(Investigative Ophthalmology and Visual Science. 1999;40:2561-2567.)
© 1999
by The Association for Research in Vision and Ophthalmology, Inc.
Direct Injection of Liposome-Encapsulated Doxorubicin Optimizes Chemomyectomy in Rabbit Eyelid
Linda K. McLoon1,2 and
Jonathan D. Wirtschafter1,3,4
From the Departments of
1 Ophthalmology,
2 Neuroscience,
3 Neurology, and
4 Neurosurgery, University of Minnesota, Minneapolis.
 |
Abstract
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PURPOSE. Doxorubicin chemomyectomy presently represents the only permanent,
nonsurgical treatment for blepharospasm and hemifacial spasm. The major
deterrent to an otherwise extremely effective treatment protocol is the
development in patients of localized inflammation, discomfort, and skin
injury over the injection site. As a potential alternative therapy,
Doxil (Sequus, Menlo Park, CA), a liposome-encapsulated form of
doxorubicin that displays tissue-selective therapeutic effects compared
with free doxorubicin, was examined. These effects have been related to
its increased retention in tissues and its sustained release over time.
For the skin, Doxil is classified as an irritant rather than a
vesicant.
METHODS. Rabbits received direct injections of 1, 2, or 3 mg Doxil alone or in
sequence with other agents directly into the lower eyelids. The treated
eyelids were examined daily for signs of skin injury. One month after
the last injection, the rabbits were euthanatized, and their eyelids
were examined histologically for the effect of Doxil on the orbicularis
oculi muscle and the skin.
RESULTS. At equivalent milligram doses of free doxorubicin, Doxil spared the
skin from injury. Doxil was only approximately 60% as effective in
killing muscles as the same milligram dose of free doxorubicin.
However, either two injections of Doxil spaced 2 months apart or
preinjury of the lid with bupivacaine before a single dose of Doxil
treatment resulted in increased muscle loss compared with a single dose
of Doxil alone and was as effective as free doxorubicin. Higher doses
of Doxil did not increase the desired myotoxic effect; apparently, the
dose effect levels off at a maximum. Signs of skin injury were minimal;
there were small or no adverse skin changes at the maximum effective
myotoxic doses.
CONCLUSIONS. Injection of Doxil resulted in significant reduction of skin injury
compared with doxorubicin alone. Although single injections of Doxil
were myotoxic, multiple exposure of the eyelid to the
liposome-encapsulated form substantially improved myotoxicity while
sparing the skin. Repeated doses of the liposome-encapsulated form of
doxorubicin may be as clinically effective as free doxorubicin
injections and may produce fewer unwanted side
effects.
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Introduction
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Blepharospasm and hemifacial spasm are muscle spasm diseases that
are characterized by forceful, involuntary contractions of the muscles
of the eyelids and surrounding face. They result in functional
blindness in affected patients, and although not life threatening are
seriously debilitating. Blepharospasm has a prevalence of 1:25,000, and
hemifacial spasm has a prevalence of between 7.4 (male) and 14.5
(female) per 100,000.1
A number of treatment options are
available for patients with blepharospasm, hemifacial spasm, and other
focal dystonic disorders. Repeated injections of botulinum A toxin and
surgical removal of the spastic muscles are the most commonly used
treatments. The former is a temporary treatment, but the latter may
yield permanent relief or partial amelioration of the muscle spasms.
