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Experimental Therapeutics |
Wellman Laboratories of Photomedicine, Department of Dermatology [M. D. G., M. R. H., I. R., T. H.], Vincent Memorial Obstetrics and Gynecology Service, Division of Gynecologic Oncology [K. G. M.], and Department of Surgical Oncology [K. T.], Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and Departments of Pathology and Medicine (Dermatology) [C. R. S.], Duke University Medical Center, Durham, North Carolina 27710
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ABSTRACT |
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INTRODUCTION |
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In a previous report (16) , we detailed the preparation of PICs between the PS chlorine6 (ce6) and the Mab 17.1A, which recognizes the human colorectal cancer-associated antigen known as EpCAM (17) . These PICs bore either polycationic or polyanionic charges, and both PICs preserved antigen-binding capacity and were taken up more by target HT 29 human colorectal tumor cells than by nontarget ovarian cancer cells. They showed higher uptakes by HT 29 cells than by PICs prepared from nonspecific rabbit IgG and killed more target cells after illumination than nontarget cells, thus demonstrating the principle of selective delivery of PS to colorectal tumor cells in vitro. However, the real challenge inherent in this approach lies in demonstrating selective PS targeting in vivo. Toward this goal, we investigated the biodistribution of these charged 17.1A PICs in an orthotopic murine model of hepatic colorectal cancer metastasis formed by injecting HT 29 cells into a lobe of the nude mouse liver.6 The anionic PIC was found to give much better accumulation of PS in the tumor than the cationic PIC, and the Mab conferred a distinct improvement in tumor selectivity compared to surrounding normal liver. Based on the results found in the previous study,6 the parameters chosen to maximize both the tumor content of PS and the tumor:normal liver ratio were to administer the polyanionic 17.1A PIC 3 h before illuminating the tumor with an interstitial fiber. This paper tests the therapeutic efficacy of interstitial PIT using the anionic PIC and unconjugated ce6. Because the light is delivered interstitially, it will be more readily absorbed by the tissue than surface illumination, and the possibility exists of creating laser-induced hyperthermia in addition to PDT. To test this possibility, we delivered the same fluence at two widely different fluence rates (30 and 300 mW) and measured the tumor response. Both short-term end points (tumor weight) and long-term end points (survival) were assessed.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Line and Mab.
HT29 tumor cell line derived from a human colorectal adenocarcinoma was
obtained from ECACC (CAMR Centre for Applied Microbiology & Research,
Wiltshire, UK) and used for all experiments. Cells were grown in
DMEM/F12 (50/50 mixture) containing 15 mM HEPES and
L-glutamine, were supplemented with 10% heat-inactivated
fetal bovine serum (Whittaker Bioproduct, Walkersville, MD), 100
units/ml penicillin, and 100 µg/ml streptomycin, and were maintained
in an incubator at 37°C in an atmosphere of 5%
CO2. 17.1A murine Mab was a kind gift from
Centacor (Malvern, PA).
Preparation and Characterization of PIC.
This has been described previously (16)
. Briefly,
17.1A IgG was partially reduced with mercaptoethylamine hydrochloride
and reacted with a succinylated poly-l-lysine
ce6 conjugate, which had been derivatized with a
heterobifunctional reagent bearing a pyridyldithiopropionamide group to
form a disulfide bond between the IgG hinge sulfhydryl group and the
succinylated poly-l-lysine ce6 conjugate.
There was an average of two poly-l-lysine chains and between
eight and nine molecules of ce6 per Mab, and the
immunoreactivity of the PIC was demonstrated by two-color
direct/indirect immunofluorescence and ELISA assays (16)
.
Animal Model.
A xenograft model for liver metastases of colorectal cancer consisting
of a discrete tumor within one lobe of the liver was used for the
experiments.6
Mice were anesthetized by
inhalation of Metofane (Pitman-Moore Inc, Mundelein, IL); 2 ml of
liquid vaporized in a 500-ml closed container. Under aseptic
conditions, mice were placed supine, and a 1-cm left median incision
(starting from the subcostal region) was made through the skin and
peritoneum to expose the left lateral lobe of the liver. That lobe was
lifted out from the abdominal cavity and secured in place by
positioning a sterile cotton-tipped stick inferior to the lobe. HT-29
cells (5 x 106
or 20 x 106
) in 50 µl of sterile DMEM F/12 were
injected between the upper surface of the lobe parenchyma and the liver
capsule using a 30-gauge needle, and the lobe was then returned into
the peritoneal cavity. The puncture wound in the capsule was sterilized
with 100 µl of povidone iodine 10% (Clinidine Solution, Clinipad
Corp., Guilford, CT). The peritoneum and abdominal wall were then
closed with sterile Ethilon 4–0 monofilament nylon sutures
(Ethicon Inc, Somerville, NJ), and the mice were monitored and kept
warm until completely recovered.
