. 2022 Sep 2;12(17):3051. doi: 10.3390/nano12173051

Table 3.

In vitro release experiments of nanodrugs from liposomes using ultrasound.

Liposome Type	Payload	US Parameters	Overview	References
Low-temperature sensitive liposomes (LTSLs) Non-thermosensitive liposomes (NTSLs)	Doxorubicin	$Pulsed high - intensity focused ultrasound, 1300 \frac{W}{c m^{2}}$ , 10% duty cycle (100 ms ON/ 900 ms OFF)	For LTSLs: ultrasound-induced hyperthermia achieved 35% release at 39 °C and 50% at 42 °C, within 2 min. A complete release was achieved after 12 min of high-intensity ultrasound exposure at 42 °C. For NTSLs: No release was detected.	[78]
PEGylated DSPE PEGylated DSPC	Doxorubicin	40 kHz, continuous mode (100% duty cycle), 20% amplitude	After 6-min ultrasound exposure, DSPE-based liposomes released 69% of the encapsu lated doxorubicin compared to 9% from DSPC-based liposome DSPE lipids enhanced the liposomes’ sonosensitivity, with the optimized formulation resulting in a 7-fold increase in doxorubicin release compared to reference liposomes.	[101]
Doxil	Doxorubicin	20 kHz, 1 and 3 MHz	20-kHz low-frequency ultrasound released more doxorubicin compared to 1- and 3-MHz high-frequency ultrasound.	[102]
PEGylated, egg PC	A buffer composed of p-xylene-bis-pyridinium bromide (DPX) and 8-aminonaphthalene-1,3,6-trisulfonic acid, disodium salt (ANTS).	$20 kHz, 0.13 \frac{W}{c m^{2}}$ , 100% duty cycle $1 MHz, 3 W / c m^{2}$ , 40% duty cycle $1.6 MHz, 46.9 \frac{W}{c m^{2}}$ , 40% duty cycle	Low-frequency ultrasound achieved higher leakage than high-frequency ultrasound. Low-frequency ultrasound induced buffer release for all lipo somal formulations tested. High-frequency ultrasound induced drug release from 300- and 1000-nm vesicles, but not from 100-nm vesicles. Vesicles’ responsivity to ultrasound enhances as their diameter increases.	[103]
PEGylated DPPC	Calcein	$20 kHz, 25 % duty cycle, 1 \frac{W}{c m^{2}}$	Hyperthermia enhanced drug release, with the largest enhancement at the lipid transition temperature (41 °C).	[79]
PEGylated, hydrogenated soybean PC	Doxorubicin Methylprednisolone hemisuccinate Cisplatin	$20 kHz, full duty cycle, varying intensities : from 0 to 7 \frac{W}{c m^{2}}$	A maximum release of 80% was reported after 3-min ultrasound exposure for all formulations. $The drug release rate increased substantially after a power density threshold of 1.3 \frac{W}{c m^{2}}$ . The proposed release mechanism is that the onset of cavitation introduced pore-like de fects in the liposomal membrane, allowing for drug release.	[105]
DOPC DOPE	Calcein	20 kHz, 10-min exposure time, 20% amplitude	DOPE-based liposomes underwent a structural change from lamellar to non-lamellar phase upon sonication, resulting in more drug release, compared to DOPC-based liposomes, which showed a lamellar phase before and after US irradiation.	[112]
PEGylated DOPE PEGylated HSPC	Doxorubicin	$40 kHz, 12 c m^{2}$ , continuous mode (100% duty cycle)	Ultrasound interacted differently with different phospholipids leading to distinct drug re lease mechanisms. Suggested mechanisms: – DOPE-based liposomes: irreversible damage and deformed structure that led to drug release. – HSPC- based liposomes: introduction of pore-like defects in the membrane through which drug escaped.	[97]
eLiposomes	Calcein	$20 kHz, intensity was varied between 0.5 and 5 \frac{W}{c m^{2}}$	$Eliposomes, containing perfluorohexane ({PFC}_{6})$ $and perfluoropentane ({PFC}_{5})$ nanoemulsions, released 3–5 times more calcein than control liposomes. eLiposomes, with 400-nm emulsions, resulted in a higher calcein release than those containing 100-nm emulsions, upon US exposure. The drug release extent depended on ultrasound’s power density and exposure time.	[119]

DSPE (1,2 distearoyl-sn-glycero-3-phosphatidylethanolamine); DSPC, (1,2 distearoyl-sn-glycero-3-phosphatidylcholine); PC (phosphatidylcholine); DPPC (dipalmitoyl phosphatidylcholine); DOPC (1,2-dioleoyl-sn-glycero-3- phosphocholine), DOPE (dioleoyl phosphatidylethanolamine); HSPC (hydrogenated soy L-α-phosphatidylcholine).