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Experimental Therapeutics, Preclinical Pharmacology |
Imperial Cancer Research Fund Oncology Unit, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London W12 0HS, United Kingdom [K. J. H., G. R-B., K. N. S.]; Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55902 [K. J. H., R. G. V.]; Sequus Pharmaceuticals Inc., 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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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the main thrust of development of pegylated liposome-encapsulated therapeutic agents has focused on systemic administration, the ability to encapsulate a range of agents stably in pegylated liposomes and the relative lack of direct toxicity after accidental local administration (10) suggests that they may also have potential applications in the sphere of locoregional drug-targeting strategies. SCCHN,2 which is characterized by a natural history of local progression and locoregional nodal spread, may serve as an ideal target for such an approach. Thus far, only limited attention has been paid to the potential worth of locoregional depot delivery of liposomal therapeutic agents. Administration of various pegylated and nonpegylated liposomal agents via the i.p. (11, 12, 13, 14, 15, 16, 17, 18) , intrapleural (19) , and intrathecal (20) routes has been shown to enhance local efficacy and to reduce systemic toxicity in a number of preclinical and clinical studies. By analogy, in the sphere of locoregional therapy targeted against a primary tumor and lymph node metastases, direct intratumoral and s.c. administration may be worth additional evaluation. In this article, each of these routes has been examined in detail with the aim of defining potential therapeutic roles. In particular, these data have been discussed in the context of delivery of liposome-encapsulated radiosensitizing agents.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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For the studies of intratumoral injection, mice that bore human KB head and neck cancer xenograft tumors (21) were used. The xenograft tumors were established as follows. KB tumor cells were grown to confluence in vitro in 175-cm2 tissue culture flasks (Falcon, Lincoln Park, NJ) in RPMI 1640 containing penicillin 100 units/ml and streptomycin 100 µg/ml, supplemented with 10% FCS (Life Technologies, Inc., Paisley, United Kingdom) at 37°C in a humidified atmosphere of 5% CO2 in air. Culture medium, 0.02% EDTA, and trypsin were supplied by the Media Production Unit at the Imperial Cancer Research Fund (Clare Hall, Herts, United Kingdom). Tumor cells were harvested by brief incubation with a 1:3 solution of trypsin/EDTA 0.02%, a single-cell suspension was prepared, and 5 x 106 tumor cells in 0.1 ml of culture medium were injected s.c. into the right flank of the mice. The animals were used for the experiment 17–21 days after tumor inoculation. For the studies of s.c. injections, non-tumor-bearing nude mice were used.
Preparation of Radiolabeled Materials
Pegylated liposome-encapsulated DTPA (Janssen Chimica, Geel,
Belgium) was provided by Sequus Pharmaceuticals, Inc. (Menlo Park, CA).
STEALTH liposomes are a registered trademark and have been described
previously (4)
. Briefly, 5 ml of DTPA-containing pegylated
liposomes [hydrogenated soybean phosphatidylcholine 56.2%,
cholesterol 38.3%, N-(carbamoyl-methoxypolyethylene glycol
2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium
salt 5.3% (values expressed in % molar ratio)] were radiolabeled by
incubating them with 0.5 ml of
111In-labeled oxine (Amersham
International plc, Amersham, United Kingdom) containing 18.5 MBq of
radioactivity. After 1 h, 4 mg of EDTA (BDH Ltd, Poole, United
Kingdom) was added to chelate any residual unencapsulated
111In and to promote the prompt excretion after
administration. Entrapment of 111In within the
pegylated liposomes was assayed by loading a 10-µl sample on to 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 gamma
counter (Pangbourne, Berks, United Kingdom). Administration proceeded
if the entrapment efficiency was found to be >90%.
Unencapsulated 111In-DTPA was prepared according to a method described previously (4) . Briefly, a 40-µl volume of InCl3 in 0.04 M HCl containing 22.2 MBq (600 µCi) of radioactivity was titrated to pH 6.0 by the addition of 60 µl of a 3.5% solution of sodium citrate. Thereafter, 10 µl of DTPA, in 10-fold molar excess relative to the InCl3, and 100 µl of a 100 mM solution of sodium acetate (pH 6.0) were added. The final solution was diluted with PBS to a final activity of 10 µCi/100 µl.
