Phase-shift, stimuli-responsive drug carriers for targeted delivery

Abstract

The intersection of particles and directed energy is a rich source of novel and useful technology that is only recently being realized for medicine. One of the most promising applications is directed drug delivery. This review focuses on phase-shift nanoparticles (that is, particles of submicron size) as well as micron-scale particles whose action depends on an external-energy triggered, first-order phase shift from a liquid to gas state of either the particle itself or of the surrounding medium. These particles have tremendous potential for actively disrupting their environment for altering transport properties and unloading drugs. This review covers in detail ultrasound and laser-activated phase-shift nano- and micro-particles and their use in drug delivery. Phase-shift based drug-delivery mechanisms and competing technologies are discussed.

Figure 1

(A) Evolution of a 17 μm droplet under the action of a single acoustic pulse of 0.5 MHz focused ultrasound with peak negative acoustic pressures of 4.7 to 10.8 MPa and 3 to 17 cycles in the acoustic pulse. (B) Time line of photographs in microseconds: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7.5, 10, 15, 30, 60, 120 and 300 Reproduced with permission of The Royal Society of Chemistry from [177].

Figure 2. The effect of the droplet size on the vaporization threshold of lipid-encapsulated dodecafluoropentane droplets sonicated at (A&C) 2.855 MHz and (B&D) 1.736 MHz

They were measured at (A&B) 22°C and (C&D) 37°C. The inertial cavitation threshold is shown for comparison. Figure adapted with permission from [179].

Figure 3. Drug encapsulated in nanodroplets is localized in nanodroplet shells

(A) The nanodroplet structure. In nanodroplets, perfluorocarbon compounds form droplet cores while amphiphilic block copolymers form droplet shells that contain two layers. The inner layer is formed by the hydrophobic block of the block copolymer (e.g., polylactide or polycaprolactone) while the outer layer is formed by the hydrophilic block, poly(ethylene oxide). Lipophilic drugs are encapsulated in the hydrophobic inner layer. (B) Laser confocal images of the droplets having the perfluoro-15-crown-5-ether cores and poly(ethlene oxide)-co-polycaprolactone shells with encapsulated doxorubicin. Some micron-scale droplets presented in panel (B) have been specially generated for better visualization of doxorubicin distribution. Doxorubicin localization on the droplet surface is manifested by fluorescence.

Figure 4. Representation of the phase diagram of perfluorocarbon–copolymer formulation in aqueous environment: blank purple – micelles; circled purple – droplets

The dotted line corresponds to critical micelle concentration of copolymer below which neither micelles nor droplets can be formed. Zone 1 corresponds to micellar solutions with perfluorocarbon dissolved in micelle cores; zone 2 corresponds to micelle–droplet mixtures; zone 3 corresponds to droplets only. At a fixed copolymer concentration, transition proceeds from zone 1 to zone 2 to zone 3 upon increasing perfluorocarbon concentration. Adapted with permission from [63].

Figure 5. Drug transfer from droplets to bubbles to cells under the action of ultrasound

PFP: Perfluoropentane; PLLA: Poly(L-lactide); PEG: Poly(ethylene oxide). Adapted with permission from [190]. © Elsevier.

Figure 6. Mouse was treated by four systemic injections of nanodroplet-encapsulated paclitaxel (20 mg/kg as paclitaxel) given twice weekly

Only one tumor was sonicated (1 MHz continuous wave ultrasound at a nominal output power density 3.4 W/cm², exposure duration 1 min; ultrasound was delivered 4.5 h after the injection of the drug formulation). (A) The tumor grew at the same rate as untreated control tumors while in (B) the tumor appeared completely resolved. Adapted with permission from [190]. © Elsevier.

Figure 7. Intravital fluorescence images of subcutaneous pancreatic tumors (A) before and (B) 3 days after focused ultrasound treatment

A mouse was injected with paclitaxel-loaded droplets 1%perfluoro-15-crown-5-ether/5% poly(ethylene oxide)–PDLA droplets 6 h before ultrasound treatment; drug dose was 40 mg/kg. Conditions of ultrasound treatment: ultrasound beam was steered for 50 s in a circle 4 mm diameter (8 ‘points’, 200 ms/point, 30 circles per treatment resulting in a total 6 s sonication of each ‘point’ with a maximum power density in the focal zone of 54 W/cm²). MRI thermometry showed tumor heating by approximately 10°C.

Figure 8. Dramatic regression of a breast cancer MDA MB231 tumor treated by four systemic injections of paclitaxel-loaded 1% perfluoro-15-crown-5-ether/0.25% poly(ethylene oxide)-co-polycaprolactone nanoemulsion and focused 1 MHz continuous-wave ultrasound applied for 60 s

Paclitaxel dose was 40 mg/kg. Figure adapted with permission from [181]. © Elsevier.

Figure 9. Growth and collapse of a plasmonic nanobubble

(A) Gold nanoparticle is rapidly heated by laser matched to its plasmon resonance frequency. (B) A thin shell of water vapor appears at hot surface. (C) Water vapor rapidly expands against pressure of liquid water even as the laser pulse is turned off and nanoparticle rapidly cools. (D) Cooling water vapor contracts.

Figure 10. A plasmonic nanobubble is used to release drug from a partially polymerized liposome nanocapsule according to Qin et al.

[234]. Laser-absorbing gold is covalently linked to the partially polymerized shell of the liposome containing the drug (doxorubicin). A single laser pulse creates a rapidly expanding nanobubble of water vapor that destroys some part of the capsule, releasing the contents.