Release of Drugs from Liposomes Varies with Particle Size

Abstract

Administration of liposomes loaded with active drugs can result in enhanced therapeutic activity 1,2) and reduced toxic side effects. [3][4][5] For example, liposomes are widely used to improve the delivery of many anticancer, antibiotic and antifungal drugs, such as doxorubicin, epirubicin, vincristine and ciprofloxacin. [6][7][8][9][10] The effectiveness of this formulation approach is dependent on the rate of drug release from the liposomes. Liposomes that rapidly release their contents in vivo will not improve delivery of drugs to target sites 2); for therapeutic value, it is important that drugs are retained in liposomes in vivo for an appropriate time.11,12) Weakly basic drugs can be actively concentrated inside liposomes using a transmembrane pH gradient [13][14][15] or an ammonium sulfate gradient.16) However, the retention of drugs in liposomes is drug-dependent and can vary dramatically. For example, the anticancer drugs doxorubicin and epirubicin are well retained inside liposomes, [17][18][19] whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. 14,19,20) In order to obtain homogenous preparations, liposomes are often extruded through polycarbonate filters of 0.4, 0.2 and 0.1 mm pore size. A high proportion of liposomes that are passed through 0.2 mm filters remain as multilamellar vesicles. On the other hand, extrusion of liposomes through 0.1 mm filters produces mainly unilamellar vesicles.21) Zhang et al. 22) reported that the release of the amphiphilic drug 5-carboxyfluorescein (CF) was greater from unilamellar liposomes than from multilamellar liposomes of similar particle size. The curvature of small unilamellar vesicles (SUVs) is greater, and packing between lipids in the membranes is looser, compared with large unilamellar vesicles. For this reason, SUVs are believed to release drugs more readily. 23,24) The aim of the present study was to identify the causes of the rapid release of drugs, such as vincristine, from liposomes and then to apply this knowledge to the development of more stable formulations. Initially, we investigated the effect of particle size on the leakage of drugs from liposomes incubated in fetal bovine serum (FBS); for these studies, doxorubicin and vincristine were used as examples of wellretained and readily released drugs, respectively. MATERIALS AND METHODS MaterialsEgg yolk phosphatidylcholine (EPC) was purchased from Nippon oil and fat (Tokyo, Japan). Vincristine and doxorubicin were acquired from Sigma-Aldrich (St. Louis, MO, U.S.A.) and Kyowa Hakko (Tokyo, Japan), respectively. FBS was obtained from GIBCO BRL (Grand Island, NY, U.S.A.). Nuclepore polycarbonate filters and Sepharose CL-6B were purchased from Corning (Acton, MA, U.S.A.) and Amersham Pharmacia Biotech (Uppsala, Sweden), respectively. All other chemicals were of analytical grade quality.Preparation of Liposomes EPC liposomes were formed by hydrating the lipid with the following buffers: (i) 100 mmol/l citric acid (pH 4.0), (ii) 10 mmol/l Tris-HCl (pH 7.3...

Liposomal and Phytosomal Formulations

“…NMR is used to study the order of chain, sugar backbone and phosphate groups of phospholipid bilayer. The lamellarity in terms of number of lipid bilayers surrounding the core can be evaluated by comparing the intensity of signals of outer layer and total signals (Yamauchi et al 2007). The naringenin-phospholipid complex phytosomes have been characterised using NMR which showed their interaction with each other (Semalty et al 2010b).…”

Are PEGylated liposomes better than conventional liposomes? A special case for vincristine

“…The leakage rate of vincristine loaded in EPC/Chol liposomes reduced when the particle size larger than 120 nm (Yamauchi et al, 2007). One reason for this is that the curvature of small liposomes was greater, and thus the packing of lipids in the bilayer was not compact; another reason was that the lamellarity of liposomes was greater than one in larger liposomes, which was confirmed by the calculation of trap volume and the measurement of 31 P-NMR, and the multilayers resulted in slower vincristine diffusion.…”

Prospects for Liposome-Encapsulated Nisin in the Prevention of Dental Caries

“…Liposomal encapsulation has been shown to stabilize the encapsulated compound against enzymatic degradation and chemical modification [36]. Liposomes can encapsulate hydrophobic and hydrophilic molecules, prevent the decomposition of the encapsulated molecules, and release the compound at designated target organs [37,38]. The bioactivity of encapsulated molecules can be maintained by the phospholipid vesicle until it is delivered to the target organ or cells, where the contents will be released [9,39].…”

“…Cholesterol interacts with fatty acids in liposomes by hydrogen bonding, increasing the cohesiveness and mechanical strength of the vesicular membrane [60]. For example, a comparison of nisin-containing phosphatidylcholine liposomes and phosphatidylcholine plus cholesterol showed that cholesterol reduced the release of nisin [38,61]. The permeability of liposomes can be altered by modifying the cholesterol concentration according to the intended application of the liposomes [57,62].…”