The choice of 111In-DTPA as the radioisotope in these studies was based on a number of factors: (a) DTPA reliably and firmly binds 111In in vitro and in vivo; (b) DTPA is a small compound with a low molecular weight, similar to that of many of the more commonly used antineoplastic cytotoxic agents; (c) 111In has a physical half-life that is sufficiently long to allow detailed analysis of biodistribution of IDLPL and unencapsulated 111In-DTPA over the 8-day period of these studies; and (d) a simple and effective means was available of radiolabeling pegylated liposomes with 111In-DTPA, which had already been validated in a previous study (4) .
Administration of Radiolabeled Materials
Intratumoral Route.
Nude mice bearing KB xenograft tumors received an intratumoral
injection of 5 µl of either IDLPL or unencapsulated
111In-DTPA containing 0.037 MBq (1 µCi) of
radioactivity. The injection was performed using a 27-gauge butterfly
needle attached via a length of fine tubing to a 100-µl Hamilton
microsyringe (Anachem, Luton, Bedfordshire, United Kingdom). After
delivery of the injection, the needle was withdrawn slowly from the
tumor, and the entry site was observed for evidence of leakage of the
injectate through the skin. In the event of observable leakage of
injectate from the tumor, the animal was excluded from the study.
Groups of five mice were dissected at 1, 4, 24, 48, 72, and 96 h
after intratumoral injection of either IDLPL or unencapsulated
111In-DTPA. The mice were anesthetized using
inhaled isoflurane (Abbott Laboratories Ltd, Queensborough,
Kent, United Kingdom) and killed by exsanguination at cardiac puncture.
The aim was to evacuate the maximum blood volume obtainable
(
1.0–1.2 ml). Voided urine was also collected. Thereafter, the
tumor, ipsilateral and contralateral inguinal and axillary lymph nodes,
liver, spleen, kidneys, and lungs were dissected out, washed in PBS,
and placed in preweighed scintillation vials (Sterilin, Stone, United
Kingdom). The content of radioactivity was assessed by counting the
tubes in a Canberra Packard Minaxi 5550 gamma counter. Standards of the
injected material were made in triplicate and used to correct for
physical decay of the 111In.
s.c. Route.
Non-tumor-bearing nude mice received a s.c. injection of 100 µl of
either IDLPL or unencapsulated 111In-DTPA
containing 0.37 MBq (10 µCi) of radioactivity in the right flank. The
aim was to deliver the injection to an area lying approximately
equidistant between the fore and hind limbs. The site of the injection,
as identified by the s.c. bleb with a small margin, was then marked
with a permanent marker pen to facilitate its localization at the time
of dissection.
Groups of five mice were dissected at 1, 4, 24, 48, 72, 96, and 192 h after s.c. injection of IDLPL and at 15 min and at 1, 4, 24, 48, 72, and 96 h after injection of unencapsulated 111In-DTPA. The animals were killed by the same protocol as detailed above. Blood and urine were collected as above. The s.c. injection site, ipsilateral and contralateral inguinal and axillary lymph nodes, liver, spleen, kidneys, and lungs were dissected out, washed in PBS, and placed in preweighed scintillation vials. The content of radioactivity was assessed by counting the tubes in the gamma counter with standards of the injected material in triplicate to correct for physical decay of the 111In, as described above.
i.v. Route.
Nude mice bearing KB xenograft tumors received an i.v. injection of 100
µl of either IDLPL or unencapsulated 111In-DTPA
containing 0.37 MBq of radioactivity via a lateral tail vein. Groups of
five mice were dissected at 1, 4, 24, 48, 72, 96, and 192 h after
i.v. injection of IDLPL and at 15 min and 1, 4, 24, 48, 72, and 96 h after the injection of unencapsulated
111In-DTPA. The mice were killed by the method
described above also. Blood and urine were collected as above. The
tumor, ipsilateral and contralateral lymph nodes, liver, spleen,
kidneys, and lungs were dissected out, washed in PBS, and placed in
preweighed scintillation vials, and the content of radioactivity was
determined as above.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 2
, respectively. Fig. 1
illustrates the intratumoral levels of
radioactivity for both IDLPL and 111In-DTPA over
the period of study. The tumor levels demonstrated prolonged retention
of IDLPL over a period of up to 96 h from a maximum level of
76.4 ± 22.7%ID/g at 1 h to 15.0 ± 5.5%ID/g at
96 h. These levels compare with the corresponding values for
111In-DTPA of 66.3 ± 12.2%ID/g at 1 h
and 0.36 ± 0.15%ID/g at 96 h. The AUC for IDLPL and
111In-DTPA was 2574.4 and 204.4%ID/g·h between
1 and 96 h, respectively. These data represent a 12.6-fold
increase in the AUC for the liposome-encapsulated radiolabel in the
tumor during the time period of the study. The different rates of
clearance of the liposome-encapsulated and -unencapsulated activity are
reflected by the levels of radioactivity measured in the blood. At
1 h the level of IDLPL was 0.066 ± 0.013%ID/g, which
increased to a peak level of 0.59 ± 0.42%ID/g at 4 h. Low
levels of circulating activity were detectable in the blood until
96 h. The peak measured value in the blood after intratumoral
injection of unencapsulated 111In-DTPA was seen
at 1 h at a level of 0.22 ± 0.02%ID/g. No activity was
detectable in the blood at 
48 h. The rapidity of clearance of the
unencapsulated radiolabel from the tumor is clearly seen from the
profile of urinary excretion of radioactivity with 45.7 ± 27.5
and 92.4 ± 62.4%ID/g present at 1 and 4 h, respectively.
