Photodynamic Therapy

– A Promising Strategy of Cancer Treatment

Dennis K. P. Ng
Department of Chemistry
The Chinese University of Hong Kong
Which of the following factors are you most concerned for cancer
therapy?
a) Cost of the therapy
b) Side-effects of the therapy
c) Time required for recovery
d) Effectiveness of the therapy
Light has been used as therapy for more than three
thousand years. Ancient Egyptian, Indian and Chinese
civilizations used light to treat various diseases, including
psoriasis and skin cancer.

Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer 2003, 3, 380.
 Photodynamic Therapy (PDT) - 光動力療法
 is an innovative approach for the treatment of a range of cancers
and age-related macular degeneration (老年性黃斑病變)
 involves three individually non-toxic components [a photosensitizer
(光敏劑), light, and oxygen] that are combined to cause cellular
and tissue damage
How is PDT used to treat cancer?

Amato, I. Science 1993, 262, 32.

Treatment of Age-Related Macular Degeneration (AMD)
- A dreaded eye disease that targets the elderly

Sun, H.; Nathans, J. Sci. Amer. 2001, Oct., 61.

The macula is at the center of
the retina, the thin sheet of
neurons that lines the back wall of
the eyeball.
In wet AMD, abnormal, leaking blood
vessels grow underneath the retina
and ultimately damage the sharp
central vision.
How PDT Works
 Photoangioplasty
– used to treat coronary artery disease (removal of
plaque that accumulate on arterial walls)

Lane, N. Sci. Amer. 2003, Jan., 26.

 Photophysical Mechanisms of PDT

Triplet (3O2) and singlet (1O2) states of oxygen:

Type II sensitization process:

Ormond, A. B.; Freeman, H. S. Materials 2013, 6, 817. Milgrom, L.; MacRobert, S. Chem. Br. 1998, May, 45.
 Biological Mechanisms of PDT
- A photosensitizer can target tumor cells directly, inducing
necrosis or apoptosis.

- A photosensitizer can also target tumor vasculature, causing the

tumor starved of oxygen-carrying blood.

- PDT can induce inflammatory and immune responses.

Castano, A. P.; Mroz, P.; Hamblin, M. R. Nat. Rev. Cancer 2006, 6, 535.
Photofrin – the First-Generation Photosensitizer

• remains as the most common clinically

used photosensitizer

• high degree of chemical heterogeneity

• poor absorption of tissue-penetrating
red light (at 630 nm, e  10,000 M-1 cm-1 )
• long-lasting cutaneous photosensitivity
• low selectivity between tumor tissue
and healthy tissue

(1) Brown, S. B.; Truscott, T. G. Chem. Br. 1993, Nov., 955.

(2) Rouhi, A. M. Chem. Eng. News 1998, Nov. 2, 22.
Absorption Spectrum of Photofrin :

Each wavelength of light reaches a

different depth in tissues. A
photosensitizer activated by
deeper-penetrating light might be
best for treating an internal tumor.
Design Criteria for Second-Generation Photosensitizers

 low cytotoxicity in the absence of light

 constant composition
 The synthesis should be as straightforward and as high-yielding
as possible
 some selectivity for the tumor, but is rapidly cleared from
the body after phototherapy
 desirable photophysical properties:
 ET > 94 kJ mol-1 (the energy of singlet oxygen above its ground state)
 the triplet must be generated in satisfactory quantum yield
 a sufficient long lifetime so that singlet oxygen is formed efficiently
 singlet oxygen quantum yield > 0.3 is desirable
 red absorption – to reduce the absorption (e.g. by hemoglobin)
and scattering – allows a deeper penetration
Selected Examples of Second-Generation Photosensitizers
Temoporfrin (Foscan) – A Second-Generation Photosensitizer
First-Generation
• Clinically approved
• Effective for the palliative treatment of
head and neck cancer
• About 100-fold more photoactive than
Photofrin
• Pure compound with a strong absorption
at 652 nm (e  30,000 M-1 cm-1 )

• Associated with a pronounced and

lengthy generalized skin photosensitivity
• Shows little initial selectivity
• Long drug-to-light interval (96 h)
 Approved PDT Drugs for Oncological Indications

(Photofrin)

Brown, S. B.; Brown, E. A.; Walker, I. Lancet Oncol. 2004, 5, 497.

