Tissue distribution and tumour localization of 99m-technetium-labelled liposomes in cancer patients

Richardson, V. J.; Ryman, Brenda E.; Jewkes, R. F.; Jeyasingh, K.; Tattersall, M. N.; Newlands, E. S.; Kaye, Stanley B.

doi:10.1038/bjc.1979.138

Cited by 78 publications

(21 citation statements)

References 27 publications

(28 reference statements)

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“…In view of the changes in tissue distribution and bioavailability, it is uncertain whether the increased tolerated dosage of L-ADM will result in enhanced antitumour activity. In agreement with the human liposome imaging studies reported by Richardson et al (1979), the liposomes used here are cleared very quickly by the RES of liver and spleen and to a lesser extent by the bone marrow. Our studies suggest that the mechanism of antitumour activity of L-ADM is complex, and presumably results from exposure of tumour cells to drug leaking from circulating liposomes and drug released from the RES.…”

Section: Discussionsupporting

confidence: 89%

Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin

Gabizón

Chisin²,

Amselem³

et al. 1991

Br J Cancer

131

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Summary Pharmacokinetic and imaging studies in 19 patients receiving liposome-entrapped adriamycin (L-ADM) were carried out within the framework of a Phase I clinical trial (Gabizon et al., 1989a). The formulation of L-ADM tested consisted of 0.2 gM-extruded multilamellar vesicles composed of egg phosphatidylcholine, egg-derived phosphatidyl-glycerol (PG), cholesterol, and ADM intercalated in the fluid lipid bilayer. Plasma clearance of total drug extracted from the plasma after L-ADM infusion followed a biexponential curve with a pattern similar to that reported for free ADM. The plasma concentration of drug circulating in liposome-associated form was also measured in a subgroup of seven patients. Liposomeassociated drug was found to be rapidly cleared from plasma. Its ratio to nonliposome-associated drug appeared to correlate with liver reserve, with highest ratios in patients with normal liver function. Liposome clearance, as measured by the plasma concentration of PG in three patients was slower than the clearance of liposome-associated ADM, suggesting that liposomes lose part of their drug payload during circulation. To learn about the liposome organ distribution, imaging studies were carried out with "'Indium-deferoxamine labelled liposomes of the same composition. Liposomes were cleared predominantly by liver and spleen and to a lesser extent by bone marrow in seven out of nine patients. In two patients with active hepatitis and severe liver dysfunction, there was minimal liver uptake and increased spleen and bone marrow uptake. Except for one hepatoma patient, intrahepatic and extrahepatic tumours were not imaged by liposomes, suggesting that liposome uptake is restricted to cells of the reticulo-endothelial system (RES). These observations indicate that a major fraction of this L-ADM formulation is rapidly cleared by the RES, and that the mechanism of drug delivery is probably the combined result of slow release from the RES depot and drug leakage from circulating liposomes.Liposome-entrapped adriamycin (L-ADM) has been shown to have reduced toxicity and preserved or improved antitumour efficacy in experimental animal models (reviewed in Perez-Soler, 1989;Gabizon, 1989). Recently we have carried out a Phase I clinical study (Gabizon et al., 1989a) with a formulation of L-ADM in which the drug is incorporated in the fluid bilayer of the vesicles (Amselem et al., 1990a). The results have been consistent with the preclinical observations, namely the maximal tolerated dose (MTD) of L-ADM was increased in relation to the MTD of free drug administered at the conventional 3-weekly schedule. However the dose limiting toxicity for L-ADM was, as for free ADM, myelotoxicity. Thus, although the toxicities of free ADM and L-ADM differ quantitatively, they are qualitatively similar.In this report we summarise pharmacokinetic and imaging studies with L-ADM and radiolabelled liposomes of the same composition in the Phase I study patients and a small group of additional patients with similar eligibility criteria. The...

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Section: Discussionsupporting

confidence: 89%

Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin

Gabizón

Chisin²,

Amselem³

et al. 1991

Br J Cancer

131

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“…Sometimes contradictory views related to the potential application of liposomes on a drug delivery system have been expressed [24]. The present study may contribute to the explanation of the varying re sults obtained according to the compound (its halflife, its stability in the presence of serum) and the schedule of the trials.…”

Section: Discussionmentioning

confidence: 69%

Comparison of the Experimental Antitumor Activities of Three Nitrosourea Derivatives Chlorozotocin, RFCNU and CNCC Encapsulated in Liposomes with Those in the Free State

et al. 1985

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L1210 leukemia was used to compare the antitumor activities of three nitrosoureas (chlorozotocin, RFCNU and CNCC) encapsulated in liposomes with those in the free state. The results obtained varied according to the chemical structure of the compound, its solubility in oil or water, the route of administration into the body, and the treatment dose. The application of liposomes in the chemotherapy of malignant disease deserves further investigations.

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“…Although tumour localisation with 99mTc-technetium-labelled liposomes in the rat has been described (Richardson et al, 1977), various tumours in several patients were not visualised after injection with 99mTc-technetium-labelled liposomes (Richardson et al, 1979). This encourages us to think that 99mTc-technetium-labelled anionic liposomes may be specific for naturally occurring abscesses.…”

Section: Discussionmentioning

confidence: 98%

Localisation of experimental staphylococcal abscesses by 99MTC-technetium-labelled liposomes

Morgan¹,

Williams²,

Davies³

et al. 1981

Journal of Medical Microbiology

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The accumulation of 99mTc-technetium-labelled liposomes in abscesses was studied. Abscesses were produced in the thighs of albino rats by intramuscular injection of Staphylococcus aureus. After 4 days these abscesses were used to determine the localisation of 99mTc-technetium-labelled anionic, cationic and neutral liposomes in the abscess area. This was achieved by radionuclide images produced by a gamma camera and an associated data-processing system. There was a pronounced uptake of 99mTc-technetium-labelled anionic liposomes in the abscess area compared with the corresponding unaffected thigh. Similar uptake was not shown by the 99mTc-technetium-labelled cationic and neutral liposomes. Abscess uptake of anionic liposomes was maximal at or before 30 min after injection and was not enhanced by prior opsonisation with aggregated rat immunoglobulin.

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Tissue distribution and tumour localization of 99m-technetium-labelled liposomes in cancer patients

Cited by 78 publications

References 27 publications

Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin

Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin

Comparison of the Experimental Antitumor Activities of Three Nitrosourea Derivatives Chlorozotocin, RFCNU and CNCC Encapsulated in Liposomes with Those in the Free State

Localisation of experimental staphylococcal abscesses by 99MTC-technetium-labelled liposomes

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