Download An overview of second generation drugs for photodynamic

An overview of second generation drugs for photodynamic
therapy including BPD-MA (benzoporphyrin derivative)
E. Sternberg and D. Dolphin
Department of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, B.C., Canada V6T 1Z1
The treatment of neoplastic diseases in Western medicine has traditionally
included three modalities; radiation, chemotherapy, and surgery. Despite the years of
experience with these modalities and increased levels of success the increased survival
rates from cancer are due primarily to the benefits derived from the early detection and
treatment of the disease; however, the treatment of severe cancers have not significantly
improved. Cancer rates in the West are on the increase (the breast cancer rates have
almost doubled in the past 30 years).1 The need for new and improved therapies for
cancer is clear and this conference deals with the fourth modality for cancer therapy,
namely, photodynamic therapy (PDT). PDT involves the activation of a drug by visible
light and results in a modified surgical technique which operates at the molecularcellular level.
The interaction of drug and light can create a toxic environment to both the cells
and microvasculature of a tumor. Two cytotoxic photochemical mechanisms are known.
They are Type I and Type II photo reactions. Most drugs for PDT generate highly
reactive singlet oxygen which results from a Type II mechanism.
Quadra Logic Technologies (QLT) and Lederle Laboratories (American
Cyanamid Company (ACCO)) have been conducting clinical trials with PHOTOFRIN®
porfimer sodium for the past few years.2 On the basis of these trials submissions are
being made to regulatory bodies around the world for approval to market PHOTOFRIN®.
Indeed as we talk submissions are being made in Europe and Japan. PHOTOFRIN®
shows only one minor side effect, namely that of prolonged skin photosensitivity in
patients, which may last up to 4-6
weeks after treatment. In addition, the
complex chemical nature of
PHOTOFRIN® makes basic scientific
studies complicated. We have learnt
from our studies with PHOTOFRIN®
what properties a second generation
photoactivable drug should have.
Tne effective penetration of
light through tissue is limited by the
absorption of light by natural
chromophores (principally oxyhemoglobin) and by light scattering which
increases with decreasing wavelength.
As can be seen in Figure 1, the effective depth of penetration of light when
moving from 630 t o 690 nm essentially doubles.3 However in moving
from 690 to 800 nm the
additional depth of
penetration is only
another 10% and these
effects are dominated
by absorption of the
light. Figure 2 shows
the optical absorption
of oxyhemoglobin
PHOTOFRINr and the
second generation drug
BPD-MA which has
recently entered clinical trials under the joint
sponsorship of QLT
and ACCO. The optical properties of any
second generation drug
are an important consideration. It is clear
from Figure 2 that as
the light absorption of
Fig. 2: Absorption spectra of I. Oxyhemoglobin; 2, PHOTOFRIN®
a drug approaches the
3. BPD-MA
near infrared then the
effective depth or penetration increases and hence more effective treatment can be
obtained. Indeed, of the second generation drugs which have recently entered clinical
trials, all of them show absorption maxima and wavelengths
longer than 630 nm where effective is activated (Figure 3).
In addition to BPD-MA (1) two other drugs are currently in phase
I clinical trials. Tne first is in California with Mono Aspartyl
Chlorin e6 (MACE, 2), (Nippon Oil) and the second in Switzerland
with Meso tetra(m-hydroxyphenyl)chlorin (3) (Scotia
Pharmaceuticals). In addition, tin etiopurpurin (4) and zinc
phthalocyanine (5) are undergoing preclinical studies.
The initial physical characteristics
for a second generation drug, in addition to
including a major absorption band with a
large extinction coefficient in the region
beyond 630 nm must also include an ability
to generate singlet oxygen upon irradiation
or exhibit some other phototoxic toxicity.4
Moreover, photobleaching of the drug
during in vivo irradiation is an important
consideration since this allows for
appropriate transmission of light through the
tissue in which the drug has accumulated as
well as allowing for a greater selectivity in
the destruction of diseased tissue compared
to healthy tissue. In the case of BPD-MA
(1) the absorption maxima is at 688 nm
with an extinction coefficient ~30,000 and a
quantum yield for singlet oxygen production
5
in the range of 50%. ln addition, BPD-MA
photobleaches in vivo at a rate comparable
to that of PHOTOFRIN® (Figure 4).
The solubility of porphyrin based
drugs for PDT varies considerably. Thus
both PHOTOFRLNR and MACE are relatively soluble in water while BPD-MA has
very limited solubility in water and zinc
phthalocyanine is completely insoluble in
water. Nevertheless, the solubility in serum
can be significantly different from that in
water and in the case of BPD-MA a solubility in serum of between .5 and 1 mg/ml can
be reached. Formulations for the above materials for clinical evaluations and clinical
trials can vary greatly. Thus the water soluble materials may be appropriately delivered
in an isotonic solution while the less water soluble materials in clinical trials have so far
been formulated into liposomes. In the case of zinc phthalocyanine a mulrilamela
liposome formulation has been suggested while for BPD-MA a unilamella liposome formulation is being used. While liposomes have not yet found wide use in the
pharmaceutical field due to their cost of large scale production, their use in PDT with its
limited number of treatments required for an individual patient and the size of the dose
are such that these considerations are not critical.
All drugs must undergo vigorous preclinical investigations before human clinical
trials can begin. Pharmacokinetic profiles, toxicology considerations, and mutagenicity,
must all be evaluated along with efficacy, method of manufacture, and formulation.
which determines the means of delivering the drug. All of these evaluations are of
course necessary with photoaciivatable drugs. However, since these drugs are activated
with light after they have been administered, significant additional investigations on the
effect of light and drug must be carried out in addition to the traditional evaluations.
