RESUMO
Lung cancer is one of the most common cancers and a leading cause of death, with poor prognosis and high unmet clinical need. Chemotherapy is a common part of the treatment, either alone or in combination with other treatment modalities, but with limited efficacy and severe side effects. Encapsulation of drugs into nanoparticles can enable a more targeted delivery with reduced off-target toxicity. Delivery to the lungs is however often insufficient due to various biological barriers in the body and in the tumor microenvironment. Here we demonstrate that by incorporating drug-loaded nanoparticles into air-filled microbubbles, a more effective targeting to the lungs can be achieved. Fluorescence imaging and mass spectrometry revealed that the microbubbles could significantly improve accumulation of drug in the lungs of mice, compared to injecting either the free drug by itself or only the drug-loaded nanoparticles. Therapeutic efficacy was verified in a preclinical mouse model with non-small cell lung cancer, monitoring tumor growth by luminescence.
Assuntos
Neoplasias Pulmonares , Microbolhas , Nanopartículas , Animais , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Células A549RESUMO
The availability of analytical methods for the characterization of lipid nanoparticles (LNPs) for in-vivo intracellular delivery of nucleic acids is critical for the fast development of innovative RNA therapies. In this study, analytical protocols to measure (i) chemical composition, (ii) drug loading, (iii) particle size, concentration, and stability as well as (iv) structure and morphology were evaluated and compared based on a comprehensive characterization strategy linking key physical and chemical properties to in-vitro efficacy and toxicity. Furthermore, the measurement protocols were assessed either by testing the reproducibility and robustness of the same technique in different laboratories, or by a correlative approach, comparing measurement results of the same attribute with orthogonal techniques. The characterization strategy and the analytical measurements described here will have an important role during formulation development and in determining robust quality attributes ultimately supporting the quality assessment of these innovative RNA therapeutics.