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The Biodistribution and Pharmacokinetics of Stealth Liposomes in Patients with Solid Tumors

The Biodistribution and Pharmacokinetics of Stealth Liposomes in Patients with Solid Tumors

ABSTRACT: Liposomes have been proposed as potential vehicles for drug therapy targeted to solid tumors, in particular, because of the increased permeability of these tumors to macromolecules. The recent development of Stealth liposomes has renewed clinicians’ interest in liposomal-targeted therapy due to their ability to evade the reticuloendothelial system. Thus they remain in circulation longer with a concomitant increase in duration of exposure to the tumors. We examined the biodistribution of indium 111-labeled Stealth liposomes in 17 patients with a variety of selected malignancies. The median half-life of 111In-labeled liposomes was 55 hours, with a pattern of biodistribution in the liver, spleen, and bone marrow consistent with uptake by the reticuloendothelial system. The high levels of 111In activity seen in some of the tumors suggest that liposomes may also be used to carry therapeutic doses of radiopharmaceuticals. Liposomes have the potential to significantly improve tumor targeting in oncology, and new liposomal drug formulations may advance drug delivery with increased tumor response rates and decreased toxicity. [ONCOLOGY 11(Suppl 11:)33-37, 1997]


Liposomes are colloidal structures composed of a lipid bilayer surrounding an aqueous medium.[1] They can be used to carry a wide spectrum of different compounds and have been postulated as potential vehicles for targeted drug therapy.[2]

Solid tumors, with their increased permeability to macromolecules, colloids, and liposomes, may be particularly susceptible to this form of therapy. These larger molecules can more easily enter tumor blood vessels because of defects between the gap junctions of the vessel’s endothelial cells.[3,4] Furthermore, the clearance of these larger molecules from the perivascular space is reduced due to both the absence of organized lymphatics and the relatively high interstitial pressure found in tumors. Liposomes trapped in the perivascular space are degraded slowly, gradually releasing their contents to the surrounding environment. Thus they deliver more chemotherapy to tumor cells in the immediately surrounding tissue than to normal cells in the more distant, healthy tissue.

Liposomal Targeted Therapy

One of the main disadvantages of conventional liposomes is that their lipid bilayer attracts plasma proteins and other opsonins onto their surfaces, leading to structural instability and leakage of their contents into the circulation. Protein-coated liposomes are rapidly cleared by the reticuloendothelial system,[5] and the plasma half-life of conventional liposomes is approximately six hours—an insufficient amount of time to efficiently access the tumor vasculature.

Stealth liposomes were devised to correct these instability problems and thus their development has renewed clinicians’ interest in liposomal-targeted therapy.[6-8] The lipid bilayer of Stealth liposomes is coated with linear segments of polyethylene glycol, a hydrophilic polymer. This polymer causes a hydrated shell to form around the external surface of the lipid bilayer, thus creating a steric barrier against interactions with plasma proteins, opsonins, and cell surface receptors. Consequently, Stealth liposomes are able to evade the reticuloendothelial system and remain in the circulation longer. Their reported plasma half-lives of about 40 to 60 hours afford them a greater opportunity to interact with the tumor vasculature.[9]

Abundant evidence supports the concept of Stealth technology. Liposome accumulation has been demonstrated in a variety of xenograft tumors in nude mice.[4] Both doxorubicin and cisplatin are found to be considerably more cytotoxic in xenograft models when given as liposomal formulations than as free drugs.[10]

In this article, we discuss clinical studies performed with two liposomal anthracycline formulations: Dauno-Xome—daunorubicin in a conventional liposome, and Doxil—doxorubicin in a stealth liposome. Both anthracycline formulations are active against HIV-related Kaposi’s sarcoma and have been compared with the combination of doxorubicin (Adriamycin), bleomycin, (Blenoxane), and vincristine (ABV) chemotherapy regimens in separate phase III trials. Liposomal daunorubicin, at an intravenous dose of 40 mg/m2 every two weeks, was shown to be approximately as effective as ABV (25% vs 28%, respectively) with significantly less toxicity.[11]

Pegylated liposomal doxorubicin (PEG-LD), at a dose of only 20 mg/m2 every three weeks, was twice as effective as the ABV combination chemotherapy regimen (response rate of 58% vs 23%).[12] Similar results were observed in a European phase III study where PEG-LD was compared with a regimen of bleomycin and vincristine (BV).[13] The activity of PEG-LD against solid tumors has, thus far, only been described in preliminary reports in metastatic breast carcinoma[14] and relapsed ovarian cancer.[15]

Designing clinical studies is difficult due to the paucity of data on the biodistribution of liposomes in patients with solid tumors. Tumor targeting in human cancers has not yet been confirmed, let alone quantified. In addition, it is not known which tumor sites or histological subtypes possess the “leaky” vasculature necessary for successful liposomal localization or over what time period this localization occurs.

The little we know about biodistribution in humans comes from studies using conventional liposomes; even less information exists on the distribution of the more promising Stealth liposomes. In order to answer these questions, we have conducted a preliminary study to examine the biodistribution of indium 111-labeled Stealth liposomes in patients with selected malignancies.


Patient Population

Seventeen patients with a variety of locally advanced biopsy-confirmed malignancies, and who were referred for radiotherapy, were entered into this study. The sites of malignancy were as follows: head and neck cancer (5 patients), breast cancer (5 patients), non-small-cell lung cancer (4 patients), high-grade glioma (2 patients), and carcinoma of the cervix (1 patient).

111In-Labeled Stealth Liposomes

Stealth liposomes containing diethylenetriaminepentacetic acid (DTPA) were supplied by Sequus Pharmaceuticals Inc., Menlo Park, CA and stored at -20°C. These liposomes were of the same composition as those used to encapsulate doxorubicin for the Doxil formulation. They measured approximately 90 nm in diameter and contained approximately 55% soybean phosphatidylcholine, 40% cholesterol, 5% polyethyleneglycol derivatized distearoylphosphatidylethanolamine, and a small quantity of a-tocopherol.

A 20 mL solution of these liposomes was thawed to room temperature and then radiolabeled by the addition of 2 mL of 111In oxine solution for a 15-minute incubation period. During the incubation, the DTPA inside the liposomes chelated and trapped 111In diffusing across the lipid bilayer. Any free 111In left in solution outside the liposomes was in turn chelated by the addition of 3.8 mg of ethylenediaminetetraacetic acid (EDTA) in a 5% solution of dextrose. This step ensured that any injected 111In not encapsulated by liposomes would be chelated by EDTA and rapidly excreted in the urine. The labeling efficiency was assayed before injection by separating a 10 µL aliquot of the liposome solution on a Sephadex G50 column.


Patients received between 65 and 107 MBq of 111In-labeled Stealth liposomes, diluted to 500 mL in 5% dextrose, as a 45-minute intravenous infusion. Blood was taken for 111In activity at 30 minutes, and again at 4, 24, 48, 72, 96, and 240 hours. Serial 24-hour urine collections were taken to monitor 111In excretion over the first 96 hours.


Gamma camera scintigraphy was performed on an MS-2 dual-headed gamma camera using high resolution, medium energy collimators. Whole body images were acquired at 6 cm per minute. Before the injection of 111In-labeled liposomes, the tissue attenuation of gamma radiation was compensated by performinga whole body transmission scan using a 57Co source. Whole body scans were undertaken at 0.5, 4, 24, 48, 73, 96, and 240 hours after injection. Single-photon emission computed tomography (SPECT) and static imaging of regions of interest were performed when appropriate. The tumor and normal organ 111In content was estimated using a validated “regions of interest” method from the scintigraphy images.


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