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Clinical Trials |
Imperial Cancer Research Fund, Oncology Unit [K. J. H., R. G. V.], and Department of Imaging [S. M., D. G., A. M. P.], Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London W12 0HS, United Kingdom; Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55902 [K. J. H., R. G. V.]; SEQUUS Pharmaceuticals Incorporated, Menlo Park, California 94025 [P. S. U.]; and Department of Radiotherapy, Charing Cross Hospital, London W6 8RP, United Kingdom [J. S. W. S.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Thus far, there have been no studies to address specifically the question of the ability of pegylated liposomes to target solid cancers. Preliminary imaging studies with conventional phospholipid vesicles in patients with cancer (9 , 10) and AIDS-KS and non-Hodgkin lymphoma (11) have confirmed that conventional liposomes accumulate in human tumors. In recent years, the treatment of patients with AIDS-KS, breast cancers, and ovarian cancers with liposomal chemotherapy has given an indication of the potential value of this modality of therapy (12, 13, 14, 15, 16) . In addition to influencing response rates, encapsulation within a pegylated liposome matrix modifies the toxicity of the agent in question. This phenomenon has been most thoroughly studied in the case of doxorubicin, in which case alopecia, vesicant activity, and cardiotoxicity are significantly reduced for the pegylated liposomal formulation (15 , 17 , 18) . However, liposome-mediated alterations in the biodistribution and pharmacokinetics of entrapped agents may have deleterious, as well as beneficial, effects. Most notably, for pegylated liposomal doxorubicin, a novel dose-limiting form of skin toxicity known as palmar-plantar erythrodysaesthesia or hand-foot syndrome has been described (19) . This side effect probably occurs as a result of extravasation of pegylated liposomes within the skin and the subsequent release of their contents.
New pegylated liposomal agents are under preclinical and Phase I/II clinical development in a range of tumor types (2 , 20) . In this study, we demonstrate targeting of IDLPL to a range of common solid tumors in patients with locally advanced cancers and extend the preliminary information on the normal tissue biodistribution and pharmacokinetics of these liposomes that has been reported previously (21) . Such information will provide an important background to future clinical studies.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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70%). Written informed consent
was obtained. Hematological and biochemical profiles were checked
before the patients were enrolled into the study. These blood tests
were repeated at the time of the final whole body scan to assess
possible toxicity of this radiolabeled liposomal preparation. Patients
were excluded from entry into the study if they met any of the
following conditions: premenopausal, pregnant, or breast-feeding
conditions; signs and symptoms of acute infection; invasive
surgical procedure or radiotherapy to the tumor in the preceding 3
weeks; cytotoxic chemotherapy or cytokine treatment administered in the
preceding 4 weeks; clinically significant abnormalities of hepatic or
renal function; confusion, disorientation, and active major psychiatric
illness; and previous radiotherapy to the site of the primary tumor or
to clinically significant metastases. Eligible patients received
65–107 MBq (1.76–2.89 mCi) of radiolabeled pegylated liposomes
diluted in 500 ml of 5% dextrose as an i.v. infusion over 30–45 min.
Patients were observed throughout the infusion for adverse reactions,
and vital signs were measured immediately after the infusion and daily
thereafter for the first 4 days and again at 10 days. In addition, a 45-year-old male patient with extensive mucocutaneous AIDS-KS (stage T1I1S1) participated in the study according to a modified protocol. He received 0.7 mCi (26 MBq) of IDLPL as an infusion in 250 ml of 5% dextrose.
Surgical Study.
