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Targeting small unilamellar liposomes to hepatic parenchymal cells by dose effect
D D Chow1, H E Essien, M M Padki
1School of Pharmacy, University of Southern California, Los Angeles.
Abstract:
A major research goal of liposome pharmacology is the selective delivery of drugs to target cell populations while minimizing extraction by phagocytic macrophages and blood monocytes of the reticuloendothelial system. The liver is an ideal organ for studying targeting strategies using a variety of liposomes, inasmuch as its discontinuous capillaries have fenestrae through which liposomes less than 0.2 microns in diameter may escape into the extravascular space. In a previous kinetic study, we proposed that the hepatic uptake of small unilamellar vesicles (SUV) in mice was compatible with a model of uptake involving dual, parallel pathways. One is a saturable, phagocytic pathway of uptake mediated by Kupffer cells, the other is a nonsaturable, pinocytotic pathway of uptake mediated by parenchymal cells, favoring the latter pathway at high liposomal dose (Beaumier et al., 1983). In the present study, we demonstrated by the techniques of liver cells fractionation that the uptake of either the bovine brain sphingomyelin/cholesterol (2:1; mole/mole) SUV or distearoyl phosphatidylcholine/cholesterol (2:1; mole/mole) SUV by hepatic parenchymal cells was enhanced markedly by increasing the amount of injected dose of SUV. As high as 85 to 90% of the total liver dose can be attributed to the uptake of SUV by the hepatic parenchymal cells alone, when the injected dose reaches at or above 7.5 to 10 micrograms of lipid per g b.wt. The dose effect on the uptake of liposomes by hepatocytes appears to be a general phenomenon of neutral SUV. Our data suggested that blockade by dose permits a feasible approach to target SUV to hepatic parenchymal cells.
Insights
Increasing liposome dose enhances drug delivery to liver parenchymal cells, a key target. This strategy minimizes uptake by phagocytic cells, improving drug targeting efficiency.
Area of Science:
- Pharmacology
- Drug Delivery
- Liposome Research
Background:
- Selective drug delivery to target cells is crucial in liposome pharmacology.
- The liver's unique vasculature allows liposomes to extravasate into the extravascular space.
- Previous studies suggested dual uptake pathways for small unilamellar vesicles (SUV) in the liver: phagocytic (Kupffer cells) and pinocytotic (parenchymal cells).
Purpose of the Study:
- To investigate the effect of liposome dose on hepatic uptake pathways.
- To determine if high liposomal doses can selectively target hepatic parenchymal cells.
- To validate the proposed dual pathway model for SUV uptake in the liver.
Main Methods:
- Utilized liver cell fractionation techniques to quantify SUV uptake by different liver cell types.
- Administered two types of neutral small unilamellar vesicles (SUV): sphingomyelin/cholesterol and distearoyl phosphatidylcholine/cholesterol.
- Varied the injected dose of SUV to assess dose-dependent uptake effects.
Main Results:
- Hepatic parenchymal cell uptake of SUV significantly increased with higher injected doses.
- At high doses (≥ 7.5–10 µg lipid/g b.wt.), parenchymal cells accounted for 85–90% of total liver SUV uptake.
- This dose-dependent enhancement of uptake by parenchymal cells was observed for neutral SUV, suggesting a general phenomenon.
Conclusions:
- Increasing the injected dose of neutral small unilamellar vesicles (SUV) effectively targets hepatic parenchymal cells.
- Dose escalation serves as a feasible strategy to direct SUV to hepatocytes, minimizing reticuloendothelial system uptake.
- This approach holds promise for enhancing the therapeutic efficacy of liposomal drugs delivered to the liver.