Nanobubbles: A Novel Targeted Drug Delivery System

Abstract Nanobubbles are nanometer size bubbles having different constituents of varying physicochemical characteristic for the inner core and outer shell. Nanobubbles are mainly fabricated to improve the stability, bioavailability and improve the biodistribution of the delivered drug to the specific targeted site. Their small sizes bubbles allow the possibility of extravasation from blood vessels into the surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. Nanobubbles are developing as important contrast agents for imaging and carriers for drug delivery at targeted region. Sonication is the primary method for preparation of nanobubbles followed by thin-layer evaporation, high shear emulsification, mechanical agitation and coacervation or coalescence. With exposure to ultrasound/extracorporeal shock waves, the drug is liberated from the nanobubbles into the target cells. This review paper is an effort to reveal the different formulation development techniques briefly and varying shell and core content for developing nanobubbles.

Inhibitory effect of targeting nanobubbles with cisplatin loading on small cell lung cancer proliferation / 中华超声影像学杂志

Objective:To prepare cisplatin-loaded anti-progastrin-releasing peptide (ProGRP) monoclonal antibody targeted nanobubbles, and to explore the proliferation inhibition effect and anti-cancer molecular mechanism of them on small cell lung cancer (SCLC).Methods:The cisplatin targeted nanobubbles were prepared by thin film hydrating method, and the physicochemical property were explored. The subcutaneous xenograft tumor models of SCLC in 10 nude mice were established, and the ultrasound molecular targeting development effect of cisplatin targeted nanobubbles was analyzed by using blank nanobubbles as control. Another 24 tumor-bearing nude mouse models were established and randomly divided into four groups: blank nanobubbles group, cisplatin group, cisplatin nanobubbles group, cisplatin targeted nanobubbles group. The tumor inhibition rate was calculated. The effect on SCLC proliferation was detected by CCK8 method. RT-PCR and Western blotting methods were used to detect SCLC proliferation related genes the P53, Rb, c-myc protein and mRNA expression level of change, the molecular regulatory mechanism was analyzed.Results:The cisplatin targeted nanobubbles were successfully prepared. The particle size was (467.3±42.3)nm, the structure was stable. The cisplatin targeted nanobubbles had a good effect of ultrasonic molecular development in SCLC xenograft.Compared with the control group, the proliferation of SCLC cells was significantly inhibited by cisplatin targeted nanobubbles. The RT-PCR and Western blotting analysis showed that compared with the control group, the mRNA and protein levels of the proliferation-related gene P53 and Rb in the cisplatin targeted nanovesicles group were significantly up-regulated, and the mRNA and protein levels of c-myc were significantly down-regulated (all P<0.05). Conclusions:The cisplatin targeted nanobubbles can inhibit the proliferation of SCLC, and may be used as a new potential targeted drug for the treatment of SCLC.

Preparation of melanin-based lipid nanobubbles for enhancing multimodal imaging in vitro / 中国医学影像技术

Objective To prepare multi-modality melanin-based lipid nanobubbles (MNBs) contrast agents,and to investigate their manifestations of ultrasound (US),photoacoustic (PA) and MRI in vitro.Methods MNBs and lipid nanobubbles (NBs) were prepared with the method of CHCl3-injection,freeze-drying and C3F8-inflation.The characteristics (shape,grain diameter,loading capacity of melanin and stability) of MNBs were obseved.US,PA and MRI were detected in vitro and the images were quantitatively analyzed.Results MNBs presented with homogenized size distribution,and transmission electron microscope (TEM) images demonstrated that the melanin particles were successfully entrapped into nanobubbles.Meanwhile,the loading capacity of melanin was 90.53 μg/mg.US signal increased in vitro with the rise of MNBs and NBs concentration.The ultrasonic manifestations of MNBs and NBs were the same,and the relative signal enhancement had no significant difference (P＞0.05).With the increased concentration of MNBs,the PA and MRI signals were stronger,but NBs showed no evident enhancement.Conclusion Multi-modality MNBs contrast agents are prepared successfully,which can enhance US,PA and MR imaging.

Preparation of melanin-based lipid nanobubbles for enhancing multimodal imaging in vitro / 中国医学影像技术

Objective To prepare multi-modality melanin-based lipid nanobubbles (MNBs) contrast agents,and to investigate their manifestations of ultrasound (US),photoacoustic (PA) and MRI in vitro.Methods MNBs and lipid nanobubbles (NBs) were prepared with the method of CHCl3-injection,freeze-drying and C3F8-inflation.The characteristics (shape,grain diameter,loading capacity of melanin and stability) of MNBs were obseved.US,PA and MRI were detected in vitro and the images were quantitatively analyzed.Results MNBs presented with homogenized size distribution,and transmission electron microscope (TEM) images demonstrated that the melanin particles were successfully entrapped into nanobubbles.Meanwhile,the loading capacity of melanin was 90.53 μg/mg.US signal increased in vitro with the rise of MNBs and NBs concentration.The ultrasonic manifestations of MNBs and NBs were the same,and the relative signal enhancement had no significant difference (P＞0.05).With the increased concentration of MNBs,the PA and MRI signals were stronger,but NBs showed no evident enhancement.Conclusion Multi-modality MNBs contrast agents are prepared successfully,which can enhance US,PA and MR imaging.