Interstitial Illumination.
PIT/PDT was performed 9 days after injection of 5 x 106
HT29 cells, or 7 days after implantation of
20 x 106
HT29 cells in the left
lateral lobe of the liver. These time points were chosen because the
tumor was still localized within the lobe and showed the appropriate
size (5–9 mm in diameter) to perform interstitial PDT. Mice were
anesthetized using Metofane and given i.v. injections (into the tail
vein) of the PIC or PS dissolved in sterile filtered PBS. The dose was
0.25 mg/kg of body weight of the ce6 equivalent,
which is equal to 
8.3 nmol of ce6
equivalent/mouse and in the case of the PIC, to 140 µg of IgG
protein/mouse. The volume injected was 40 µl of a solution of 200
µM ce6 equivalent, and
the injection lasted 20–30 s for each mouse. Three h later, mice were
again anesthetized, and the tumor-bearing lobe of the liver was exposed
as described above. An argon-pumped dye laser (Coherent, Palo Alto,
CA), focused through a x10 microscope objective onto the proximal end
of an optical fiber, was used to deliver 666 nm of light for the PIC
and 654 nm of light for free ce6
interstitially via a 7.0 mm x 0.4-mm cylindrically
diffusing fiberoptic tip (built in house). These wavelengths were
previously shown (16)
to correspond with the absorption
maxima of the conjugate and free ce6. The
power output was measured by an integrating sphere and an oscilloscope.
A 22-gauge catheter was introduced longitudinally into the
tumor-bearing lobe so that the tip passed through the tumor and the
entire diffusing tip was passed through the catheter, which was then
withdrawn. The diffusing tip was then centered in the tumor using
forceps to detect its presence within the lobe. After treatment, the
surgical wound was closed as described above.
Phototoxicology and Extent of Liver Damage in Normal Mice.
This study was carried out with non-tumor-bearing mice.
17.1A-pl-ce6-succ (0.25 mg/kg of
ce6 equivalent) was injected as described, and
illumination was performed after 3 h. Light was delivered as
described above into the normal left lateral lobe of the mouse liver.
Two fluence rates were used, 100 and 450 mW, and light doses of 20, 40,
60, 80, 100, 150, and 200 J total out of the fiber tip were used. These
values corresponded to 143 and 643 mW/cm length of diffusing tip, and
the fluences were 28, 57, 86, 114, 143, 214, and 286 J/cm of diffuser
tip, respectively. The fluence rate of 450 mW was chosen to determine
whether a high fluence rate with attendant possibility of causing
thermal damage would produce toxicity in the mice. For an initial
screening for toxicity, one mouse was treated at each light dose and
fluence rate. Mice were carefully monitored after treatment and left
for 4 days in the cages. At the 4th day, mice were sacrificed by carbon
dioxide inhalation, and the whole liver was removed. Pieces (3-mm
thick) of liver from the treated lobe, the border between treated and
untreated liver, and untreated liver (right lobe) were dissected and
fixed for histology.
Treatment Study 1.
This study was performed on mice implanted with 5 x 106
HT29 cells which, after 9 days, led to liver
tumors with a diameter ranging from 5 to 7 mm. Mice were injected with
the 17.1A-pl-ce6-succ or free
ce6 as described above, and 3 h later, the
tumor was illuminated with interstitial light. A total light dose of 80
J was delivered at a fluence rate of 100mW over a period of 13.3 min.
This corresponded to 114 J at 143 mW/cm of diffusing tip. Three groups
of controls were used. Control group 1 had interstitial insertion of
the fiber into the tumor but no PS or light. Control group 2 had
interstitial insertion of fiber and light delivered but no injection of
PS. Control group 3 had an injection of
17.1A-pl-ce6-succ or free
ce6 and interstitial fiber insertion but no
light. All experimental groups were divided into two subgroups. In the
short-term subgroup, mice were sacrificed 9 days after PIT/PDT, and in
the long-term subgroup, mice were followed for survival. In control
groups 2 and 3, there were six mice in each short-term subgroup and two
mice in each long-term subgroup, whereas control group 1 had six mice
in the short-term subgroup and three mice in the long-term subgroup.