In two patients with surgically resectable SCCHN, the levels of uptake
of IDLPL within tumor and adjacent normal tissues were determined to
investigate the feasibility of using liposome-encapsulated
radiosensitizers in the treatment of SCCHN. The study was approved by
the Research Ethics Committee of Hammersmith Hospitals National Health
Service Trust and the Administration of Radioactive Substances Advisory
Committee. Patient 1 was a 54-year-old male with a
T2N0M0 squamous cell cancer
of the lateral border of the tongue. He underwent laser left
hemiglossectomy and left supraomohyoid neck dissection. Patient 2 had a
T2N2bM0 squamous cell cancer of the
left tongue base with nodal metastases and underwent a left neck
dissection, mandibular swing and resection of tongue base. The patients
received an infusion of 26 MBq (0.7 mCi) of IDLPL in 250 ml of 5%
dextrose 48 h before surgery. Samples of the primary tumor,
adjacent normal mucosa, salivary gland, sternocleidomastoid muscle,
adipose tissue, and skin were obtained at the time of surgery.
Pegylated Liposomes and Radiolabeling Protocol.
DTPA (Janssen Chimica, Geel, Belgium) was entrapped by SEQUUS
Pharmaceuticals, Inc. (Menlo Park,
CA)3
in a proprietary pegylated liposome matrix with the following lipid
composition (values expressed in percentage molar ratio): hydrogenated
soybean phosphatidylcholine (56.2%); cholesterol (38.3%); and
N-(carbamoyl-MPEG
2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium
salt (5.3%). The liposomes were supplied, aliquoted in sterile 20-ml
vials at -20°C, and were subsequently stored at this temperature
until the time of use. The phospholipid doses received were 374 mg of
hydrogenated soybean phosphatidylcholine and 128 mg of
N-(carbamoyl-MPEG
2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine
sodium salt/20-ml vial. Liposomes were labeled by the method described
previously (22)
. Briefly, 2 ml of
111In-labeled oxine (Amersham International
plc, Amersham, United Kingdom) were incubated with 20 ml of
DTPA-containing pegylated liposomes for 60 min at room temperature.
Subsequently, any residual unencapsulated
111In-labeled oxine was chelated by addition of
EDTA (BDH Limited, Poole, United Kingdom) to promote its prompt
excretion after i.v. injection. Entrapment of
111In within the pegylated liposomes was assayed
by loading a 10-µl sample onto a 20-ml Sephadex G-50 column
(Pharmacia, Uppsala, Sweden). Thirty consecutive 1-ml fractions were
eluted with PBS, and the activity of each fraction was counted in a
Canberra Packard Minaxi 5550 (Canberra Packard, Pangbourne, Berks,
United Kingdom) gamma counter. Administration proceeded if the labeling
efficiency was >90%.
Scintigraphy.
All of the scans were performed on a MS2 dual-headed gamma camera
(Siemens plc, Germany) using high resolution, medium energy
collimators. All of the whole body images were acquired at 6 cm/min.
Before injection of the radiolabeled pegylated liposomes, a whole body
transmission scan was performed using a
57Co-labeled source (Amersham
International, Amersham, United Kingdom) to allow correction for tissue
attenuation. In addition, the syringe containing the radiolabeled
liposomes was counted on the gamma camera before administration for the
purpose of calibrating the system (see below). For the biodistribution,
pharmacokinetic, and imaging study, whole body double-headed gamma
camera images were taken at 0.5, 4, 24, 48, 72, 96, and 240 h
after liposome injection. SPECT and static imaging of ROI were
performed as appropriate. The scans were viewed by an experienced
assessor without prior knowledge of the diagnosis and without reference
to previous radiological examinations. For the patient with AIDS-KS,
whole body nuclear medicine scans were performed at 4, 24, 72, and
168 h. A preinjection transmission scan was not performed, and
there was no attempt to estimate uptake in ROI. Blood, plasma, and
urine pharmacokinetics were not performed. For the two patients in the
surgical study, whole body and SPECT nuclear medicine scans were
performed at 2 h (patient 1) and 20 h (patient 2) before
surgery.
Blood, Plasma, and Urine Pharmacokinetics.
