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Experimental Therapeutics |
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada [J. K. J., H. M. B.]; Cancer Endocrinology, British Columbia Cancer Agency, Prostate Cancer Research Group, Jack Bell Research Centre, Vancouver, British Columbia, V6M 3Z6 Canada [M. E. G., V. Y., E. B.]; and Angiotech Pharmaceuticals, Inc., University of British Columbia, Vancouver, British Columbia, V6T 1Z4 Canada [W. L. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-caprolactone (PLC) with
poly(ethyleneglycol) [PEG; PLC-PEG-PLC] blended with
methoxypoly(ethylene glycol) in a 40:60 ratio. Human prostate LNCaP
tumors grown s.c. in castrated athymic male mice were injected with 100
µl of this paste at room temperature. Changes in tumor progression
were assessed using both serum prostate-specific antigen (PSA) levels
and tumor size. Paclitaxel inhibited LNCaP cell growth in
vitro in a concentration-dependent fashion with an
IC50 of 1 nM. Apoptosis was documented using
DNA fragmentation analysis. The paste formulation solidified over a
period of 1 h both in vivo and in aqueous media at
37°C as the methoxypoly(ethylene glycol) component partitioned out of
the insoluble PLC-PEG-PLC/paclitaxel matrix. The semisolid implant
released drug at a rate of about 100 µg/day in vitro.
In control mice treated with paste without paclitaxel, serum PSA
levels increased from 2–8 ng/ml (mean, 4.3 ± 2 ng/ml)
to 60–292 ng/ml (mean, 181 ± 88 ng/ml), and tumor
volume increased from 30 to 1000 mm3. In mice treated with
a single 100-µl injection 3 weeks after castration (early-phase
treatment group), tumors decreased in volume from a mean of
43 ± 19 mm3 to nonpalpable, and PSA levels
decreased from a mean of 22 ± 8 to 2 ± 1 ng/ml by 8 weeks after castration. In mice treated 5 weeks after
castration (androgen-independent tumors; late-phase treatment group),
tumors decreased in volume from a mean of 233 ± 136
mm3 to nonpalpable, and serum PSA decreased from
24 ± 8 to 9 ± 4 ng/ml. Observed side
effects of the treatment were limited to minor ulceration at the needle
injection site in paclitaxel-treated mice only. The controlled-release
formulation can be injected via 22-gauge needles and is effective in
inhibiting LNCaP tumor growth and PSA levels in mice bearing multiple
nonmetastatic tumors. Paclitaxel may be an effective therapy for
patients with localized tumors recurring after radiotherapy and for
some patients with localized tumors who are not candidates for radical
treatment. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The natural history of localized prostate cancer is variable but is generally one of slow local progression with later development of regional and distant metastasis. More than two-thirds of patients will suffer local or systemic progression, and more than half of patients with prostate cancer will die from their disease within 10 years (6) . Significant morbidity can result from local tumor progression, including bladder outlet and ureteral obstruction, pain, and bleeding. Although radical prostatectomy and radiation therapy are both effective forms of treatment, both have low but significant morbidity, and not all patients are suitable candidates. In addition, serum PSA measurements allow for the detection of biochemical and local recurrences after radiotherapy and identify men destined to experience disease recurrence, who may benefit from early and additional adjuvant therapy. Androgen withdrawal therapy remains the only efficacious treatment for advanced or recurrent prostate cancer. However, both surgical castration and LHRH agonist treatments are associated with significant short-term and long-term side effects. Unfortunately, LHRH agonist treatment is also expensive. Furthermore, over time, the tumor becomes hormone resistant. Therefore, patients with recurrent localized tumors after radiotherapy and some patients with localized tumors who are not candidates for aggressive therapy would benefit from additional well tolerated, minimally invasive, local treatment modalities.