The treatment group with free ce6 had six mice
in the short-term subgroup and seven in the long-term subgroup. The
treatment group with 17.1A-pl-ce6-succ had seven
mice in the short-term subgroup and nine mice in the long-term
subgroup. No mortality occurred during the procedures. The short-term
mice were sacrificed 9 days after treatment. The entire liver was
removed and weighed. The liver was then dissected, and normal tissue
and tumor were weighed separately.
Treatment Study 2.
The following experiment was carried out to compare the effect of
delivering a low light dose at two widely different fluence rates.
Three groups of six mice had 20 x 106
HT29 cells in 50 µl of PBS injected in the
left lateral lobe of the liver as described previously. This number of
cells was chosen to produce a tumor with a more uniform growth rate and
hence a more predictable survival time among different control animals.
Seven days later, when the tumors had a diameter of 7–9 mm, two groups
of six mice were injected with 17.1A-pl-ce6-succ
(0.25 mg/kg of ce6 equivalent) in the tail vein
as previously described. Three h later, all three groups were subjected
to interstitial placement of the fiber in the tumor-bearing lobe of the
liver. The control group received no light, whereas the two injected
groups received 10 J of 666 nm light delivered at 30 mW (5.5 min)
and 300 mW (33 s). These values correspond to 14 J at 43 or 430 mW/cm
of diffusing tip. These mice were followed for long-term tumor response
and survival.
Survival Studies.
Mice for survival were monitored twice daily, and the end point was
defined as death attributable to disease or tumor burden that affected
the animal’s ability to move or feed normally. At necropsy, the mice
were dissected, and the entire liver, hepatic tumor, normal liver, and
any metastatic tumor deposits were removed and weighed. All
extrahepatic tumor was dissected and weighed.
Histology.
At necropsy, after weights of tumor and normal liver were obtained,
pieces of tissue (200–300 mg) were removed from the right lobe, the
treated area of the left lobe, and from any normal liver, which
remained within the left lobe, and immediately placed in 10% formalin
followed by routine processing for paraffin embedding and histological
study. Sections were stained with H&E and examined by light microscopy.
Statistics.
All values are expressed as ± SE. SEs of the ratios of
two means were calculated in quadrature. Comparison between two means
was carried out using a two-tailed Student’s t test
assuming equal or unequal variances as appropriate. Survival analysis
was performed using the Kaplan-Meier method. Survival curves were
compared, and differences in survival were tested for significance
using a log-rank test in the computer program GraphPad Prism (GraphPad
Software Inc., San Diego, CA). Ps < 0.05
were considered significant. Linear fit to correlation plots was
performed using the computer program Kaleidagraph 3.0.5 (Abelbeck
Software, Reading, PA).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). There were lymphocytic infiltrates at the well-defined
interface of viable and necrotic liver and extensive coagulative
necrosis of liver. Surprisingly, there was only a very weak light dose
response in the degree of damage to the treated lobes seen by
histology. The lobe treated at 20 J seemed to have slightly less damage
than those treated with higher light doses (40–200 J). No
abnormalities were seen in sections taken from the untreated right
lobes of the livers.
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The results of the two treatment groups versus the combined
control group are shown in Table 1
. Although PDT with free ce6 reduced the mean
tumor weight to 43% of the control mean weight, this did not reach
statistical significance (P = 0.066). The
reduction in the mean tumor weight after treatment with the
17.1A-pl-ce6-succ (18% of control) was,
however, highly significant (P = 0.0035). PDT
with free ce6 led to a significant increase in
the weight of normal liver (137% of control, P = 0.044), and in the case of PIT with
17.1A-pl-ce6-succ, the increase was highly
significant (151% of control, P = 0.001).
The mean of the total liver weights was reduced from 1.62 g in
controls, to 1.44 g with ce6 PDT, to
1.34 g after PIT, but these differences were not significant. When
the percentage of the total liver replaced by tumor was calculated, the
reduction from 44% in controls to 26% after
ce6 PDT was not significant
(P = 0.069), whereas the reduction to 11%
after PIT was highly significant (P < 0.0001).