Long-term studies have shown that direct injection of doxorubicin into
the eyelid of patients with blepharospasm and hemifacial spasm was an
effective treatment for such patients, providing permanent or long-term
amelioration of symptoms, best evidenced by the lack of patient
requests for short-term rescue therapy with botulinum
toxin.2
3
When biopsy samples of eyelid tissue from a
patient 2 years after the last doxorubicin injection were examined,
there were either small foci of muscle tissue or no myofibers at all in
the histologic sections from the treated eyelids.4
Doxorubicin chemomyectomy remains the only permanent, nonsurgical
treatment for these patients. As with any medical treatment, there are
side effects that are caused by these injections.2
3
5
Although a few patients were treated successfully with a single dose of
doxorubicin, most patients required up to three separate injection
series in each eyelid for complete localized abatement of the muscle
spasms. Each successive exposure to doxorubicin increases the risk of
skin injury. The major patient deterrent to the use of local
doxorubicin injections into the eyelid for treatment of these muscle
spasm diseases is the possible development of local skin inflammation,
ulcers, contracted scars, and hyperpigmentation. Of course, localized
soreness and skin changes also occur after surgical removal of muscle
from the eyelid (orbicularis myectomy), and these changes require
secondary surgical touch-ups in some patients. Moreover, some areas of
symptomatic periocular facial muscles are not as easily removed with
myectomy surgery—particularly, the orbital portions of the orbicularis
oculi muscles underlying the eyebrows, the eyelid depressors,
corrigators, and procerus muscles.
We have investigated the ability of a variety of anti-inflammatory
mediators, such as cyclosporin6
and corticotropin
releasing factor,7
8
to decrease the localized
inflammation after doxorubicin treatment. These are effective in
reducing either edema6
or localized inflammatory cell
infiltration7
8
and in reducing the incidence of skin
injury. Although these treatments represent improvements to the free
doxorubicin chemomyectomy protocol, we wanted to examine other forms of
doxorubicin as they became available. One potential approach to
improving doxorubicin chemomyectomy would be to administer doxorubicin
in a liposome-encapsulated form. This method of administration has
improved treatment effectiveness in certain cohorts of cancer patients
by increasing tissue retention while substantially reducing systemic
side effects.9
Systemic administration of
liposome-encapsulated doxorubicin in specific groups of cancer patients
reduced short-term side effects, such as nausea, vomiting, and
alopecia, while maintaining therapeutic effectiveness.10
Liposome encapsulation of doxorubicin significantly reduced
cardiomyopathy and other long-term side effects of systemic application
as well11
and thus may represent a safer alternative than
free doxorubicin to patients. Liposome-encapsulated doxorubicin was
reported to have few side effects at sites of infiltration of
intravenous solutions compared with free doxorubicin.12
13
In fact, regarding its effect on human skin, Doxil (Sequus, Menlo Park,
CA), a liposome-encapsulated form of doxorubicin, is classified as an
irritant, whereas free doxorubicin is a vesicant. One hypothesis for
the increased therapeutic effectiveness of liposome-encapsulated
doxorubicin compared with free doxorubicin is prolonged exposure of the
tumor to the liposomal doxorubicin because of its local accumulation
and slow release at the tumor site.14
15
16
Doxil was injected directly into the eyelids of rabbits to determine
its chemomyectomy effect after local application. Rabbits were
monitored daily for changes in the skin over the injection site. One
month after the last treatment, the eyelids were assessed for muscle
loss induced by the Doxil treatment and for any changes in the
overlaying skin.
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Materials and Methods
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The New Zealand White rabbits used for this study were obtained
from Birchwood Valley Farms (Redwing, MN) and housed in the Research
Animal Resources facility at the University of Minnesota. All research
conformed to the guidelines published by the National Institutes of
Health and the ARVO Statement for the Use of Animals in Ophthalmic and
Vision Research.
The rabbits were anesthetized with an intramuscular injection of
ketamine-xylazine, 1:1, (10 mg/kg and 2 mg/kg, respectively).
Proparicaine drops were placed in the conjunctival cul-de-sac before
eyelid injection. Doxil, liposome-encapsulated doxorubicin, was
injected into the lower eyelids. Care was taken to ensure that the
injection extended from the medial to the lateral extent of the eyelid.
The red coloration of the Doxil solution allows visual confirmation of
the injection site. The Doxil was injected in the following doses: 0.5,
1, or 2 mg in 1 ml sterile isotonic saline or 3 mg in 1.5 ml. A second
set of animals received two injections of 1, 2, or 3 mg Doxil,
administered 1 month apart. A third set of rabbits received two sets of
injections into both lower eyelids of 150 U hyaluronidase (Wydase;
Wyeth Ayerst, Philadelphia, PA) in 1 ml 0.75% bupivacaine HCl in
isotonic saline with 1:200,000 epinephrine (Sensorcaine; Astra
Pharmaceutical Products, Westborough, MA) spaced 18 hours
apart.17
Previous studies have shown that the peak of
satellite cell activation in the orbicularis oculi muscle occurs 2 days
after a local anesthetic injury to the eyelid,18
and that
injection of doxorubicin 2 days after injury significantly increases
muscle loss.19
The two doses of local anesthetic treatment
were followed 2 days later with an injection of either 1 or 2 mg Doxil.