The anatomical location of the prostate gland is amenable to direct local injection with agents capable of inducing apoptosis. Brachytherapy for localized prostate cancer is now performed by transperineal placement of radioactive seed implants under transrectal ultrasound guidance. It is conceivable that the prostate gland could also be infiltrated with chemotherapeutic agents using similar techniques. Paclitaxel has been described previously to have cytotoxic activity against a number of prostate cancer cell lines in vitro (7, 8, 9) . The nonmetastatic cell line JCA-1 established from primary human prostate sites was shown to be sensitive to paclitaxel with an IC50 value of 20 nM (9) . Similarly, the LNCaP cell line was shown to undergo apoptosis when subjected to paclitaxel concentrations in the low micromolar concentration range, although the IC50 was not measured in that study (8) . Paclitaxel has also been shown to have a potent inhibitory effect on angiogenesis (10 , 11) , a process that has been proposed as a target for the chemotherapeutic treatment of prostate cancer (12) . Unfortunately, the low water solubility of paclitaxel necessitates the use of ethanol/cremophor formulations for i.v. administration with significant toxicity including hypersensitivity reactions to the cremophor (13 , 14) .
An alternative approach to the administration of this drug for the
treatment of localized prostate tumors might be via a
controlled-release implant that could deliver pharmacologically
effective doses of paclitaxel to the tumor site. Such a site-directed
paclitaxel delivery system might avoid the systemic toxicities
associated with the repeated use of the cremophor/paclitaxel
formulation. In our laboratory, we have developed a variety of
biodegradable injectable polymeric paste formulations based on the low
melting point polymers poly(-caprolactone) and a triblock copolymer
of poly(D,L-lactide) and PEG (15
, 16)
. In this work, a biodegradable triblock copolymer of
a random PLC with PEG was used to form PLC-PEG-PLC. The injectable
polymer paste was formulated by blending PLC-PEG-PLC with MePEG in a
40:60 ratio.
We have previously described the use of the LNCaP tumor model as a valid model for the in vivo study of the effects of androgen ablation or chemotherapy in prostate cancer (17 , 18) . Serum PSA levels are directly proportional to tumor volume in noncastrated mice, and both androgens and tumor volume are important codeterminants of circulating PSA levels. Immediately after castration, serum PSA levels decrease rapidly by approximately 80% and increase up to 20-fold after androgen supplementation, without detectable castration-induced tumor cell death or concomitant changes in tumor volume. These changes in PSA production in vivo reflect changes in androgen-regulated PSA gene expression. Beginning approximately 4 weeks after castration, PSA production rises to precastration levels, and tumor volume increases in the absence of testicular androgens, reflecting the onset of androgen-independent regulation of the PSA gene and androgen-independent tumor growth (17 , 18) . The LNCaP prostate tumor model permits study of the efficacy of castration in combination with treatment with other apoptotic enhancers.
The objective of this study was to determine the effectiveness of intratumoral delivery of paclitaxel in an injectable, biodegradable polymeric paste formulation against s.c. grown LNCaP tumors in mice. This system does not directly model tumors localized in the prostate gland or tumors that have been previously exposed to radiation that might be treated with site-directed controlled-release anticancer formulations in humans. However, the model allows for the determination of the efficacy of the paste formulation against localized human prostate tumors. The formulation was used as early adjunct therapy to castration in androgen-dependent LNCaP tumors and as salvage therapy in recurrent androgen-independent tumors.
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MATERIALS AND METHODS |
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In Vitro Drug Release Studies.
Fifteen mg of the 10% drug-loaded paste were weighed into 20-ml glass
scintillation vials (Fisher Scientific). The vials were then warmed to
50°C on a 60 degree angle until the fluid paste collected at the base
of the vial, and then the vial was cooled quickly to 4°C so that the
paste solidified as a defined mass. Four ml of cold PBS (pH 7.4)
containing human serum albumin at 0.2% (Fraction 4; Boehringer
Mannheim, Mannheim, Germany.) were added to the vial, followed
by 4 ml of 1-octanol (Fisher Scientific). The vials were then capped
and placed in a 37°C oven. As paclitaxel was released from the paste
into the PBS, a concentration gradient-dependent diffusion of drug was
established to the 1-octanol phase, in which the paclitaxel is highly
soluble. Samples of the 1-octanol phase were removed, and the
paclitaxel concentration in the samples was determined
spectrophotometrically using absorbance at 232 nm. Samples were
analyzed every day for the first week and then analyzed at appropriate
time points afterward. The sample was then gently placed back in the
remaining 1-octanol in the vial. Paclitaxel concentrations in the
1-octanol were also determined on days 10, 20, 30, 40, 50, and 60 by
high-performance liquid chromatography methods. Briefly, 50 µl of the
1-octanol sample were diluted into 450 µl of methanol for analysis by
high-performance liquid chromatography (Waters 600 series) using a
mobile phase of 58% acetonitrile:37% water:5% methanol (flow
rate = 1 ml/min) with a 20-µl injection volume onto a
reverse-phase C18 column (Waters, Nova-Pak) and detection at 232 nm.