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, b-f. Fig. 1b
(light but no PS)
shows a moderately differentiated adenocarcinoma growing in and
invading normal liver. Mucin droplets can be clearly seen, and there is
no evidence of damage. Fig. 1c
is from a tumor-bearing lobe
after PDT with free ce6. Several nodules of
viable adenocarcinoma are surrounded by fibrous stroma and at the
periphery, necrotic tumor. In Fig. 1
, d-f, all sections are
from tumor-bearing lobes after PIT. Fig. 1d
shows an island
of viable metastatic adenocarcinoma, containing mucinous glands,
surrounded by zones of hemorrhagic and necrotic tumor and necrotic
liver tissue. Fig. 1e
shows viable carcinoma surrounded by
areas of extensive hemorrhagic necrosis and fibrosis. Fig. 1f
shows viable adenocarcinoma surrounded by fibrosis and at
the periphery, necrotic tumor.
PIT 1 Long-term Survival.
These mice were from the same experimental groups as the short-term
tumor weight study and received the same tumor inoculum,
i.e., 5 x 106
cells.
All of the other parameters were also identical to those in the
short-term study (light dose, fluence rate, and times of treatment).
Mice were sacrificed when they became moribund or were suffering from a
tumor burden that prevented normal locomotion or feeding. A few mice
had extensive visible extrahepatic tumor, frequently at the s.c.
injection site but also in other sites, such as the axillae and back of
the neck. The Kaplan-Meier curves are shown in Fig. 2A
. The median survivals of the experimental groups were as
follows: control, 62.5 days; ce6 PDT, 77 days;
and 17.1A-pl-ce6-succ PIT, 102 days. The
survival curves were compared by a log-rank test, and the curve for the
ce6 PDT group was not significantly different
from that of the control group (P = 0.2),
whereas the curves for the 17.1A-pl-ce6-succ PIT
group and the control group were significantly different
(P = 0.015).
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. One mouse treated with 17.1A-pl-ce6-succ PIT
survived for 144 days; at necropsy, it had no hepatic tumor, its liver
weighed 1.36 g, and there was no extrahepatic tumor. There were
few significant differences between treatment groups in any of the
parameters measured. The mean weight of normal liver in the case of the
ce6 PDT group was significantly higher than the
control (P = 0.009), but this difference
became less in the case of 17.1A-pl-ce6-succ PIT
(P = 0.082). The
17.1A-pl-ce6-succ PIT group had more than twice
as much extrahepatic tumor as the other groups (5.26 g
versus 2.05 and 1.66 g), but because of wide variations
in individual mice, this did not reach statistical significance.
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. Median survival
times were as follows: control, 29.5 days;
17.1A-pl-ce6-succ PIT delivered at 30 mW, 34
days; and 17.1A-pl-ce6-succ PIT delivered at 300
mW, 56 days. The survival curve for the 300-mW group was significantly
different from that of the control group (P = 0.028), but not from the 30-mW group (P = 0.079).
At necropsy, mice were dissected as before, and whole liver,
liver tumor, normal liver, and total extrahepatic tumor were weighed as
described. The results are given in Table 2
. The 300-mW group had a
significantly greater (P = 0.011) mean weight
of normal liver than the control group, and the percentage of liver
replaced by tumor was also significantly smaller
(P = 0.049), whereas the total weight of
extrahepatic tumor was significantly greater than controls
(P = 0.036). There was also a significant
increase (P = 0.045) over controls in total
liver weight in the 30-mW group, which was not seen in the 300-mW
group.
In Fig. 1
, g-h, the histological appearance of sections from
the treated liver lobes at necropsy are shown. Fig. 1g
is
taken from a mouse that was treated with PIT of 80 J delivered at 100
mW in the first survival study and which survived 92 days. It shows
viable adenocarcinoma, surrounded by marked fibrosis and remnants of
liver tissue; no significant necrosis is evident. Fig. 1h
came from a mouse that had PIT with 10 J delivered at 30 mW and
survived 39 days. It shows viable adenocarcinoma with large amounts of
mucin, surrounded by liver tissue with nuclear pyknosis.
