Blood Circulation Time Of Liposomes Research Articles

Ginsenoside Rg3 endows liposomes with prolonged blood circulation and reduced accelerated blood clearance

PEGylated cholesterol-containing liposomes (Chol-PEG-lipo) have been widely used as a drug carrier for their good stealth property in blood circulation where cholesterol maintains the stability of the liposomal lipid bilayer and PEGylation endows liposomes with long circulation capability. However, cholesterol-related disadvantages and the accelerated blood clearance (ABC) phenomenon caused by PEGylation greatly limit the application of conventional stealth liposomes in clinic. Herein, ginsenoside Rg3 was selected to substitute cholesterol and PEG for liposomes preparation (Rg3-lipo). Rg3 was proved with similar liposomal membrane regulation ability to cholesterol and comparable long circulation effect to PEG. In addition, repeated administrations of Chol-PEG-lipo and Rg3-lipo were performed. The circulation time of the second dose of Chol-PEG-lipo was substantially reduced accompanied by a greatly increased accumulation in the liver due to the induction of anti-PEG IgM and the subsequent activated complement system. In contrast, no significantly increased level of relative plasma cells, IgM secretion and the complement activation in blood circulation was observed after the second injection of Rg3-lipo. As a result, Rg3-lipo showed great stealth property without ABC phenomenon. Therefore, developing liposomes utilizing Rg3 instead of PEG and cholesterol presents a promising strategy to prolong the blood circulation time of liposomes without triggering the ABC phenomenon and activated immune responses.

Polysarcosine-Coated liposomes attenuating immune response induction and prolonging blood circulation

HypothesisLiposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon. ExperimentsIn this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions. FindingsAlthough all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.

Low molecular weight heparin modified bone targeting liposomes for orthotopic osteosarcoma and breast cancer bone metastatic tumors

The standard-of-care chemotherapy is important in the treatment of osteosarcoma and bone metastastic tumors. However, the efficacy is limited by the specific physiological environment of the bone. Thus, developing an efficient antitumor and anti-metastasis chemotherapeutic formulation is desired for treatment of bone tumors. Herein, we utilized the alendronate (ALN) and low molecular weight heparin (LMWH) modified liposomes to deliver the antitumor drug doxorubicin (DOX), where traditionally-believed non-active drug carrier, targeting moiety could also exhibit biological functions and realize anti-tumor and anti-metastasis efficiency synergistically with the antitumor drug. Specifically, ALN could serve as the bone targeting moiety and the therapeutic agents of anti-osteoporosis. LMWH could enhance the blood circulation time of liposomes and exhibit anti-metastasis efficiency. Besides characterization of typical physiochemical properties of the delivery system, both the orthotopic osteosarcoma model and bone metastasis cancer model were adopted to evaluate the in vivo efficacy. The results proved this system could remarkably suppress tumor growth and inhibit tumor metastasis.

Repeated Administration of Hyaluronic Acid Coated Liposomes with Improved Pharmacokinetics and Reduced Immune Response.

PEGylated liposomes (PEG-Lip) have been widely used as a drug carrier for their good stealth property in blood circulation. However, the second injection of PEG-Lip was reported to result in the accelerated blood clearance (ABC) phenomenon and trigger hypersensitivity reactions in sensitive individuals for its complement activation effect. To avoid adverse immune responses, HA was selected to modify liposomes to afford HA modified liposomes (HA-Lip). Repeated administrations of PEG-Lip and HA-Lip were performed in rats. Our results showed that PEG-Lip induced the ABC phenomenon accompanied by a greatly increased accumulation of PEG-Lip in the liver. In contrast, HA-Lip showed good stealth property without inducing either the ABC phenomenon or an increase in liver uptake. Moreover, HA-Lip did not trigger complement activation in human serum in vitro and in rat blood in vivo. Consequently, HA modification represents a viable strategy to prolong the blood circulation time of liposomes without inducing the ABC phenomenon and adverse immune responses.