Animals and Cell Lines.
Male 6–8-week-old athymic nude mice (BALB/c strain) were purchased
from Charles River Laboratory (Montreal, Quebec, Canada). LNCaP cells
(passage number 40–48) were maintained in RPMI 1640 (Terry Fox
Laboratory, Vancouver, British Columbia, Canada) with 5% fetal bovine
serum (Life Technologies, Inc., Burlington, Ontario, Canada) as
described previously (17)
.
In Vitro Mitogenic Assays.
To measure the effect of paclitaxel on LNCaP cell growth in
vitro, we used a 96-well assay based on the uptake and elution of
crystal violet dye by the cells in each well (17)
. Three
thousand LNCaP cells were plated per well in 96-well plates (Falcon) in
RPMI 1640 with 5% fetal bovine serum, and the cell media were changed
to various concentrations of paclitaxel 24 h later. The medium was
changed every 2 days; 7–10 days later, the cells were fixed in 1%
glutaraldehyde (Sigma) and stained with 0.5% crystal violet (Sigma).
Plates were washed and air-dried, and the dye was eluted with 100 µl
of Sorensen’s solution (9 mg of trisodium citrate in 305 ml of
distilled water, 195 ml of 0.1 N hydrochloric
acid, and 500 ml of 90% ethanol). Absorbance of each well was measured
by a Titertek Multiskan TCC/340 (Flow Laboratories, McLean, VA) at 560
nm. Control experiments demonstrated that absorbance was directly
proportional to the number of cells in each well.
DNA Fragmentation Analysis.
DNA fragmentation was analyzed by agarose gel electrophoresis as
described previously (19)
. Briefly, fragmented genomic DNA
was extracted by incubation of cells in Tris extraction buffer [10
mM Tris-HCl (pH 7.4), 10 mM EDTA, and 0.5%
Triton X-100] at 4°C for 5 min. The cell suspension was centrifuged
for 10 min at 4°C. The resultant supernatant was incubated for 1 h at 37°C in the presence of proteinase K (400 µg/ml) before
extraction with phenol/chloroform. The fragmented DNA was precipitated
with salt and isopropyl alcohol and then analyzed by agarose gel
electrophoresis.
Inoculation of LNCaP Cells.
All animals were anesthetized with methoxyfluorane before injection of
LNCaP cells. To establish s.c. tumors, 2 x 106 LNCaP cells were suspended in 75 µl of RPMI
1640 plus 5% FBS and 75 µl of Matrigel (Collaborative Biomedical
Laboratories, Bedford, MA) and injected via 27-gauge needle into the
s.c. space of the flank region. Tumors were measured twice weekly using
calipers, and their volumes were calculated by the following formula:
length x width x height x 0.5236 (20)
.
Determination of Serum PSA Levels.
Blood samples were obtained by tail vein incision of mice at specified
times as described previously (17)
. Serum PSA levels were
determined by an enzymatic immunoassay kit with a lower limit of
sensitivity of 0.2 ng/ml (Abbott IMX, Montreal, Quebec, Canada)
according to the manufacturer’s protocol. Fifteen µl of mouse serum
were diluted with 135 µl of diluent to perform the assay; the lower
limit of sensitivity in this murine model was therefore 2 ng/ml.
Treatment Protocols.
When LNCaP tumor volume reached between 100–200
mm3
and serum PSA levels were approximately 10
ng/ml, mice were anesthetized using methoxyfluorane and castrated via
abdominal approach (18)
. The castration of all treatment
groups helped to avoid any possible paclitaxel-related fluctuations in
androgen-regulated serum PSA production. Mice were then randomly
divided into three groups: (a) a control group treated with
control paste; (b) an early-phase treatment group treated 3
weeks after castration, when serum PSA levels were still at nadir
levels; and (c) a late-phase treatment
(androgen-independent) group treated >6 weeks after castration, when
serum PSA had increased to levels above the precastration levels. Mice
in control and the early- and late-phase treatment groups were treated
with a single intratumoral injection of 100 µl of control paste or
10% paclitaxel-loaded paste (containing approximately 10 mg of drug).