Preparation and properties of docetaxel-loaded nanobubbles / 国际药学研究杂志

Objective To optimize the formulation and preparation technology of docetaxel (DTX)-loaded nanobubbles, and evaluate their properties. Methods The best ratio of methoxypoly(ethylene glycol)-poly(.DL-lactide-co-glycolide) (mPEG-PLGA) and different membrane stabilizers were optimized with Langmuir membrane balance. DTX-Loaded nano-micelles were encapsulated by mPEG-PLGA with an injection method. Nanoemulsions was formed after being added with perfluoropentane (PFP, the boiling point of 29.5 °C) as the organic phase. The formulations and preparation techniques of nanoemulsions were optimized and the conditions of nanobubbles formulaion was also evaluated. Cytotoxicity of DTX-loaded nanobubbles on MCF-7 cells was evaluated with the MTT method. Results The best ratio of mPEG-PLGA and Span 20 was 10: 1 (mol/mol). The membrane elasticity of the prepared nanobubbles with optimized formulations and the preparation techniques was good. In addition, they were obviously temperature-sensitive and ultrasonic-sensitive. The particle size of nanobubbles increased with higher temperature and decreased with lower temperature. The size of nanobubbles increased upon ultrasound application and then decreased a little. The cytotoxicity of DTX-loaded nanobubbles on MCF-7 cells was obvious and dose-dependent. Conclusion DTX-Loaded nanobubbles are a novel formulation with tumor-targeted and ultrasound-sensitive drug release.

Preparation and properties of docetaxel-loaded nanobubbles / 国际药学研究杂志

Objective To optimize the formulation and preparation technology of docetaxel(DTX)-loaded nanobubbles,and evaluate their properties. Methods The best ratio of methoxypoly(ethylene glycol)-poly(DL-lactide-co-glycolide)(mPEG-PLGA) and different membrane stabilizers were optimized with Langmuir membrane balance. DTX-Loaded nano-micelles were encapsulated by mPEG-PLGA with an injection method. Nanoemulsions was formed after being added with perfluoropentane(PFP,the boiling point of 29.5℃)as the organic phase. The formulations and preparation techniques of nanoemulsions were optimized and the conditions of nanobubbles formulaion was also evaluated. Cytotoxicity of DTX-loaded nanobubbles on MCF-7 cells was evaluated with the MTT meth?od. Results The best ratio of mPEG-PLGA and Span 20 was 10∶1(mol/mol). The membrane elasticity of the prepared nanobubbles with optimized formulations and the preparation techniques was good. In addition,they were obviously temperature-sensitive and ultra?sonic-sensitive. The particle size of nanobubbles increased with higher temperature and decreased with lower temperature. The size of nanobubbles increased upon ultrasound application and then decreased a little. The cytotoxicity of DTX-loaded nanobubbles on MCF-7 cells was obvious and dose-dependent. Conclusion DTX-Loaded nanobubbles are a novel formulation with tumor-targeted and ultra?sound-sensitive drug release.

Explicit and implicit modeling of nanobubbles in hydrophobic confinement

Water at normal conditions is a fluid thermodynamically close to the liquid-vapor phase coexistence and features a large surface tension. This combination can lead to interesting capillary phenomena on microscopic scales. Explicit water molecular dynamics (MD) computer simulations of hydrophobic solutes, for instance, give evidence of capillary evaporation on nanometer scales, i.e., the formation of nanometer-sized vapor bubbles (nanobubbles) between confining hydrophobic surfaces. This phenomenon has been exemplified for solutes with varying complexity, e.g., paraffin plates, coarse-grained homopolymers, biological and solid-state channels, and atomistically resolved proteins. It has been argued that nanobubbles strongly impact interactions in nanofluidic devices, translocation processes, and even in protein stability, function, and folding. As large-scale MD simulations are computationally expensive, the efficient multiscale modeling of nanobubbles and the prediction of their stability poses a formidable task to the'nanophysical' community. Recently, we have presented a conceptually novel and versatile implicit solvent model, namely, the variational implicit solvent model (VISM), which is based on a geometric energy functional. As reviewed here, first solvation studies of simple hydrophobic solutes using VISM coupled with the numerical level-set scheme show promising results, and, in particular, capture nanobubble formation and its subtle competition to local energetic potentials in hydrophobic confinement.

Água em condições normais consiste de um fluido termodinamicamente próximo à fase líquida-vapor exibindo alta tensão superficial. Esta combinação conduz a fenômenos capilares interessantes na escala microscópica. Simulações computacionais baseadas em técnicas de Dinâmica Molecular em solutos hidrofóbicos por exemplo fornecem evidências do fenômeno de evaporação capilar em escalas nanométricas dando origem à formação de bolhas nanométricas confinadas entre superfícies hidrofóbicas. Este fenômeno tem sido exemplificado em solutos de complexidade variável, ex placas de parafina, polímeros, canais biológicos e de estado sólido bem como proteínas tratadas atomicamente. Tem sido arguido quebolhas nanométricas possuem impacto significativo nos mecanismos fluídicos nanométricos e na estabilidade e dobramento de proteínas. Dado que simulações baseadas em dinâmica molecular são custosas computacionalmente, o desenvolvimento de uma modelagem multiescala eficiente sob o ponto de vista computacional impõe uma tarefa formidável à comunidadenano-física. Recentemente apresentamos um novo e versátil modelo de solvente denominado modelo implícito variacional de solvente (VISM) o qual é baseado em um funcional deenergia geométrica. Tal como apresentado aqui os primeiros estudos de solvatação de solutos hidrofóbicos simples usando VISM acoplados com esquemas numéricos de conjunto de níveis mostraram resultados promissores e em particular capturaram a formação de nano-bolhas e a sua competição com potenciais localmente energéticos em condições de confinamento hidrofóbico.