Prolonged Blood Circulation Time of Antimony in Dogs with Visceral Leishmaniasis from Liposomes with 175-nm Diameter

The achievement of parasitological cure of dogs with visceral Leishmaniasis (VL) remains a great challenge, since dogs act as main reservoir for transmission of Leishmania infantum to humans and respond poorly to conventional drugs including pentavalent antimonials. Liposome-encapsulated antimonials are hundreds of times more effective than the free drugs against VL based on parasite suppression in the liver. However, complete parasite elimination in dogs seems to depend on the ability of liposomes to reach less accessible infection sites such as the bone marrow and the skin. Recently, the reduction of liposome size from 1200- to 400-nm diameter was found to improve the targeting of Sb to the bone marrow of dogs with VL. In the present work, the influence of further reduction of vesicle diameter from 400- to 175-nm on the pharmacokinetics of Sb in dogs with VL and on the distribution of Sb in the liver, spleen and bone marrow were investigated. For this purpose, two liposome formulations of meglumine antimoniate with the same lipid composition but different mean hydrodynamic diameters were prepared. The formulations were given to mongrel dogs with VL as a single intravenous bolus injection and Sb concentrations were determined by graphite furnace atomic absorption spectroscopy. Surprisingly, much more prolonged blood levels of Sb were achieved from small size (175 nm) than medium size (400 nm) liposomes. Small size vesicles were also less effective than medium size ones in targeting Sb to the liver. On the other hand, similar Sb concentrations were achieved in both spleen and bone marrow. In conclusion, the prolonged blood circulation time of liposomes with 175-nm diameter makes this nanosystem suitable for passive drug targeting to the less accessible infection sites in dogs with VL.

Preparation of long-circulating immunoliposomes containing adriamycin by a novel method to coat immunoliposomes with poly(ethylene glycol)

Modifications of liposomes with poly (ethylene glycol) (PEG) have been reported to prolong blood circulation time of liposomes. In this report, an adriamycin-encapsulated immunoliposomes were modified with PEG by two different approaches: one is the pre-coating method using lipid derivative of PEG as described by Allen et al. The other is post-coating method which is presented here. The former pre-coating method did not allow coupling of antibody due to the steric hindrance of PEG which had been introduced on liposome surface. On the other hand, in the later post-coating method, PEG-succinylcysteine was synthesized and was successfully conjugated with immunoliposomes via maleimido linker. Resultant PEG-coated immunoliposomes containing adriamycin retained their binding activity and cytotoxicity to target cells, and also showed significantly prolonged blood circulating time as compared with conventional immunoliposomes. This is a novel method to coat immunoliposomes with PEG.

Monosialoganglioside GM1 shortens the blood circulation time of liposomes in rats.

Inclusion of monosialoganglioside GM1 into liposomes significantly enhances the circulation time of liposomes in mice. Conversely, intravenously injected GM1-containing liposomes were rapidly removed from the blood circulation and accumulated in the liver and spleen in rats. In rats, increasing the GM1 content in liposomes resulted in more rapid clearance from the blood. Increasing the membrane rigidity of liposomes further increased the liver uptake of GM1-containing liposomes. The activity of GM1 in enhancing the liposome uptake by rat liver appears to be mediated by complement components.

Effects of glycophorin and ganglioside GM 3 on the blood circulation and tissue distribution of liposomes in rats

The effects of glycophorin (GP) and ganglioside GM 3 (GM 3) on the blood circulation and tissue distribution of liposomes were investigated in rats. Liposomes composed of dipalmitoylphosphatidylcholine (DPPC)/cholesterol (Chol) or sphingomyelin (SM)/Chol, which contained additionally GP and/or GM 3, were prepared and the blood concentration and tissue (liver, kidney, lung and spleen) distribution after intravenous administration were compared with the control liposomes which contained neither GP nor GM 3. The blood concentration of DPPC liposomes containing GP and GM 3 (GP-GM 3-Lip[DPPC]) was significantly higher than those of the other DPPC liposomes for up to 6 h after administration, and about 3.3-fold higher than that of control liposomes (Con-Lip[DPPC]) at 6 h. The liver uptake of GP-GM 3-Lip[DPPC] at 6 h was significantly reduced compared with that of Con-Lip[DPPC], while the spleen uptake was increased significantly. Similarly, in the case of SM liposomes, the liposomes containing GP and GM 3 (GP-GM 3-Lip[SM]) prolonged the blood circulation time of liposomes and reduced their uptake by the liver, and the blood concentration was about 3.7-fold higher than that of control liposomes (Con-Lip[SM]) at 6 h. It was found that GP and GM 3 were useful and valuable for prolonging the blood circulation time of liposomes and reducing the uptake of liposomes by the liver.