Tumor volume and serum PSA levels were measured once weekly. Data
points for both sets of experiments were expressed as average tumor
volumes ± SEs of the mean based on at least five
determinations.
To determine the effects of systemic uptake of paclitaxel on tumor volume and serum PSA, a set of mice was treated by injection of the paste at a remote location away from the tumor. Five mice, each bearing one tumor, were castrated and treated with 100 µl of 10% paclitaxel-loaded paste by injection (i.e., using the same treatment protocol used for other mice). However, these mice were treated by injection at a site more than 1 cm from the tumor masses.
Apoptosis Immunolabeling.
Mice were treated under the early-phase treatment regimen with
paclitaxel paste or with control paste. After 3 days, the mice were
sacrificed, and the tumors were excised from the s.c. sites. The tumors
were fixed in 10% neutral buffered formalin and embedded in paraffin.
Fixed sections (5 µm) were cut from the specimens and stained for
apoptosis (Apoptag kit; Oncor, Gaithersburg, MD) using a methylene blue
counterstain. Apoptotic cells stain brown using this method.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Concentrations as low as 0.1 nM inhibited LNCaP
cell growth with an IC50 below 1
nM. Cell detachment began after 48 h and was
associated with DNA laddering on agarose gel electrophoresis,
consistent with apoptosis (Fig. 1
, inset).
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). After an initial burst of paclitaxel release over the first few days
(approximately 5% of the encapsulated drug was released), the release
rate decreased to 0.5% per day for the next 2 weeks. After 2 weeks,
the paste pellet began to disintegrate, and release rates increased to
approximately 1.2% of the drug released per day.
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Changes in LNCaP tumor growth and serum PSA levels between control and
early versus late phase paclitaxel paste-treated mice are
compared in Fig. 3
, A—C, respectively. Mean pretreatment PSA levels were
24.1 ± 7, 21.9 ± 7.6, and
24.4 ± 7.6 ng/ml for the control, early-phase
treatment, and late-phase treatment groups, respectively. After
castration, serum PSA decreased by 60–70% in all three groups and
reached nadir levels by 2 weeks after castration. In the control mice
(n = 7), serum PSA increased beginning at
3–4 weeks after castration, and by week 10, serum PSA levels had risen
to a mean of 180 ± 88 ng/ml (range, 60–292 ng/ml). In
contrast, serum PSA levels decreased in mice treated with a single
intratumoral injection of paclitaxel paste. In the early-phase
treatment group injected 3 weeks after castration
(n = 7), serum PSA levels decreased in all
mice from a mean preinjection level of 7.26 ± 3.8 ng/ml
at 3 weeks after castration to 1.83 ± 1.01 ng/ml by 7
weeks after castration (Fig. 3B
). By week 11, one mouse had
a slightly elevated level of 13 ng/ml, but all other serum PSA levels
remained below or near detectable levels (2.2 ± 0.25
ng/ml). In the late-phase treatment group (n = 5), serum PSA levels decreased from 24.4 ± 7.6
to 8.72 ± 3.7 ng/ml (Fig. 3C
). By week 5,
four mice had serum PSA levels that were higher than the precastration
levels, and these mice were treated with 10% paclitaxel-loaded paste.
The one remaining mouse was treated at week 8, when the serum PSA level
had risen to 52 ng/ml. After treatment, serum PSA levels decreased in
all mice to a mean of 4.6 ± 2.0 ng/ml by 4 weeks after
injection. It should be noted that the data in Fig. 3C
show
the mean values of all of the serum PSA values at each time point,
including the data from the mouse treated at week 8, although this
mouse was treated 2 weeks later than the other mice.
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. Mean pretreatment LNCaP tumor volumes were 57 ± 12,
68 ± 24, and 82 ± 40
mm3
for the control, early-phase treatment, and
late-phase treatment groups, respectively. After castration, a minimal
decrease in tumor volume was observed. In the control mice
(n = 7), tumor volume continued to increase
after injection to a mean of 398 ± 137
mm3
by week 8, as shown in Fig. 4A
.