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DISCUSSION |
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The results from the previous biodistribution study6 showed that the anionic PIC gave not only higher absolute uptake of ce6 in the tumor tissue, but also superior selectivity for the tumor over normal liver compared to the cationic 17.1A PIC. Free ce6, however, gave only very low tissue uptakes, although the selectivity for the tumor was quite good. The 3-h time point after injection was chosen because the tumor:normal liver ratio for 17.1A-pl-ce6-succ was better at 3 h than at 24 h, and also, the amount of free ce6 in the tumor was much greater at 3 h.
There have been reports in the literature that PDT using unconjugated PS (especially in small rodents) can produce a systemic toxicity leading to death within 12–36 h after illumination (28, 29, 30) . This resembles a shock-syndrome with systemic vascular permeability, hypotension, rhabdomyolysis, and death, and it has been shown to occur with PS administered both i.v. and i.p (31) . However, we have observed that with the use of conjugated PS, this systemic toxicity is much reduced or eliminated (32) . To confirm this observation in the present study, an increasing series of fluences was interstitially delivered 3 h after i.v. injection of the anionic PIC in non-tumor-bearing mice. Even at the highest fluences (200 and 150 J delivered at 450 mW), the mice, although showing some temporary lethargy, recovered well after 12 h, and after 24 h, were indistinguishable from untreated mice. Histological slides taken 4 days after treatment showed well-confined focal areas of severe liver damage.
The short-term tumor response studies showed that the significant reduction in hepatic tumor found after PIT (18% of controls) was paralleled by a significant increase in the mean weight of normal liver. The percentage of total liver replaced by tumor was only 11% compared to 44% for controls. Histological slides showed focal areas of tissue damage, which were slightly more diffuse than those seen after 4 days in the normal livers of the phototoxicology mice. The destruction was more pronounced in areas of tumor, but areas of normal liver also suffered damage. Treatment with free ce6 proved much less effective in reducing tumor, leading to a reduction in mean tumor weight to 43% of controls and a reduction in the percentage of liver replaced by tumor to 26% (neither statistically significant). These data are in agreement with the values for the amount of ce6 delivered per gram of tumor in the biodistribution study.6 There it was reported that at 3 h after injection, the 17.1A-pl-ce6-succ PIC delivered more than three times as much ce6 to the tumor as the same injected dose of free ce6. However, the amounts of ce6 delivered to normal liver (although a fraction of those delivered to the tumor) were also several times higher for the PIC than for free ce6.
The increase in survival (control 62 days compared to PIT 102 days) might at first seem disappointing, but considering that the HT29 tumor is fast growing in nude mice with a doubling time of the order of 2–3 days, the increase in survival of 39 days represents many tumor doublings. The second survival experiment studied PIT with light delivered at two widely differing fluence rates, i.e., 30 and 300 mW. The results show that delivering the same low light dose at the higher power gave a significant increase in survival compared to the lower power and that both gave a significant increase in survival over controls. This finding of increased PIT efficacy at a higher fluence rate in vivo contrasts with many reports in the literature that show that low fluence rates tend to give higher PDT efficacy. The explanation usually proposed for these findings (4) is that PDT in vivo may consume most of the oxygen in the tissue, and in addition, lead to rapid onset of vascular shutdown that reduces the reoxygenation of the tissue by the blood flow. This oxygen depletion then sharply reduces the amount of reactive oxygen species generated and consequently reduces the efficacy of the treatment (33 , 34) . In the present case, an alternative explanation for the finding that higher power led to a significant increase in the efficacy of the treatment must be sought. Such an explanation might lie in the fact that the light delivery in the present study was by interstitial fiber into the liver, which is a particularly high-absorbing tissue (6) . It may well be that this energy deposition led to a rise in temperature of a few degrees Celsius, which could cause sufficient hyperthermia to potentiate PDT, without causing any tissue damage when PS was not present. When the low fluence was used, the tissue cooling produced by the circulating blood may have been sufficient to remove any heat generated. This hypothesis could be tested in future work by measurement of the tissue temperatures by interstitial probes. There have been many reports in the literature of PDT being potentiated by mild hyperthermia (35 , 36) . The combination works best when the hyperthermia is administered after or during the PDT rather than before (37) , and in some studies, the combination showed synergism (38) . A report by Leunig et al. (39) compared Photofrin PDT of a hamster melanoma at 100 or 200 mW/cm2 and found that the higher fluence that also raised the tissue temperature to 43°C produced a greater tumor response.