Animals were examined daily for skin injury. At least four eyelids were
examined for each dose of Doxil and for each distinct set of treatment
parameters. Doxil data were compared with doxorubicin-only data
prepared with the identical injection and analysis
procedures.6
7
Additional control eyelids were prepared by
injection of saline only.
One month after the final injections, the animals were euthanatized
with an overdose of barbiturate anesthesia. Samples were removed from
the lateral, middle, and medial portions of the treated and control
lids and frozen in 2-methylbutane chilled to a slurry on liquid
nitrogen. Cross-sections were cut at 12 µm, and the tissue sections
were stained by myosin adenosine triphosphatase (ATPase) histochemistry
to detect type 1 and type 2 muscle fibers. Additionally, eyelid
cross-sections were stained with hematoxylin and eosin so that the skin
epithelium nuclei could be examined for precancerous cellular atypia.
Muscle fiber number and cross-sectional areas were determined by
computer-assisted morphometric analysis using commercial software
(Bioquant; R & M Biometrics, Nashville, TN).20
Results
were compared with control data from doxorubicin-only injections
administered in the same manner.6
7
All injection and
analysis methods were unchanged from the original free doxorubicin
studies, and all injections were administered by the principal
investigator. Statistical significance was determined using an
unpaired, two-tailed t-test using statistical analysis software
(Prism and Statmate; Graphpad, San Diego, CA), with significance at
P < 0.005. An F-test indicated that the variances of
the control and experimental groups were not significantly different.
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Results
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Safety
Injection of free doxorubicin alone resulted in localized
inflammation characterized by edema, erythema, and the development of a
skin ulcer followed by scab formation in 100% of treated
rabbits.6
7
None of the eyelids that received injections
of 0.5 or 1 mg Doxil into their lower eyelids showed any sign of skin
surface breakdown (Fig. 1)
. At a dose of 2 mg Doxil, only two of eight eyelids injected showed a
small scab. One appeared on day 8 and was present for 3 days, and one
appeared on day 14 and was no longer visible the next day. Neither of
these scabs was preceded by a recognizable blister or ulcer. The
additional 6 eyelids showed no signs of skin injury. These results were
in marked contrast to the extent and duration of eyelid ulcers and skin
crusting after free doxorubicin injections of 2 mg, a higher dose than
the recommended therapeutic dose in patients. After free doxorubicin
injections of 2 mg, skin ulcers and scabs were large and routinely
lasted up to 1 month.6
7
At a dose of 3 mg Doxil, a dose
too toxic to the skin to administer as free doxorubicin, one of the
five treated eyelids showed, for only 1 day, a small scab between 2 and
3 mm in diameter. When two sets of injections of Doxil were
administered 1 month apart, there was no increase in the likelihood of
development of injury of the eyelid skin compared with the single doses
of Doxil. Moreover, the eyelids on which scabs developed the first time
did not have a scab after the second injection. There was some edema in
the treated lids, and as has been seen with local free doxorubicin
injections in the eyelid, eyelid hair loss but not eyelash loss was
seen after the higher doses of Doxil. The remainder of the eyelid
anatomy appeared normal, including the skin, nerves, and tarsal glands
(Figs. 2 and 3)
. Histologic examination of the eyelid skin epithelium showed no signs
of atypia, often a prelude to carcinogenesis.
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Figure 1. Onset and duration of detectable skin injury in all treated eyelids
after Doxil (Sequus, Menlo Park, CA) injections; 2x, two injection
sessions spaced 1 month apart tabulated after the second injection;
preinj, injection of bupivacaine 2 days before injection with Doxil.