These tumors grew rapidly to over 1000 mm3
.
Accurate LNCaP tumor volume measurements were difficult after paste
injection because of persisting paste in the tumor bed. In the
early-phase treatment group, in which animals were treated 3
weeks after castration (n = 7; Fig. 4B
), tumor decreased in volume from a preinjection mean of
43 ± 19 mm3
three weeks after
castration to nonpalpable by 7 weeks after castration. By week 11,
there was still no evidence of tumor growth. In the late-phase
treatment group (n = 5; Fig. 4C
),
tumor decreased in volume from 233 ± 136
mm3
to nonpalpable within 2 weeks of treatment
with paclitaxel paste. These tumors remained nonpalpable at week 16. On
exposure of the tissue area around the implants after this time (at the
time of sacrifice), there was no visible evidence of residual tumor
tissue. Although histological analysis of the tissue from this area
might be performed to confirm the full extinction of tumor growth, this
was not possible in these mice. There was no clear boundary between the
tissue and the implant; therefore, collection of all of the appropriate
tissue was not possible. The nonpalpability of the tumors some 11 weeks
after treatment may be considered strong evidence of the extinction of
the tumors. This is further supported by nondetectable serum PSA levels
at the later stages of the experiments.
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Mice were treated using the early-phase treatment regimen or with
control paste and sacrificed 3 days after exposure to the paste. The
s.c. areas were excised, fixed in formalin, and subjected to staining
with Apoptag for apoptosis measurement. Extensive apoptosis was
observed in the tumor tissue from the paclitaxel-treated animal, as
evidenced by brown staining against a blue counterstain (normal tumor
tissue) seen in Fig. 5
. Tissue taken from the tumor treated with control paste was only
stained blue, demonstrating that no apoptosis was occurring in these
tissues. These data are not shown because nonapoptotic cells may be
seen in the tissue taken from paclitaxel-treated tumors (Fig. 5
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Despite several hundred clinical studies of both experimental and approved single agents, systemic chemotherapy has limited antitumor activity in hormone-refractory prostate cancer (24) . The poor response to systemic chemotherapy is seen in part because patients are generally old with poor performance status, which compromises their chemotherapeutic schedules. Estramustine and vinblastine, which inhibit microtubule function, have shown some efficacy against prostate cancer both in vitro (7 , 9 , 24) and in vivo (25, 26, 27) . Paclitaxel, an anticancer agent isolated from the bark of Taxus brevifolia, has a broad range of antineoplastic activity and a unique mechanism of action involving stabilization of microtubules and angiogenesis inhibition (28 , 29) . Paclitaxel has shown efficacy against advanced breast, ovarian, and non-small cell lung cancer (25) . Recently, paclitaxel has been reported to inhibit human prostate cancer cell growth in vitro (7, 8, 9) . In this study, we have shown that paclitaxel induced apoptosis in the human prostate cancer cell line LNCaP with an IC50 of about 0.1 nM, confirming a previous report that described susceptibility of this cell line to paclitaxel at 10 µM (8) . The reduced tolerance to systemic chemotherapy in elderly patients may be circumvented by developing methods to deliver high and sustained concentrations of cytotoxic agents within the local tumor environment.
Walter et al. (30) described the effectiveness of a paclitaxel-loaded polymeric implant placed besides brain tumors or within tumor resection sites in rats after invasive surgery. We have previously described the effective use of biocompatible, biodegradable polymeric pastes for the site-directed delivery of antineoplastic agents such as paclitaxel (15) or bis(maltolato)oxovanadium (31) . These surgical pastes were originally designed as an adjunct to tumor resection therapy whereby a residual slow-release formulation of the drug would be applied to the resection site to prevent tumor regrowth. Such pastes were composed of PCL blended with MePEG and applied as a viscous molten paste at 56°C setting to a solid drug-polymer implant at body temperature. Pilot studies using this paclitaxel-loaded polycaprolactone paste applied intratumorally in the s.c. LNCaP tumor in mice were successful in reducing both serum PSA levels and tumor volume.4 However, the paste was very difficult to inject because of the viscosity of the polymer, and some large tumors failed to respond fully to the drug implant, probably due to the very slow release of the formulation (15) .