At necropsy, the weights of hepatic tumor, normal liver, and extrahepatic tumor were measured. Correlation plots were constructed using all of the mice from the long-term survival experiments to try to establish precisely what relationship the survival time had with weights of liver tumor, normal liver tissue, percentage of liver replaced with tumor, or total tumor burden. The correlation of survival with the amount of normal liver tissue (r = 0.645) was clearly the best and showed better correlation than that with the amount of liver tumor (r = 0.249) and with the percentage of liver replaced by tumor (r = 0.544). The correlation plot with total tumor burden (r = 0.422) actually showed a weak inverse correlation, i.e., the longer the mice lived, the more extrahepatic tumor they accumulated. The implication is that extrahepatic tumor is relatively harmless, and even hepatic tumor is probably not the main cause of mortality. If there is a correlation between the amount of normal liver tissue and survival, then too much PIT/PDT-mediated destruction in the liver may not only have destroyed the tumor, but also enough normal liver tissue to shorten life. Conversely, control mice with growing hepatic tumors have their normal liver rapidly replaced by tumor, which also reduces the amount of normal liver. The treated mice that died early with only small liver tumors may have had systemic disease from liver destruction. These conclusions reinforce the need for selectivity between normal liver and tumor.
Previous studies have been carried out to investigate the possibility of using PDT on animal models of hepatic metastasis. Nishiwaki et al. (40) used intra-arterial Lipiodol contrast medium to transport pheophorbide a to VX-2 liver tumors in rabbits, and surface illumination of 200 J/cm2 at a power density of 100 mW/cm2. The surface temperature increased by 2.5°C, and they found selective necrosis of tumors with only slight damage to normal liver. Van Hillegersberg (1) used Photofrin (5 mg/kg) and interstitial light (100–1600 J/cm delivered at 200 mW/cm from a diffusing tip) to treat rats with a syngeneic colon cancer implanted in the liver. The best results were seen at 800 J/cm where 60% of the animals were cured. Svanberg et al. (41) used i.v. 5-aminolevulanic acid (a precursor of protoporphyrin IX) to sensitize liver tumors in a similar rat model. They delivered 100 J/cm2 surface illumination at 110 mW/cm2 that produced no temperature rise and found a significant reduction in tumor growth rate.
In conclusion, we have demonstrated that a PIC derived from a Mab recognizing a colorectal cancer-associated antigen and bearing a polyanionic charge can efficiently target PS to a model of metastatic cancer in the liver after i.v. injection. PIT shows promise as a local therapy for colorectal cancer metastasis in the liver, but the exact parameters of conjugate, light dose, and delivery need to be optimized. It is possible that administration of the PIC via the hepatic artery could significantly improve the tumor selectivity compared with that found with i.v. administration.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NIH (Grant R01 AR40352) and the
Department of Defense Medical Free Electron Laser Program (Grant
N 00014-94-1-0927). 
2 Present address: Department of Chirurgia III,
Ospedale Policlinico S. Orsola, Via Massarenti 9, Bologna 40100
Italy.
3 Present address: Department of Obstetrics &
Gynecology, and Olson Center for Women’s Health, University of
Nebraska Medical Center, Omaha, NE 68198-3255.
4 To whom requests for reprints should be
addressed, at WEL 224, Massachusetts General Hospital, 55 Fruit Street,
Boston, MA 02114. Phone: (617) 726-6996; Fax: (617) 726-3192; E-mail
hasan@helix.mgh.harvard.edu.
5 The abbreviations used are: PDT, photodynamic
therapy; 17.1A-pl-ce6-succ, conjugate between
17.1A monoclonal antibody and succinylated polylysine chlorin
e6; ce6,
chlorine6; Mab, monoclonal antibody; PIC,
photoimmunoconjugate; PIT, photoimmunotherapy; PS, photosensitizer.
6 M. R. Hamblin, M. Del Governatore, and T.
Hasan. Biodistribution of charged 17.1A photoimmunoconjugates in a
mouse model of hepatic metastasis of colorectal cancer, submitted for
publication, 1999.
Received 12/21/99. Accepted 5/30/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-aminolaevulinic acid-induced protoporphyrin IX sensitisation in experimental hepatic tumours in rats. Br. J. Cancer, 74: 1526-1533, 1996.[Medline]
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