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. Peak levels were achieved
in both the inguinal and axillary nodes at 4 h after the
injection. The data confirmed that there was significant drainage and
retention of liposomes within the ipsilateral compared with the
contralateral lymph nodes. These values showed considerable
variability, but, when analyzed according to the ratio of levels in the
ipsilateral and contralateral nodal areas, there appeared to be a
pattern demonstrating a progressive increase in the ratio in the
ipsilateral nodes to a maximum of approximately 8:1 (2.2
versus 0.27%ID/g) for the inguinal region at 24 h and
19:1 (2.5 versus 0.13%ID/g) for the axillary nodes at
48 h. In comparison, the same data for unencapsulated
111In-DTPA showed no evidence of progressive
accumulation in regional nodes, no evidence of increased uptake in the
ipsilateral compared with the contralateral lymph node groups, and no
suggestion of prolonged retention (Fig. 2b)
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s.c. Route.
The detailed results for the biodistribution of IDLPL and
111In-DTPA after s.c. injection are shown in
Tables 3
and 4
, respectively. Figure 3
illustrates the s.c. levels of
radioactivity for both IDLPL and 111In-DTPA over
the period of study. These data clearly demonstrate that the IDLPL was
cleared very slowly from the injection site with 74.7 ± 9.5%
ID/g retained at 192 h. These data contrast directly with those
for unencapsulated 111In-DTPA, which was cleared
rapidly from the s.c. injection site from a maximal level of 59.1 ± 13.7%ID/g at 15 min to 3.7 ± 1.0%ID/g at 1 h. The
corresponding AUC between 1 and 192 h for IDLPL and
111In-DTPA were 24,051.1 and 46.4%ID/g·h,
respectively. These data represent a 518-fold increase in the AUC for
the liposome-encapsulated radiolabel at the s.c. injection site in this
time period. The levels of radioactivity measured in the blood showed
evidence of these different patterns of absorption. The peak blood
level of IDLPL of 0.74 ± 0.09%ID/g was reached at 24 h,
whereas for the unencapsulated 111In-DTPA, the
maximum level of 3.2 ± 0.3%ID/g was measured in the blood at 15
min, falling rapidly to 0.27 ± 0.04%ID/g at 1 h.
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. When compared with the
corresponding contralateral nodal groups, maximal ratios of 121:1 (57.9
versus 0.48%ID/g) at 24 h for the inguinal nodes and
17:1 (5.2 versus 0.30%ID/g) at 72 h for the axillary
nodes were documented. These data contrast with those recorded for
unencapsulated 111In-DTPA in which no significant
retention of radioactivity was seen in the draining nodes, with a
maximum level seen for all of the groups at 15 min. The ratios of
uptake in the ipsilateral relative to the contralateral inguinal and
axillary nodes were maximal at 15 min at 3.8:1 and 1.3:1, respectively.
By 1 h there was no significant difference between the levels in
the ipsilateral and contralateral nodes. These data would be consistent
with a phase of rapid absorption from the s.c. injection site, both by
means of uptake into the blood and by lymphatics, followed by prompt
excretion.
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i.v. Route.
The results for the levels of IDLPL and
111In-DTPA in tumor, inguinal, and axillary nodes
after i.v. injection are shown in Tables 5
and 6
,
respectively. For IDLPL, it can be seen that the levels of
radioactivity in the tumor were significantly lower than those seen
after intratumoral injection. As regards the various nodal areas, the
levels were essentially uniform, with a phase of accumulation in the
nodes between 1 and 24 h, relatively stable levels between 24 and
72 h, and then a gradual decline to 192 h. There was no
evidence of differences between ipsilateral and contralateral groups
(relative to the side of the xenograft tumor), in contrast to the
findings for both the intratumoral and the s.c. injections. For
unencapsulated 111In-DTPA, there was no evidence
of accumulation of this radiolabel in any of the nodes, with levels
essentially undetectable at 24 h and beyond.