*At this dose, no skin injury developed on eyelids; # the results after
the second injection only; + all first injections at this dose.
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Figure 2. The skin (A) and nerves (B) within the treated
eyelids showed normal morphology 1 month after 2 mg Doxil (Sequus,
Menlo Park, CA) treatment. Arrowheads indicate basal
lamina of the skin. Arrows indicate nerves in
longitudinal section. Bar, 100 µm.
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Figure 3. Orbicularis oculi muscle in the untreated (A) and Doxil
(Sequus, Menlo Park, CA)-injected (B) eyelid cross-sections.
Doxil injections caused a significant loss of myofibers
(arrows) in the treated orbicularis oculi muscle. No
pathologic changes were seen in the other eyelid structures, including
the skin and tarsal glands. Bar, 50 µm.
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None of the treated eyelids showed scabs after bupivacaine preinjury of
the orbicularis oculi muscle 2 days before Doxil injection, a method
previously demonstrated to improve substantially the myotoxicity of
free doxorubicin.19
Effectiveness
Single injections of Doxil were approximately 60% as myotoxic to
the myofibers of the orbicularis oculi compared with single injections
of the same dose of doxorubicin (Figs. 3
and 4)
. Whereas single free doxorubicin injections demonstrated a
dose-dependent myotoxicity, single Doxil injections resulted in the
same myotoxic effect at 0.5-, 1-, and 2-mg injection doses. Only at the
3-mg Doxil injection dose was there a slight increase in myotoxicity
compared with the other doses, but the increase was not significant.
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Figure 4. Muscle loss in orbicularis oculi after a single injection of
doxorubicin or Doxil (Sequus, Menlo Park, CA). Chemomyectomy effects of
single injections of Doxil are compared with those of free
doxorubicin6
7
injections based on muscle fiber counts.
Single injections of 1 or 2 mg Doxil were significantly less myotoxic
than equivalent doses of free doxorubicin (**). *This injection dose
was not used.
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Increased myotoxicity was seen when 1 or 2 mg Doxil was administered at
two separate times spaced 1 month apart compared with single injections
(Fig. 5)
. At both 1 and 2 mg Doxil these differences were statistically
significant. Preinjury of the orbicularis oculi with bupivacaine 2 days
before Doxil treatment significantly improved muscle loss over single
injections of Doxil
alone. Injection of 1 mg free doxorubicin alone resulted in loss of
approximately 74% of the myofibers and 2 mg free doxorubicin alone
resulted in loss of approximately 87% of the myofibers.
Single-injection comparable doses of Doxil resulted in loss of
approximately 60% of the treated myofibers. Treatment with either
preinjury with bupivacaine before a single Doxil injection or two
injections of Doxil spaced 1 month apart both resulted in loss of
approximately 74% of the treated myofibers, essentially the same
result as was obtained with 1 mg doxorubicin alone, except that the
skin was spared from injury.
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Figure 5. Chemomyectomy effects at 1- and 2-mg injections of free doxorubicin
(dxn)6
7
; 1, 2, or 3 mg Doxil (Sequus, Menlo Park, CA);
eyelids preinjured with bupivacaine (Doxil/preinj); and two sequential
injections of Doxil (Doxil/2x) compared with control. *Statistically
significant difference when compared with single injection of
liposome-encapsulated doxorubicin; **statistically significant
difference from all other treatment parameters; dxn, doxorubicin; 2x,
two injection sessions spaced 1 month apart; preinj, injection of
bupivacaine 2 days before injection with Doxil.
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Discussion
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Overall, Doxil, a liposome-encapsulated form of doxorubicin, when
injected directly into the rabbit eyelid, substantially increased the
dermatologic safety of chemomyectomy without much sacrifice in the
efficacy of muscle loss from each injection session compared with a
1-mg dose of doxorubicin alone. Moreover, Doxil treatment at the
maximum effective dose resulted in little or no skin injury. Although
the myotoxicity of Doxil was improved by either serial injections of
Doxil or by pretreatment of the eyelid with bupivacaine 2 days before
Doxil injection, chemomyectomy was never as complete as that seen with
doxorubicin alone.