Blood samples (10 ml) were taken into tubes containing anticoagulant
(lithium heparin) at each of the above time points. Whole blood
radioactivity was measured by counting triplicate 1-ml specimens of
whole blood and standard dilutions (10-1 to
10-4) of the injected liposomes in the gamma
counter. The remainder of the blood sample was then centrifuged at 2000
rpm for 15 min to separate the cellular components from the plasma
fraction. Triplicate 0.5-ml samples of plasma were taken, and their
content of radioactivity was measured separately. In addition, serial
24-h urine collections were performed for 96 h, and the daily and
cumulative urinary excretion of 111In in that
time period was determined. The content of radioactivity in blood,
plasma, and urine was initially expressed as a percentage of the
injected dose/g of fluid. The total amount of radioactivity present at
each time point in the blood and plasma was estimated by deriving the
total blood volume and the plasma volume from standard nomograms using
the patient’s sex and body surface area (calculated from height and
weight). For the purpose of these estimations, it was assumed that 1 ml
of blood and plasma weighed 1 g. Similarly, the total amount of
radioactivity excreted/day in the urine was calculated from the volume
of urine collected in that day.
Estimation of Liposome Uptake From ROI.
The uptake of radiolabeled liposomes in tumor and in specific organs
(liver, spleen, kidney, and lung) was estimated by measuring the total
number of counts in identical ROI on the geometric mean images
(anterior and posterior) derived from the emission scans and correcting
for attenuation of the body using the transmission images. Briefly, if
A is the total count in the organ or tumor defined by the
ROI, then the count from the anterior image
(Ca) is given, to a good
approximation, by:
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where L = patient thickness over the ROI. The
geometric mean of the anterior and posterior counts
is
.
The square of the geometric mean of the counts is therefore:
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The anterior and posterior counts from the transmission scan are
given by:
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and
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where S = activity of known
57Co-labeled source. Thus, the attenuation term
eµL in equation
(A) equates to
Sp/Sa.
Substituting this in equation (A) gives:
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To obtain an absolute measure of the uptake in MBq, a calibration factor (counts/MBq) was estimated using sheets of perspex as a tissue equivalent material. The count from a syringe containing the radiolabeled liposomes at a known activity was measured using the same principles as those used for the transmission and emission scans for the patients. Therefore, as shown in equation (B), knowledge of the geometry of the detailed distribution of radionuclide and of the linear attenuation coefficient were not required.
Estimation of Tumor and Organ Uptake.
The data were initially calculated in the form of whole organ uptake
values. In addition, an attempt was made to estimate the level of
uptake as a % ID/kg of tissue. The mass of the individual organs for
both men and women were obtained from standard texts: liver, 1.6 kg
(male), 1.3 kg (female); spleen, 0.15 kg; kidney, 0.15 kg; and lung,
0.625 kg (right), 0.565 kg (left). In the case of the tumor, its
diameter in three dimensions (d1,
d2, and d3) was estimated
from the available clinical and radiological information, and the tumor
volume was calculated by the following equation:
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For the purposes of this study, it was assumed that the relative density of the tumor tissue was 1.0 in all of the cases. Therefore, the tumor volume in ml was assumed to equate to the tumor mass in g.
Measurement of Uptake of Radiolabeled Pegylated Liposomes in Tumor
and Adjacent Normal Tissues in Patients with Head and Neck Cancer.
Samples of the resected tumor, adjacent mucosa (from two different
sites within a hypothetical radiotherapy portal), salivary gland, skin,
muscle, and fat were placed in weighed tubes and counted along with
standard dilutions (10-1 to
10-4) of the injected liposomes in the gamma
counter. The tubes were then reweighed, and their content of
radiolabeled liposomes was expressed in terms of % ID/kg.
In Vivo Stability of IDLPL in the Circulation.
The stability of IDLPL in the circulation was assessed by taking blood
samples at 24, 48, 72, and 96 h into tubes containing
anticoagulant and centrifuging them at 2000 rpm for 15 min. Samples of
500 µl of plasma were taken, filtered through a 0.2-µm filter
(Acrodisc; Gelman Science, Inc., Ann Arbor, MI), and run on a
Superose-6 FPLC column. Eighty fractions of 0.5 ml were collected and
counted in the gamma counter. As a standard, a 100-µl sample of the
radiolabeled liposomes was run on the same column.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The liposome-encapsulated 111In-DTPA was
collected in fractions 6 to 12, and the peak of unencapsulated
EDTA-bound 111In was collected in fractions 16 to
21. For the purpose of calculating the labeling efficiency, the counts
collected in fractions 6 to 12 were expressed as a percentage of the
total number of counts in all of the 30 fractions.