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DISCUSSION |
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shows that, had dissection time points been performed beyond
96 h, the calculated difference between the AUC for encapsulated
and unencapsulated 111In-DTPA would have been
considerably higher. In the context of targeted delivery of
radiosensitizers, the prolonged retention of IDLPL that is documented
here suggests that they may act as an effective means of achieving
sustained intratumor release of entrapped agents. As regards the issue
of local normal tissue toxicity, Madhavan and Northfelt
(10)
have reported that encapsulation of doxorubicin
within pegylated liposomes abrogates the severe local toxicity of this
agent after inadvertent extravasation (27
, 28)
. It is
likely that encapsulation of other radiosensitizing agents, such as
cisplatin or 5-iodo-2'-deoxyuridine, would afford similar protection
against local toxicity. In addition, the systemic toxicity arising from
the absorption of pegylated liposomal agents might reasonably be
expected to be reduced, in line with the data for i.v. administration
(6, 7, 8, 9)
. Therefore, on this basis, pegylated liposomes seem
to be an attractive vehicle for the delivery of locoregional therapy. The above considerations will only have clinical utility, however, if the contents of locally administered pegylated liposomes are released within the interstitium of the tumor. In this regard, there is compelling evidence confirming such release in tumor tissue after i.v. administration. In particular, microfluorimetric techniques have shown release of doxorubicin within xenograft tumor deposits after the initial accumulation of liposomes in the perivascular space (29 , 30) . Furthermore, the responses of a variety of xenograft tumors to therapeutic nonpegylated and pegylated liposomes provides a wealth of indirect evidence of the ability of the agents retained in them to become bioavailable and exert a biological effect (5) . The superiority of both pegylated liposomal doxorubicin and cisplatin over the respective unencapsulated agents in this tumor model also has been confirmed in studies in which the agent was delivered by i.v. injection (31) . As yet, there have been no studies of direct intratumor injection of liposomal therapeutic agents. Konno et al. (32) reported a significant reduction in the growth rate of s.c. AH-66 hepatoma tumors with little toxicity after peritumoral s.c. injections of interleukin-2 encapsulated in nonpegylated, small unilamellar vesicles.
The data from these studies of intratumoral administration suggest that this approach also may represent an effective means of targeting the locoregional lymph node drainage areas, because substances injected directly into tumor deposits may be cleared from the tumor, at least in part, via lymphatic channels in a pattern that may recapitulate the likely spread of lymphatic metastases. The validity of this approach has been supported in recent years by studies seeking to identify "sentinel nodes" in patients with breast cancer and malignant melanoma by intratumoral injections of radiolabeled colloids (33 , 34) . Therefore, in addition to local therapeutic effects in the tumor, direct intratumoral injection of pegylated liposomal agents may achieve the additional benefit of concentrating them within the sites of lymphatic spread over a prolonged period, without causing unacceptable local toxicity. Although the absolute levels of radiolabeled liposomes that accumulated in the locoregional nodes after intratumoral injection were relatively low, the pattern of preferential deposition in ipsilateral as opposed to contralateral nodes confirmed that there was locoregional trafficking of pegylated liposomes within the lymphatic system. The retention of the radioactivity within the nodal tissue confirmed that it remained encapsulated within a liposome; otherwise, it would have been cleared as rapidly as unencapsulated 111In-DTPA, which showed no evidence of prolonged nodal deposition. However, the relatively poorly developed lymphatic drainage of the tumors (as shown by the relatively slow clearance of 111In-DTPA after intratumoral but not s.c. injection) and the absence of lymph node metastases from KB xenograft tumors (data not shown) suggest that this model may not accurately reflect clinical situations. For SCCHN, the patterns of lymphatic metastasis occur in a predictable fashion based on tumor site, stage, and grade (35) and can be described in terms of the Memorial Sloan-Kettering Cancer Center classification (36) . Furthermore, the ability to define sentinel nodes in the head and neck after intratumoral injection has been confirmed, although that particular study (33) involved patients with malignant melanoma. Therefore, it is reasonable to hypothesize that the clinical targeting of lymph nodes after intratumoral injection of pegylated liposomal radiosensitizers may be more successful in patients by virtue of the effective drainage pathways.
