Novel Temperature-Sensitive Liposomes with Prolonged Circulation Time

Abstract

Hyperthermia increases the efficiency of various chemotherapeutic drugs and is administered as an adjunct to chemotherapy for the treatment of cancer patients. The temperature-dependent effect can be strongly increased by the use of temperature-sensitive liposomes in combination with regional hyperthermia, which specifically releases the entrapped drug in the heated tumor tissue. The novel lipid 1.2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPP-GOG), which is closely related to the naturally occurring 1.2-dipalmitoyl-sn-glycero-3-phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine and 1.2-distearoyl-sn-glycero-3-phosphocholine provides longcirculating temperature-sensitive liposomes with favorable properties under mildly hyperthermic conditions (41-42°C). DPPGOG facilitates temperature-triggered drug release from these liposomes (diameter, 175 nm) and leads to a substantially prolonged plasma half-life for the encapsulated drug with t 1/2 ‫؍‬ 9.6 h in hamsters and t 1/2 ‫؍‬ 5.0 h in rats. Quantitative fluorescence microscopy of amelanotic melanoma grown in the transparent dorsal skin fold chamber of hamsters demonstrated a favorable drug accumulation in heated tissue after i.v. application of these liposomes (42°C for 1 h). The mean area under the curve for tissue drug concentration was increased by more than sixfold by application of the new liposomes compared with nonliposomal drug delivery. In summary, we present a new DPPGOGbased liposomal formulation enabling long circulation time combined with fast and efficient drug release under mild hyperthermia. This adds positively to the results with lipidgrafted polyethylenglycol used thus far in temperaturesensitive liposomes and widens the possibilities for clinical applications.

Ultrasonic drug delivery – a general review

“…Gene delivery is a topic of intense interest in targeted drug delivery [43][44][45][46][47][48][49]. The use of ultrasound in gene delivery has exceptional potential because the beam can be focused on a particular tissue.…”

Thermosensitive liposomal drug delivery systems: state of the art review

“…Thermosensitive liposomal drug delivery systems 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG 2 ), was reported by Lindner et al 67 DPPG 2 is a synthetic phospholipid with a molecular weight close to that of natural occurring 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, because only one additional glycerol molecule is bound via an ether bond to the head group. 67 The molecular class of oligoglycerols ( Figure 1B, DPPG n ) was developed to increase the circulation half-life of vesicles in the same way as for PEGylated lipids.…”

“…67 The molecular class of oligoglycerols ( Figure 1B, DPPG n ) was developed to increase the circulation half-life of vesicles in the same way as for PEGylated lipids. Lasic et al postulated that highly hydrated groups like PEG on the liposomal surface are capable of sterically inhibiting electrostatic and hydrophobic interactions with blood components.…”

“…Lasic et al postulated that highly hydrated groups like PEG on the liposomal surface are capable of sterically inhibiting electrostatic and hydrophobic interactions with blood components. 68 Incorporation of DPPG 2 led to a prolonged circulation time in non-thermosensitive 69 and thermosensitive 28,67 formulations. The plasma half-life of carboxyfluorescein encapsulated into DPPG 2 -TSL was reported to be 9.6 hours in hamsters and 5 hours in rats.…”

“…The plasma half-life of carboxyfluorescein encapsulated into DPPG 2 -TSL was reported to be 9.6 hours in hamsters and 5 hours in rats. 67 Because of the significantly smaller head group modification of the phospholipid compared to DSPE-PEG 2000 (74 Da versus approximately 2,000 Da), DPPG n forms lamellar structures and could be incorporated into TSL formulations with up to 70 mol%. 67 Incorporation of DSPE-PEG 2000 instead is limited to concentrations below 10% mol, since it acts like a surfactant with a critical micelle concentration of 0.5-1.0 µM.…”