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. Fig. 2
shows the clearance of the IDLPL from the blood and plasma over the
240-h period of the study. It can be seen that all of the
111In was contained in the plasma fraction, which
suggested that none of the circulating radioactivity was associated
with blood cells.
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where t1/2 = 0.693/k. Using this
method, the t1/2ß was found to be
76.1 h. The goodness of fit was within 95% of expected limits for
a correct model of the data. The data available did not permit accurate
derivation of a t1/2
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The median cumulative urinary excretion of 111In
over the first 96 h was 19.5% (range 3.5–28.4%). The time
course of urinary excretion of 111In is shown in
Table 2
. As can be seen, the majority of the 111In was
excreted in the first 24 h. A significant proportion of this was
undoubtedly because of rapid excretion of the unencapsulated EDTA-bound
radioactivity. The remainder of this early urinary excretion was
probably because of initial intravascular rupture or RES degradation of
damaged or defective liposomes. A small percentage of the injected
radioactivity was excreted on each of the subsequent days, suggesting
slow degradation of the pegylated liposomes within the blood or tissues
and gradual elimination of their content of
111In-DTPA.
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Positive tumor images were obtained in a total of 18 of 20 studies. For
the 17 patients who participated in the biodistribution and
pharmacokinetic study according to the full protocol, the tumor was
seen in 15 patients (Table 3)
. Clear visualization of the tumors was not usually obtained until
48–72 h after injection because of the high blood background signal.
In 12 of the 17 patients, the tumor was clearly seen on the whole body
images and, in an additional 3 patients (2 gliomas, 1 cervical cancer),
SPECT scans of the ROI were required to identify the tumor. Fig. 3
, Fig. 4
, and Fig. 5
show representative scans of three patients, one each with breast,
lung, and head and neck cancer. Fig. 6
shows the whole body scans at 4, 24, 72, and 168 h in the patient
with AIDS-KS in whom a large number of lesions over the left foot, left
calf, thigh, arms, and face were clearly delineated.
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Estimation of Tumor and Organ Uptake from Regions of Interest.
In the 12 tumors that were clearly seen on the whole body scans, the
maximum level of uptake varied from 0.3 to 3.6% of the injected dose
at 72 h. The mean estimated tumor volumes for the various tumor
groups were as follows: 36.2 ± 18.0 cm3
for
SCCHN; 114.5 ± 42.0 cm3
for lung tumors;
and 234.7 ± 101.4 cm3
for breast tumors.
When the liposome uptake data were expressed in terms of the % ID/kg
of tumor, the results varied between 2.7 and 53.0% ID/kg. When these
data were analyzed separately according to the site of the primary
tumor site, there was considerable variation (Fig. 7)
. The greatest levels of uptake were seen in the SCCHN (33.0 ±
15.8% ID/kg). The uptake in the lung tumors was at an intermediate
level (18.3 ± 5.7% ID/kg), and the breast cancers showed
relatively low levels of uptake (5.3 ± 2.6% ID/kg). These data
were calculated only for the tumors that were visualized on the whole
body scans. The two patients with negative scans, one each with breast
and lung cancer, were not included in this analysis.
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. As can be seen, absolute uptake was greatest in the liver, which
reached a peak at 4 h and remained virtually constant throughout
the period of the study. The uptake in the spleen increased throughout
the first 3 days to reach a peak value at 72 h. These data
demonstrate that, although pegylated liposomes are engineered to evade
the RES, there is still a significant amount of clearance via this
route. When the uptake is expressed in terms of % ID/kg of tissue, the
relative uptake in the spleen exceeds that in the liver by a factor of
4 (Table 4)
. The activity localized in the kidneys was greatest at the
0.5-h scan and showed a gradual decline during the study period. In
addition to tissue localization of radiolabeled liposomes, this pattern
was probably because of initial accumulation of unentrapped
111In-EDTA and subsequent daily excretion of
released 111In-DTPA. The activity localized in
the lung declined progressively throughout the study period from a
maximum at 0.5 h, probably representing blood pool activity in the
lungs.