The liposome-encapsulated doxorubicin formulation substantially alters
the toxic and therapeutic profile of doxorubicin. Liposome
encapsulation lessens the toxicity of doxorubicin, reducing
cardiomyotoxicity, which is the major dose-limiting consideration in
the use of free doxorubicin as a first-line cancer chemotherapeutic
agent.21
Liposome encapsulation also reduces the
acute adverse effects seen with free doxorubicin that lead to
ulceration and scarring at sites of inadvertent extravasation at
percutaneous intravenous sites. In fact, this has led to the
administration of doxorubicin by central venous catheter, whereas Doxil
is routinely administered by percutaneous injection. Doxil does not
possess the vesicant properties of doxorubicin and has been
demonstrated to be safer for the skin.22
Skin Toxicity
Local injection of free doxorubicin produces acute skin
toxicity3
4
that is substantially reduced when an equal
dose is injected in a liposome-encapsulated form. This study examined
both the acute inflammatory injury and the possibility of cellular
atypia after direct local injections of Doxil into rabbit eyelid.
Although milligram-equivalent doses of liposome-encapsulated
doxorubicin were less myotoxic than free doxorubicin alone, the sparing
of the skin over the injection site represents a major advantage to the
use of liposome-encapsulated doxorubicin for localized injection. After
free doxorubicin injections at doses of 1 or 2 mg in rabbits, all
eyelids showed skin injury, and the scabs that developed remained for
up to 1 month.6
7
Because of the development of injury to
the skin, in the clinical protocol the threshold toxic dose of
doxorubicin is 1.5 mg per eyelid per injection session.3
At milligram-equivalent doses of Doxil, no skin injury developed in the
treated rabbits. Even at twice the clinical toxic dose of free
doxorubicin of 3 mg or after serial injections, if scabs developed,
they were small and disappeared within 2 to 3 days. It is noteworthy
that the second of two injections of Doxil were not associated with
skin injury, even if skin injury occurred after the first injection.
This protective effect is in direct contrast to the effects of multiple
exposure of the eyelid skin to free doxorubicin, in which each
subsequent exposure increased the risk of skin
injury.2
3
5
The relative absence of injury to rabbit eyelid skin in the present
application is interesting, because the dose-limiting toxicity for high
systemic doses of liposome-encapsulated doxorubicin is cutaneous
erythema and hyperemia.21
23
When Doxil is administered
intravenously in humans, the drug is selectively extravasated into the
tumor tissues and into the palms of the hands and the soles of the feet
where it can cause an erythematous reaction and scaling. We did not
observe these changes in the rabbits at any time after Doxil injection.
Although a long-term assessment of Doxil is beyond the scope of this
study, it is important to note that there have been no published
reports of Doxil-induced skin cancer, even after high-dose systemic use
for cancer treatment. In the patients who received doxorubicin
chemomyectomy, many of whom have now had more than 10 years elapse
since treatment, no precancerous skin changes have been seen in the
regions over the injection sites. Furthermore, a number of studies have
been published indicating the efficacy of systemic injections of either
doxorubicin or Doxil specifically as an anticancer drug to shrink skin
cancer24
25
and other solid tumors.26
Doxil,
in its use as a systemic high-dose chemotherapeutic agent, has fewer
side effects than does free doxorubicin.21
Free
doxorubicin, although used primarily as a chemotherapeutic agent, may
have carcinogenic potential, and this potential is the basis for the
recommendations for the safe handling of doxorubicin and other
anthracyclines by health care personnel. In spite of perhaps thousands
of episodes of extravasation, we found only one report in the
literature of human skin cancer that occurred 10 years after an
untreated ulcer caused by extravasation of doxorubicin during
chemotherapy.27
There is evidence that encapsulation of
potential mutagens markedly diminishes and even abolishes their
genotoxic effects.28
We have now locally injected two patients affected by blepharospasm
with Doxil, three times each in the same eyelids. Both patients have
had no skin ulceration or blisters over the injection sites at any time
after the Doxil injections.
