Lipid-Based Intelligent Vehicle Capabilitized with Physical and Physiological Activation

Abstract

Intelligent drug delivery system based on "stimulus-response" mode emerging a promising perspective in next generation lipid-based nanoparticle. Here, we classify signal sources into physical and physiological stimulation according to their origin. The physical signals include temperature, ultrasound, and electromagnetic wave, while physiological signals involve pH, redox condition, and associated proteins. We first summarize external physical response from three main points about efficiency, particle state, and on-demand release. Afterwards, we describe how to design drug delivery using the physiological environment in vivo and present different current application methods. Lastly, we draw a vision of possible future development.

Figure 1

Scheme diagram of intelligent lipid-based nanoparticle. Physical signals, thermal, ultrasound, and electromagnetic wave, act as external remote controls initiate carrier response in circulatory labyrinth. While physiological signals, pH, redox and proteins, act as internal keys induce carrier activation.

Figure 2

Three main applications of physical signal-activated lipid-based nanoparticles. Efficiency is associated with complete contents release. Integrality is related to preleakage and elimination. On-demand release correlates about precise control quantitatively.

Figure 3

Thermal response for lipid phase control. (a) Nearly 80% of DOX releases in 20 seconds under 42°C in TSL contained MSPC [23]; (b) asymmetric liposomes with different components of inward and outward membrane enhance endocytosis after thermal stimulation [25]; (c) edge stabilizer SC-C5 gives bicelles dilution tolerance and thermoresponsiveness since it has extremely low CMC [38]; (d) thermosensitive on/off switch liposome achieves a reversible drug release on demand [40].

Figure 4

Ultrasound response for lipid permeability regulation. (a) Cy-droplet can conduct phase change by laser or ultrasound stimulation [47]; (b) porphyrin-conjugated liposome reduces required ultrasound intensity [49]; (c) PEG coat can be removed after ultrasound to enhance cell uptake [51]; (d) nerve block is controlled by insonation parameters, extent and intensity [55]; (e) schematic diagram of liposome and exosome [51] .

Figure 5

Electromagnetic wave response for lipid conformation stability. (a) MW converter EF blasts lipid shell by gasification to accelerate DOX release [57]; (b) PLsPC response to ROS that is generated by ICG after ultrasound [61]; (c) charge of liposome convers from neutral to cation through UV irradiation [62]; (d) X-ray induces singly linear oxygen by verteporfin to cause liposome response [59].

Figure 6

Three main aspects of physiological signal-activated lipid-based nanoparticles.

Figure 7

pH dependent lipid-based drug delivery. (a) platesome pH-response process; (b) platesome in vitro pH-responsive cleavage process [75]; (c) exposure to positive charges in the tumor microenvironment at pH < 7.0 promotes cellular uptake [76]; (d) iPhos lipids consist of an ionizable amine phospholipid head and three hydrophobic alkyl chain tails [81].

Figure 8

ROS/GSH activated sulfur-based lipid cleavage for drug release. (a) Thioether-containing lipid carrier for ROS-responsive drug release [91]; (b) Disulfide-containing lipid carrier for GSH-responsive drug release [92]; (c) Trisulfide-containing lipid carrier for ROS and GSH dual-responsive drug release [100].

Figure 9

Lipid-based enzyme-responsive drug delivery. (a) MMP-2 responsive functional liposomes inhibit tumor mesenchyme thereby enhancing chemotherapeutic drug perfusion [106]; (b) Functionalized sphingomyelin self-assembles to form camptothesome [114].

Figure 10

Protein corona mediates SORT LNP tissue-specific delivery. (a) SORT LNP achieves tissue-specific targeting [121]; (b) SORT LNP is an endogenous targeting mediated through the principle of protein corona adsorption [122].