The s.c. space has not been evaluated in detail as a potential route of clinical administration for cytotoxic therapies, although it is used for the delivery of cytokines (IFN, interleukin 2; Ref. 37 ), luteinizing-hormone-releasing hormone analogues (38) , and a range of agents in the palliative care setting (39) . A number of preclinical studies of s.c. administered nonpegylated liposomal agents as depot preparations have been reported in the context of inflammatory/infective (40, 41, 42) and neoplastic (43 , 44) disorders. Because the s.c. space itself is not a meaningful target for anticancer therapies, the use of s.c. injected pegylated liposomes is likely to be valuable only in the context of locoregionally targeted therapeutic strategies. The s.c. tissues are permeated by a rich network of lymphatic channels that drain to locoregional lymph nodes. These nodes also receive afferent lymphatic channels from primary tumor masses. Therefore, the administration of pegylated liposomal agents by the s.c. route may provide a useful means of delivering high concentrations of drugs to lymph nodes clinically involved with metastatic disease or, indeed, clinically uninvolved lymph nodes that may harbor micrometastatic disease. Kaledin et al. (45) demonstrated the ability of s.c. injections of liposomal cisplatin and hydrocortisone to reduce the incidence of regional (popliteal) lymphadenopathy after injection of murine hepatoma and pulmonary adenocarcinomas into the footpad of mice. Significantly, there was no effect on the incidence of distant metastatic disease, suggesting that the liposomal therapy was exerting only a locoregional effect. Effective lymphatic targeting of 99mTc-labeled nonpegylated liposomes administered s.c. or intralymphatically has been demonstrated in animal and clinical studies (46 , 47) . Allen et al. (48) have also reported the ability of 125I-radiolabeled pegylated liposomes to target the cervical and axillary nodes after s.c. injection in a rodent model. Interestingly, with their formulation of pegylated liposomes of 80- to 90-nm diameter, up to 30% of the injected radiolabel was detected in the blood between 12 and 24 h after s.c. injection. Such levels are greatly in excess of the levels reported here, which suggests that this formulation possesses a greater ability to act as a locoregional depot agent.
The studies reported here provided clear evidence of drainage of pegylated liposomes to locoregional lymph nodes. The levels achieved in the ipsilateral inguinal lymph nodes were significantly higher after s.c. injection compared with i.v. injection. That the measured radioactivity within the lymph nodes was likely to be retained within liposomes was strongly suggested by the fact that there was no evidence of the retention of unencapsulated 111In-DTPA within the locoregional lymph nodes. Therefore, it is likely that in the setting of lymph nodes involved with metastatic disease, the tumor deposits would be exposed to relatively high concentrations of the encapsulated drug. In the context of the treatment of SCCHN, this approach may be useful as a means of targeting radiation sensitizers to lymph nodes containing clinically apparent deposits of metastatic disease or even nodal areas suspected of harboring micrometastatic disease. The patterns of lymphatic drainage of the skin in the head and neck are well documented. Thus, it may be possible to inject pegylated liposomes containing radiosensitizers s.c. in an area that will drain to lymph nodes that will be included in the radiation treatment portals. If the site of the s.c. injection lies beyond the field boundaries of the radiation portal, this area will not be sensitized to the effect of the radiation, and there should be little or no additional toxicity from this strategy. However, it must be borne in mind that the s.c. space of a loose-skinned animal such as a mouse is very different from that of humans. The capacity of the s.c. space in mice is large, such that it will accommodate relatively large volumes of injectate. In contrast, the s.c. space in humans is a potential space with limited capacity, especially in areas such as the head and neck. Attempts to deliver large injection volumes in these sites is likely to be limited by pain. Nonetheless, small-volume, single or repeated injections should be feasible without excessive toxicity.
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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 First Street SW, Rochester, Minnesota 55902. Phone:
(507) 266-0488; Fax: (507) 266-4797; E-mail: Harrington.Kevin{at}mayo.edu 
2 The abbreviations used are: SCCHN, squamous cell
cancer of the head and neck; DTPA, diethylenetriaminepentaacetic acid;
IDLPL, DTPA encapsulated in pegylated liposomes; AUC, area(s) under the
curve; %ID/g·h, % injected dose per gram hour(s).
Received 1/25/00; revised 3/20/00; accepted 3/21/00.
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-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J. Clin. Oncol., 14: 7-17, 1996.[Abstract]
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