Chemomyectomy
Single local injections of Doxil into the eyelid were not as
myotoxic as the milligram-equivalent dose of free doxorubicin. The
maximal dose for a single injection of free doxorubicin for patients is
1.5 mg per eyelid per injection, which is insufficient for total relief
of muscle spasms in most patients.3
The patients have
usually required one or two additional injection sessions, for an
average cumulative dose of approximately 3 mg per eyelid for complete
abatement of muscle spasms. To minimize skin injury, botulinum toxin
injections are incorporated into the 2- to 3-month cycle, and the free
doxorubicin treatment is administered over the course of 6 to 9 months.
Serial injections of Doxil and preinjury followed sequentially by Doxil
treatment increased myotoxicity over single injections of Doxil alone,
and the skin was largely spared from injury. Thus, Doxil should be as
effective a chemomyectomy agent as free doxorubicin but with a reduced
incidence of the concomitant skin changes. It should be pointed out
that in this study, Doxil was administered locally within the eyelid,
not systemically into the blood stream, as it is when used for
chemotherapeutic purposes. Although we did not study empty liposomes as
a control, we note that a number of studies have demonstrated that
empty liposomes injected intramuscularly do not cause muscle tissue
damage.29
30
Mechanism of Action
The mechanism of cellular uptake of liposome-encapsulated drugs is
not known.16
Liposome-encapsulated doxorubicin is composed
of sterically stabilized liposomes, which improves stability and drug
retention.31
Liposomes slowly disintegrate, and this
increases the length of drug exposure at the site of liposome
accumulation. Subcutaneous administration of liposomes, in particular,
results in more sustained drug release, particularly for drugs such as
doxorubicin, which have a very short half-life as free
drug.32
Of note, by themselves empty liposomes of the same
composition as used in the present study do not induce myotoxicity when
directly injected into muscles.29
30
Liposomes themselves
are not taken up intracellularly by fusion with plasma
membranes.33
Recent studies also suggest that sterically
stabilized liposomes are not taken up by cells through
endocytosis.14
34
Their enhanced cytotoxic effects appear
to be caused by increased concentrations in the interstitial fluid at
the site of their accumulation and their ability to display sustained
release over time.16
29
Yet, at the same time, the
liposomal encapsulation protects the surrounding tissue from the type
of damage seen after injection of free doxorubicin.30
The
local injection protocol of Doxil reduces the potential for adverse
systemic side effects compared with systemic administration. The
potential movement of Doxil from the site of local administration into
the eyelid is currently under investigation.
The direct injection of Doxil could represent a major improvement to
the doxorubicin chemomyectomy protocol for the treatment of
blepharospasm and hemifacial spasm. Doxil treatment spared the skin
from the severe type of inflammation and development of scabs that may
occur after the injection of free doxorubicin directly into the eyelid.
Subsequent exposure of a previously treated eyelid did not increase the
risk of the eyelid to the development of skin injury. Although Doxil
was less myotoxic to the orbicularis oculi muscle than was free
doxorubicin, it still caused a significant loss of muscle compared with
that in the control eyelids. By preinjuring the eyelid muscle with
bupivacaine or treating the eyelid with more than one injection session
of Doxil, myotoxicity was the same as the results after lower doses of
free doxorubicin. The ability to maintain a high degree of muscle loss
while minimizing or preventing skin injury represents a major advantage
to the patients with these conditions. Sparing the eyelid skin from
inflammation and skin injury should improve patient acceptance of this
new treatment protocol.
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Footnotes
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Supported by Grant EY07935 from the National Institutes of Health, the
Minnesota Lions and Lionesses, the Frank Burch Chair in Ophthalmology
(JDW), and an unrestricted grant to the Department of Ophthalmology
from Research to Prevent Blindness.
Submitted for publication December 29, 1998; revised April 29, 1999; accepted June 21, 1999.
Commercial relationships policy: N.
Corresponding author: Linda K. McLoon, University of Minnesota, Room
374 Lions Research Building, 2001 6th Street SE, Minneapolis, MN
55455. E-mail: mcloo001{at}tc.umn.edu
|
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Abstract
Introduction
