção & controle , Peptídeos , Citocinas , Camundongos Endogâmicos BALB C , Anticorpos Antiprotozoários , Toxoplasmose Animal/prevenção & controleRESUMO
Bioadhesives are intended to facilitate the fast and efficient reconnection of tissues to restore their functionality after surgery or injury. The use of mussel-inspired hydrogel systems containing pendant catechol moieties is promising for tissue attachment under wet conditions. However, the adhesion strength is not yet ideal. One way to overcome these limitations is to add polymeric nanoparticles to create nanocomposites with improved adhesion characteristics. To further enhance adhesiveness, polydopamine nanoparticles with controlled size prepared using an optimized process, were combined with a mussel-inspired hyaluronic acid (HA) hydrogel to form a nanocomposite. The effects of sizes and concentrations of polydopamine nanoparticles on the adhesive profiles of mussel-inspired HA hydrogels were investigated. Results show that the inclusion of polydopamine nanoparticles in nanocomposites increased adhesion strength, as compared to the addition of poly (lactic-co-glycolic acid) (PLGA), and PLGA-(N-hydroxysuccinimide) (PLGA-NHS) nanoparticles. A nanocomposite with demonstrated cytocompatibility and an optimal lap shear strength (47 ± 3 kPa) was achieved by combining polydopamine nanoparticles of 200 nm (12.5% w/v) with a HA hydrogel (40% w/v). This nanocomposite adhesive shows its potential as a tissue glue for biomedical applications.
Assuntos
Nanocompostos , Nanopartículas , Adesivos Teciduais , Adesivos/farmacologia , Ácido Hialurônico/farmacologia , Hidrogéis/farmacologia , Indóis , Nanocompostos/uso terapêutico , Polímeros , Adesivos Teciduais/farmacologiaRESUMO
Melanoma is one of the most aggressive skin cancers, and the American Cancer Society reports that every hour, one person dies from melanoma. While there are a number of treatments currently available for melanoma (e.g., surgery, chemotherapy, immunotherapy, and radiation therapy), they face several problems including inadequate response rates, high toxicity, severe side effects due to non-specific targeting of anti-cancer drugs, and the development of multidrug resistance during prolonged treatment. To improve chemo-drug therapeutic efficiency and overcome these mentioned limitations, a multifunctional nanoparticle has been developed to effectively target and treat melanoma. Specifically, poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were coated with a cellular membrane derived from the T cell hybridoma, 19LF6 endowed with a melanoma-specific anti-gp100/HLA-A2 T-cell receptor (TCR) and loaded with an FDA-approved melanoma chemotherapeutic drug Trametinib. T-cell membrane camouflaged Trametinib loaded PLGA NPs displayed high stability, hemo- and cyto-compatibility. They also demonstrated membrane coating dependent drug release profiles with the most sustained release from the NPs proportional with the highest amount of membrane used. 19LF6 membrane-coated NPs produced a threefold increase in cellular uptake toward the melanoma cell line in vitro compared to that of the bare nanoparticle. Moreover, the binding kinetics and cellular uptake of these particles were shown to be membrane/TCR concentration-dependent. The in vitro cancer killing efficiencies of these NPs were significantly higher compared to other NP groups and aligned with binding and uptake characteristics. Particles with the higher membrane content (greater anti-gp100 TCR content) were shown to be more effective when compared to the free drug and negative controls. In vivo biodistribution studies displayed the theragnostic capabilities of these NPs with more than a twofold increase in the tumor retention compared to the uncoated and non-specific membrane coated groups. Based on these studies, these T-cell membrane coated NPs emerge as a potential theragnostic carrier for imaging and therapy applications associated with melanoma.
RESUMO
Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability. Despite recent advancement in nanotechnology platforms, this approach still falls short to meet the complexity of biological systems and diseases, such as avoiding systemic side effects, manipulating biological interactions and overcoming drug resistance, which hinders the therapeutic outcomes of the NP-based drug delivery systems. To address these issues, various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers. Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions, targeting, and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest. In this context, we comprehensively discuss various cell- and cell membrane-based drug delivery approaches towards cancer therapy, the therapeutic potential of these strategies, and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers. Finally, we review various cell types and cell membrane receptors for their potential in targeting, immunomodulation and overcoming drug resistance in cancer.