Second generation drugs for PDT must have properties which are superior to
PHOTOFRIN®. The leading contenders seem to have reasonable short lifetimes in the
body which translates to a low level of long term skin sensitivity. At the present time all
of these compounds are activated using argon pumped dye lasers which can function
effectively between 630 and 700 nm. However, the development of new diode lasers in
this spectral region are proceeding to the point where they may be readily available for
these drugs when marketing approval is granted. Before any drug is approved for human
clinical trials extensive preclinical toxicology studies must be carried out. In the case of
BPD-MA we have found no signficiant toxicity even at high dosage levels of the drug.
In animals, skin photosensitivy disappears rapidly after 24 hours with standard
therapeutic doses. Accumulation of BPD-MA into tumors exceeds that of the surrounding tissue and therapeutic evaluation shows that light penetration into tissue is greater
than that seen with PHOTOFRIN® Evaluation by standard mutagenicity tests in vitro
with Salmonella typhimurium/E.coli (5 strains: TA98 TA100, TA535, TA1337, and
TA1538), rat hepatocytes for unscheduled DNA synthesis, Chinese hamster ovary cells,
explored for chromosome elaboration and mammalian point mutation along with in vivo
mouse bone marrow cells to investigate micronucleus aberrations have been carried out
both with BPD-MA in the dark and after activation in light, all such studies have been
7
negative for mutagenicity.
Figure 5 shows the
human serum plasma levels of
BPD-MA. It can be seen that
concentrations dropped well
below 15 ng/mL after 12 hours.
This level of clearance is
encouraging in that there is
generally a correlation between
blood levels and level of drug in
the skin.8 Indeed skin photosensitivity with BPD-MA returns to
the original base line a few days
after treatment and no adverse
skin photosensitivity has been
seen with any of the patients so
far treated.
Fig. 5: Plasma concentrations in pAatients vs. time of BPD-MA following
I.V. infusion
The level of drug concentration to tumor and surrounding healthy tissue is
assayed using both a scanning fluorometer and spectrophotometer. These techniques
offer the investigator ability to observe the appearance and disappearance of drug during
therapy. Like all phase I clinical trials the safety of the drug and in the case of
BPD-MA. drug and light combination, are being evaluated. Basal cell carcinoma
(recurrent and de novo), basal cell nevus syndrome, and cutaneous lesions of metastatic
origin are being treated in these clinical trials. While phase I studies emphasize an.
evaluation of drug safety, biological response has been seen in the tumors being treated
with BPD-MA which is both drug and light dependent.
At this early stage in the phase I clinical trials BPD-MA meets all of our preclinical expectations and we shall begin our phase II studies shortly. What can we expect for
third generation drugs? In order to improve on any of the new compounds currently
under clinical or preclinical studies for PDT a major consideration will be that of
improved biodistribution which in turn will mean improved efficacy and safety. In order
to design such third generation drugs we must begin to understand structure-functionbiodistribution relationships as well as covalently linking photoactivatable chromophobes
to ligands which will direct biodistribution. In addition improved formulations may add
to improved biodistribution. We are currently exploring all of these alternatives in the
joint collaboration between QLT and ACCO.
References
1. a) Smith K. Pronies of Health and Disease in America. Facts on File Inc New
York, New York. 1937, p. 149.
b) Kurihara M, Aoki K. Hisamichi S. eds. Cancer Mortality Statistics in the Woric
1950-1935, University of Nagoya Press, 19S9.
2. a) Marcus A. "Photodynamic Therapy of Human Cancer: Clinical Status” SPIE..
Vol. IS6: Future Directions and Applications in Photodynamic Therapy (Gomer:
C, ed. 1991, pp 5-56.
b) Manyak M. "Photodynamic Therapy: Present Concepts and Future
Applications". Tne Cancer Journal 1990, 3(2): 104-109.
c) Coulter A. 'The Status of Photodynamic Research: An Overview of Current
and Future Cancer Clinical Treatments", Journal of Clinical Laser Medicine and
Surgery 1990: 2-6.
3. Wilson B, James W. Lowe D, Adam G. In: Progress in Clinical and BioIogicai
Research, 170 Porphyrin Localization and Treatment of Tumors (Doiron D "and
Gomer D. eds) Alan R. Liss. New York, 1984; 115-126.
4. Sternberg E, DolphLn D. "Medical Applications of Infrared Absorbing Dyes". In:
Topics of Applied Chernistrvl Infrared Absorbing Dves, (Matsuoka. M. ed) 1990;
193-210.
5. a) Richter A, Waterfield E, Jain A. Sternberg E, Dolphin D, Levy J. "In Vitro,)
Evaluations of Phototoxic Properties of Four Structurally Related Benzoporphyrin Derivarives"', J. Photochem. and Photobiol. 1990: 52: 495-500.
b) Richter A. Wateriield. E, Jain A. Sternberg. Dolphin. D. Levy J.
"Photosensitzing Potency of Srructurally Analogous of Benzoporphvrin
Derivatives", Bntish J. Cancer 1991: 63: 87-93.
6. a) See 5b.
b) Allardic J. Rowland A. Grain A. et a. "Photosensitized Patients and Operating
Lights", Lasers in Med. Science 19S9; 4: 269.
7. Specifics on mutagenicity tests are available from Barbara Kelly. Quadra Log:*Technologies Inc.
S. Hansen C. Samrres P. Tayior J. Comprehensive Medicinal Chemistry Biopharmaceutics (Taylor J. ed.) Vol. 5. 1990: Pergammon Press. N.Y.