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. Tumor uptake was 8.8 and 15.9% ID/kg, respectively. Tumor uptake
exceeded the uptake in any of the normal tissues by a factor of between
1.4 and 16.9. The mean tumor:normal tissue ratio for the four separate
samples of head and neck mucosa was 2.3. The levels of uptake were
lowest in the muscle and adipose tissues.
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. The estimated encapsulated and unencapsulated
111In-DTPA values are detailed in Table 6
. The trace for the preinjection sample of radiolabeled liposomes shows
that the peak of radioactivity runs between fractions 16 and 30, with a
small amount of unencapsulated 111In running in
fractions 40 to 50. The traces for the plasma samples out to 96 h
clearly demonstrate that the same pattern is present, with virtually
all of the radioactivity contained within the fractions that correspond
to radiolabeled pegylated liposomes. There is a minor shift in the peak
of unencapsulated 111In toward earlier fractions,
perhaps representing a small amount of transchelation of
111In to plasma proteins. However, it can be
concluded that the measured and imaged radioactivity is likely to
represent the biodistribution and pharmacokinetics of IDLPL.
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DISCUSSION |
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Although this study has clearly demonstrated that pegylated liposomes
are able to accumulate in solid tumors at high concentrations and
remain there for prolonged periods, there was considerable
heterogeneity of uptake of the liposomes both between different tumor
types and between different patients with the same tumor type. The
differences are accentuated if the liposome uptake is expressed as a
function of a relative unit of tumor mass. The levels of uptake seen in
the breast tumors (5.3 ± 2.6% ID/kg) were considerably lower
than those seen in the lung (18.3 ± 5.7% ID/kg) and head and
neck tumors (33.0 ± 15.8% ID/kg). It is unclear why certain
tumors showed higher levels of uptake than others and, indeed, why two
of the tumors (1 breast cancer, 1 lung cancer) were not seen on either
whole body or SPECT imaging. Detailed information regarding the
histology and vascular architecture of the tumors was not available,
although it is intriguing to hypothesize that differences in the
density and structural and functional integrity of the tumor
neovasculature may be responsible for at least some of the variability.
Koukourakis et al. (26)
have studied this issue
in patients with lung and head and neck cancers who received
99mTc-DTPA-labeled pegylated liposomes and
demonstrated that microvessel density assessed with anti-CD31
monoclonal antibody staining directly correlated with the degree of the
liposome accumulation. In addition, the size of the tumors and the
presence of areas of poor vascularization, or even necrosis, may have
influenced the results. There is evidence from xenograft studies that
larger tumors have lower levels of liposome uptake and are more likely
to contain necrotic areas (27)
. In terms of estimated
tumor mass, the breast tumors were the largest, and the SCCHN were the
smallest. These data mirrored the results for tumor liposome uptake
shown in Fig. 7
. However, this relationship was not absolute, and
tumors of different histological types but similar sizes had different
levels of liposome uptake. Another potentially important factor is the
presence or absence of associated inflammation. Pegylated liposomes
have been shown to localize efficiently to inflamed areas in a number
of animal studies (28
, 29)
. It is interesting to note that
a common feature of patients with locally advanced SCCHN and lung
cancers is the presence of tissue inflammation with or without
superadded infection. This may well have accounted, in part, for the
higher levels of tumor localization in these primary sites.
This heterogeneity of liposome uptake in the different tumor types may explain the results of a Phase II study of pegylated liposome-encapsulated doxorubicin in patients with breast cancer in which the response rate was 31%. This is approximately the same as would be expected for free doxorubicin in this disease (15) . However, these data are in keeping with the findings of this study, which suggest that some breast cancers will fail to be targeted by pegylated liposomes and that others will take up subtherapeutic doses of drug. In contrast, the prominent liposome uptake in head and neck and lung cancers suggests that these tumors might be suitable targets for liposomally targeted therapies. The incorporation of a pretreatment IDLPL uptake scan into future Phase II studies offers the possibility of testing whether this investigation can predict the likelihood of a response to treatment in different groups of patients.
