RESUMO
Lipid nanovesicles are widely present as transport vehicles in living organisms and can serve as efficient drug delivery vectors. It is known that the size and surface charge of nanovesicles can affect their diffusion behaviors in biological hydrogels such as mucus. However, how temperature effects, including those of both ambient temperature and phase transition temperature (Tm), influence vehicle transport across various biological barriers outside and inside the cell remains unclear. Here, we utilize a series of liposomes with different Tm as typical models of nanovesicles to examine their diffusion behavior in vitro in biological hydrogels. We observe that the liposomes gain optimal diffusivity when their Tm is around the ambient temperature, which signals a drastic change in the nanovesicle rigidity, and that liposomes with Tm around body temperature (i.e., â¼37 °C) exhibit enhanced cellular uptake in mucus-secreting epithelium and show significant improvement in oral insulin delivery efficacy in diabetic rats compared with those with higher or lower Tm Molecular-dynamics (MD) simulations and superresolution microscopy reveal a temperature- and rigidity-mediated rapid transport mechanism in which the liposomes frequently deform into an ellipsoidal shape near the phase transition temperature during diffusion in biological hydrogels. These findings enhance our understanding of the effect of temperature and rigidity on extracellular and intracellular functions of nanovesicles such as endosomes, exosomes, and argosomes, and suggest that matching Tm to ambient temperature could be a feasible way to design highly efficient nanovesicle-based drug delivery vectors.
Assuntos
Hidrogéis/administração & dosagem , Hidrogéis/química , Lipídeos/química , Nanopartículas/química , Animais , Transporte Biológico/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Difusão/efeitos dos fármacos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Epitélio/metabolismo , Insulina/administração & dosagem , Insulina/química , Lipossomos/química , Masculino , Transição de Fase/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , TemperaturaRESUMO
Polyethylene glycols (PEGs) can improve the diffusivity of nanoparticles (NPs) in biological hydrogels, while extended PEG chains severely impede cellular uptake of NPs. Inspired by invasive germs with flagellum-driven mucus-penetrating and fimbriae-mediated epithelium-adhering abilities, we developed germ-mimetic NPs (GMNPs) to overcome multiple barriers in mucosal and tumor tissues. In vitro studies and computational simulations revealed that the tip-specific extended PEG chains on GMNP functioned similarly to flagella, facilitating GMNP diffusion (up to 83.0-fold faster than their counterparts). Meanwhile, the packed PEG chains on the bodies of GMNP mediated strong adhesive interactions with cells similarly to the fimbriae, preserving cellular uptake efficiency. The in vivo results proved the superior tumor permeability and improved oral bioavailability provided by the GMNP (21.9-fold over administration of crystalline drugs). These findings offer useful guidelines for the rational design of NPs by manipulating surface polymer conformation to realize multiple functions and to enhance delivery efficacy.
Assuntos
Biomimética , Conformação Molecular , Nanopartículas/química , Polietilenoglicóis/química , Animais , Biomimética/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Simulação de Dinâmica Molecular , Nanopartículas/ultraestruturaRESUMO
Small unilamellar vesicles (SUVs), ubiquitous in organisms, play key and active roles in various biological processes. Although the physical properties of the constituent lipid molecules (i.e., the acyl chain length and saturation) are known to affect the mechanical properties of SUVs and consequently regulate their biological behaviors and functions, the underlying mechanism remains elusive. Here, we combined theoretical modeling and experimental investigation to probe the mechanical behaviors of SUVs with different lipid compositions. The membrane bending rigidity of SUVs increased with increasing chain length and saturation, resulting in differences in the vesicle rigidity and deformable capacity. Furthermore, we tested the tumor delivery capacity of liposomes with low, intermediate, and high rigidity as typical models for SUVs. Interestingly, liposomes with intermediate rigidity exhibited better tumor extracellular matrix diffusion and multicellular spheroid (MCS) penetration and retention than that of their stiffer or softer counterparts, contributing to improved tumor suppression. Stiff SUVs had superior cellular internalization capacity but intermediate tumor delivery efficacy. Stimulated emission depletion microscopy directly showed that the optimal formulation was able to transform to a rod-like shape in MCSs, which stimulated fast transport in tumor tissues. In contrast, stiff liposomes hardly deformed, whereas soft liposomes changed their shape irregularly, which slowed their MCS penetration. Our findings introduce special perspectives from which to map the detailed mechanical properties of SUVs with different compositions, provide clues for understanding the biological functions of SUVs, and suggest that liposome mechanics may be a design parameter for enhancing drug delivery.
Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias Pancreáticas/tratamento farmacológico , Estresse Mecânico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Camptotecina/química , Camptotecina/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipossomos/sangue , Lipossomos/síntese química , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Imagem Óptica , Neoplasias Pancreáticas/patologia , Tamanho da Partícula , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.