The polymeric paste formulation used in this study is a viscous liquid
or paste at room temperature that may be injected through a small-gauge
needle and that solidifies within 1 h in vivo. This
forms a controlled-release implant that releases the drug locally at
the site of action. In vitro studies showed that the
formulation released paclitaxel at a rate of approximately 1% of the
total encapsulated drug per day (Fig. 2
). This novel polymeric
injection vehicle takes advantage of the hydrophobic nature of
paclitaxel, which facilitates dissolution of the drug in the
hydrophobic PLC-PEG-PLC/MePEG blend. On injection into an aqueous
compartment, the MePEG partitions out of the blend, and the residual
PLC-PEG-PLC/paclitaxel components solidify. This solidification arises
from two factors, the increasing melting point of the blend (due to the
decreasing concentration of the low melting point MePEG component) and
the partial precipitation of the paclitaxel in the blend as the
concentration of the drug increases. The high affinity of the drug for
the hydrophobic matrix and the low solubility of the drug in the
aqueous tissue compartment lead to the controlled release of the drug
from the semisolid implant. In in vitro studies in aqueous
buffer, 10% paclitaxel-loaded paste showed evidence of mass loss and
of diminished structural integrity after 2 weeks. The paste completely
degraded in 3–4 months. After s.c. injection/implantation in tumors,
there was evidence of residual paste at week 8 in both the early- and
late-phase treatment groups, indicating that degradation was
incomplete in vivo at that time.
These studies were designed to assess the efficacy of an injectable slow-release depot formulation of paclitaxel against human tumors grown in mice. This system does not directly model the clinical situation for human prostate cancer patients because the tumor is not growing in the prostate gland, and the tumor has not been subjected to radiation therapy. However, this animal model may reflect a potential treatment method for patients with recurrent prostate cancer, using androgen ablation with an adjuvant cytotoxic agent. Serum PSA levels in this s.c. LNCaP model have been shown to be directly related to tumor volume (17) and therefore provide an additional surrogate marker to monitor tumor progression and treatment efficacy. Serum PSA levels and tumor volume in the early- and late (androgen-independent)-treatment groups decreased after paclitaxel paste injection but continued to increase in control mice. The therapeutic efficacy of paclitaxel paste resulted from the induction of apoptosis in the LNCaP tumors, which was documented both in vitro and in vivo. Although paclitaxel has been previously reported to inhibit endothelial cell growth and to have antiangiogenic effects (10 , 11) , the apoptotic effects of paclitaxel on LNCaP tumor cells probably represent the major inhibitory effect of the drug on tumor growth described in this study. Future studies may investigate the effect of paclitaxel on tumor-associated angiogenesis in mice. Local ulceration was present in some mice, probably due to irritation and scratching of the skin followed by paclitaxel inhibition of wound healing, as has been reported previously for this drug (32 , 33) .
In summary, we have provided preclinical efficacy data and proof of principle for a site-directed, injectable, controlled-release formulation of paclitaxel as an effective treatment for localized prostate tumors. The paste formulation released paclitaxel into local tumor tissues and induced apoptotic regression of androgen-independent LNCaP prostate tumors. Although the study was performed in mice, we believe that the paclitaxel paste may offer a potentially effective therapy for patients with localized tumors recurring after radiotherapy and for some patients with localized tumors who are not candidates for radical treatment. Future studies may investigate combination therapy of the paste with radiation in LNCaP tumors grown in mice and issues of toxicology.
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FOOTNOTES |
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1 Supported by Angiotech Pharmaceuticals Inc.
(Vancouver, British Columbia, Canada). 
2 To whom requests for reprints should be
addressed, at Division of Pharmaceutics and Biopharmaceutics, Faculty
of Pharmaceutical Sciences, 2146 East Mall, University of British
Columbia, Vancouver, British Columbia, V6T 1Z3 Canada. Phone:
(604) 822-2440.
3 The abbreviations used are: PSA,
prostate-specific antigen; PEG, poly(ethylene glycol); MePEG,
methoxypoly(ethylene glycol); PLC, copolymer of
D,L-lactide and -caprolactone.
4 J. K. Jackson and H. M. Burt, unpublished
observations.
Received 5/ 4/99. Accepted 6/ 1/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-caprolactone) pastes: effect of water soluble additives. J. Controlled Release, 44: 87-94, 1997.
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