This study also underlines the interpatient variability in pharmacokinetics of pegylated liposomes, with the t1/2ß varying from 40 to 100 h. Such differences may have important clinical implications in terms of both the efficacy and toxicity of therapy. From first principles, prolonged circulation would be expected to increase liposome accumulation in tumors and, hence, improve response rates. However, toxicity may also be a function of liposomal longevity in the circulation, because this would also be expected to increase exposure of dose-limiting tissues (bone marrow, skin, and mucous membranes) to the encapsulated agent.
In addition to the delivery of cytotoxic drugs, pegylated liposomes have the potential to function as a carrier vehicle for a range of anticancer agents to solid tumors, facilitating exploration of a range of novel targeted strategies. One potential application that is currently under investigation in our laboratory is liposomal entrapment of drugs that sensitize cells to the effects of ionizing radiation. A variety of radiosensitizers have impressive in vitro activities but cause significant local and systemic toxicity, which has hindered their clinical utility. In addition, the lack of tumor targeting means that there may be equal radiosensitization in both the tumor and adjacent normal tissues. Entrapment of radiosensitizers within pegylated liposomes offers the prospect of dramatically altering the biodistribution and pharmacokinetics of these agents, thus increasing the tumor concentration of the radiosensitizing drug as compared with the adjacent normal tissues. This phenomenon is demonstrated clearly in the clinical images and suggests that an advantageous differential radiosensitization effect could be achieved in the tumor without unacceptable local normal tissue toxicity. Furthermore, the limited data available from the two patients who underwent surgical excision of their tumors revealed that the uptake of the liposomes into the tumor does exceed that in the adjacent dose-limiting normal structures. Indeed, the tumor:normal tissue ratios for skeletal muscle were very similar to those obtained in a previous study in two patients with bone metastases from breast cancer (30) . Most importantly, the mean ratio of uptake in the tumor compared with the mucosa was 2.4:1 (range 1.4 to 3.2), suggesting that targeted delivery of liposome-entrapped radiosensitizers may yield a preferential radiosensitizing effect in the tumor. Alteration of the biodistribution and pharmacokinetics of the drug also has the potential to reduce systemic drug toxicity, perhaps allowing greater doses of the radiosensitizer to be delivered. Preclinical studies of such liposomally entrapped radiosensitizing agents are in progress in our laboratory. In addition, the high levels of IDLPL delivered to solid tumors, especially those of the head and neck, raise the possibility that pegylated liposomes containing ß-emitting radiopharmaceuticals might be capable of delivering a therapeutic radiation boost to tumors in an analogous manner to that under investigation for radiolabeled monoclonal antibodies (31) . Detailed studies are in progress to examine the feasibility of this approach.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Molecular Medicine Program, Guggenheim 1836, Mayo Clinic,
200 1st Street SW, Rochester, MN 55902. Phone:
(507) 538-0727; Fax: (507) 266-4797; E-mail: harrington.kevin{at}mayo.edu 
2 The abbreviations used are: MPEG,
methoxypolyethylene glycol; DTPA, diethylenetriaminepentaacetic acid;
IDLPL, 111In-DTPAlabeled pegylated liposomes; RES,
reticulo-endothelial system; AIDS-KS, AIDS-related Kaposi sarcoma;
SCCHN, squamous cell cancer of the head and neck; SPECT, single photon
emission computed tomography; ROI, region of interest; % ID/kg,
percentage of the injected dose/kg; FPLC, fast protein liquid
chromatography.
3 STEALTH liposomes are a registered trademark of
ALZA Corp., Palo Alto, CA.
Received 8/ 1/00; revised 10/10/00; accepted 10/18/00.
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REFERENCES |
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| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
