Endocytosis of liposomes and intracellular fate of encapsulated molecules: Encounter with a low pH compartment after internalization in coated vesicles

Straubinger, Robert M.; Hong, Keelung; Friend, Daniel S.; Papahadjopoulos, Demetrios

doi:10.1016/0092-8674(83)90291-x

Cited by 379 publications

(166 citation statements)

References 42 publications

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“…Small liposomes (<100 nm) can apparently reach the parenchymal area of the liver to a significant scale (Poste et al, 1982) and are more efficiently incorporated by non-phagocytic cells when compared to large-sized vesicles (Straubinger et al, 1983;Machy & Leserman, 1983;Matthay et al, 1984), suggesting that they constitute the most advantageous vesicles for in vivo tissue penetrability and delivery of cytotoxic drugs to tumour cells. It is at present unclear whether drug-loaded vesicles of similar size prepared by different methods such as sonication, membrane extrusion, and French press (reviewed by Szoka & Papahadjopoulos, 1980) have the same biological activity.…”

Section: Discussionmentioning

confidence: 99%

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model

Gabizón¹,

Goren²,

Fuks³

et al. 1985

Br J Cancer

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The use of liposomes as carriers of adriamycin (ADM) seems to offer important advantages with regard to the attenuation of the dose-dependent anthracycline-induced cardiomyopathy. This effect has been shown in rodents (Rahman et al., 1980(Rahman et al., , 1982Forssen & Tokes, 1981;Olson et al., 1982) and dogs (Herman et al., 1983) and is apparently related at least partially to the reduced uptake of the drug in the cardiac tissue of animals treated with liposome-entrapped ADM (L-ADM) (Forssen & Tokes, 1979, 1983 Rahman et al., 1980;Gabizon et al., 1982Gabizon et al., , 1983Olson et al., 1982). Obviously, if this delivery system is to be useful therapeutically, it is crucial to evaluate its anti-tumour activity. Since liposomes home preferentially in tissues with sinusoidal capillaries and rich in cells of the reticuloendothelial system, such as the liver and spleen (Segal et al., 1974;Poste et al., 1982), it is reasonable to assume that tumour colonies residing in these organs constitute a suitable target for liposome-mediated delivery of cytotoxic drugs. The purpose of this paper is to describe the antitumour In previous studies we showed that liposomes containing negatively charged phospholipids capture ADM very efficiently and cause important changes in the tissue distribution of the drug, viz. decreased levels in the heart and increased and sustained levels in the liver and spleen. These changes were observed in normal (Gabizon et al., 1982) and in tumour-bearing mice (Gabizon et al., 1983). Furthermore, when metastatic tumour cells were isolated from the liver we found significantly higher intracellular levels of ADM in tumour cells of mice treated with L-ADM as compared to free ADM treatment. Also, the proliferative ability of intrahepatic metastatic cells in in vitro qultures and in vivo transfer assays was markedly more impaired after L-ADM treatment than after ADM alone (Gabizon et al., 1983).These results, and especially the ability of liposomes to increase the intracellular levels of ADM in liver-residing tumour cells, provided a rational basis for therapeutic experiments. In the present study, we have compared the survival of tumour-inoculated mice treated either with L-ADM or with free ADM using the metastatic liver model of the J-6456 lymphoma. Our results suggest that the therapeutic index of ADM can be significantly improved by liposome association in a group of

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Section: Discussionmentioning

confidence: 99%

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model

Gabizón¹,

Goren²,

Fuks³

et al. 1985

Br J Cancer

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“…Liposomes can improve pharmacokinetics, provide protection from degradation, mediate targeting to the pathological site and facilitate uptake by the target cells (1,2). However, although pharmacokinetics, tissue distribution, and cellular uptake can be improved using (targeted) liposomes, the liposomal drug usually ends up in the endo-and lysosomes, where both the liposome particles as well as the encapsulated macromolecules are subject to degradation (3,4).…”

Section: Introductionmentioning

confidence: 99%

Cytosolic Delivery of Liposomally Targeted Proteins Induced by Photochemical Internalization

et al. 2007

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Purpose. The application of therapeutic proteins is often hampered by limited cell entrance and lysosomal degradation, as intracellular targets are not reached. By encapsulation of proteins into targeted liposomes, cellular uptake via endocytosis can be enhanced. To prevent subsequent lysosomal degradation and promote endosomal escape, photochemical internalization (PCI) was studied here as a tool to enhance endosomal escape. PCI makes use of photosensitising agents which localize in endocytic vesicles, inducing endosomal release upon light exposure. Materials and Methods. The cytotoxic protein saporin was encapsulated in different types of targeted liposomes. Human ovarian carcinoma cells were incubated with the photosensitiser TPPS2a and liposomes. To achieve photochemical internalization, the cells were illuminated for various time periods. Cell viability was used as read-out. Illumination time and amount of encapsulated proteins were varied to investigate the influence of these parameters. Results. The cytotoxic effect of liposomally targeted saporin was enhanced by applying PCI, likely due to enhanced endosomal escape. The cytotoxic effect was dependent on the amount of encapsulated saporin and the illumination time. Conclusion. PCI is a promising technique for promoting cytosolic delivery of liposomally targeted saporin. PCI may also be applicable to other liposomally targeted therapeutic proteins with intracellular targets.

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“…Furthermore, MAC increases the efficiency of overall liposome uptake by cells. This characteristic arises from the negative surface charge MAC imparts to the liposomes, a property that has been demonstrated to enhance cellular adhesion, leading to greater internalization via clathrin-mediated endocytosis (31)(32)(33)(34).…”

mentioning

confidence: 99%

Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

Kueffer

Maitz

Khan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

100

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The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10 B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl- sn -glycero-3-phosphocholine and incorporating Na 3 [1-(2′-B 10 H 9 )-2-NH 3 B 10 H 8 ] in the aqueous interior and K[ nido -7-CH 3 (CH 2 ) 15 -7,8-C 2 B 9 H 11 ] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 10 12 neutrons per cm 2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study.

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Endocytosis of liposomes and intracellular fate of encapsulated molecules: Encounter with a low pH compartment after internalization in coated vesicles

Cited by 379 publications

References 42 publications

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model

Cytosolic Delivery of Liposomally Targeted Proteins Induced by Photochemical Internalization

Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

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