Treating a mouth-cancer patient with laser-activated PDT
 Patient with advanced lung cancer (stage IIIB)
with an obstructed left main stem bronchus

before treatment 2 weeks after treatment

with Photofrin
http://www.chestsurg.org/pdtcstd2.htm
 Patient with Bowen’s disease

before treatment 2 months after treatment

with aminolevulinic acid
Brown, S. B.; Brown, E. A.; Walker, I. Lancet Oncol. 2004, 5, 497.
What are the advantages of PDT compared with the traditional
therapeutic methods for cancer treatment?
a) It has no side effects.
b) It is more effective.
c) It can be applied repeatedly.
d) It can be used to treat metastatic cancer (i.e. cancer that has
spread from the place where it first started to another place in the body).
 Potential Advantages of PDT
 It is comparatively non-invasive
 It can be targeted accurately
mainly achieved through precise application of the light with modern
fiber-optic systems and various types of endoscopy
 Repeated doses can be given without the total-dose
limitations associated with radiotherapy
 It does not have the multidrug resistant problem in
chemotherapy
 The healing process results in little or no scarring
 It can usually be done in an outpatient or day-care setting
 It has no significant side-effects
 Phthalocyanines (酞菁)
As Promising Fluorescent Probes and Photosensitizers

strong absorption in the tissue-penetrating

N
N N near-IR region (lmax > 670 nm, log e > 5 )
N M N
N N
Desirable and tuneable photophysical
N properties
ease of chemical modification
low toxicity in the absence of light

(1) Ali, H.; van Lier, J. E. Chem. Rev. 1999, 99, 2379.
(2) Taquet, J.-P.; Frochot, C.; Manneville, V.; Barberi-Heyob, M. Curr. Med. Chem. 2007, 14, 1673.
(3) Sekkat, N.; van den Bergh, H.; Nyokong, T.; Lange, N. Molecules 2012, 17, 98.
 Phthalocyanine-Based Photosensitizers for PDT

J. Med. Chem. 2012, 55, 5446

J. Med. Chem. 2007, 50, 2100

Polyethylene glycol

Chem. Asian J. 2013, 8, 55

Chem. Eur. J. 2011, 17, 7569

Polyamine
Chem. Commun. 2011, 47, 9657

J. Med. Chem. 2011, 54, 320

Dalton Trans. 2009, 4129
 Targeted PDT Via Receptor Mediated Delivery Systems
e.g. serum proteins, steroids, peptides, folic acids, etc.

A folate-BODIPY conjugate: A cRGD-phthalocyanine conjugate:

- a potential integrin-targeted probe

14

12
Relative Fluorescence Intensity

10

0
KB Cells MCF-7 Cells
 EGFR-Medicated Intracellular Delivery of a Nanophotosensitizer

EGFR = epidermal growth factor receptor

- upregulated on the surface of cancer cells

which can target EGFR

Master, A. M.; Qi, Y.; Oleinick, N. L.; Gupta, A. S. Nanomed. Nanotech. Biol. Med. 2012, 8, 655.
 EPR-Mediated Passive Targeting and Subsequent Receptor-Mediated
Active Targeting of a Nanophotosensitizer

EPR = enhanced permeation and retention

- by which macromolecular drugs tend to accumulate in tumor tissue much more than they do in normal tissues
- due to the leaky vasculature and poor lymphatic drainage in tumors

Master, A.; Malamas, A.; Solanki, R.; Clausen, D. M.; Eiseman, J. L.; Gupta, A. S. Mol. Pharmaceutics
2013, 10, 1988.
 A Phthalocyanine-Peptide Conjugate for Targeted PDT

A phthalocyanine-NLS conjugate: In Vivo Images of Nude-mice Bearing HT29 Tumor

15
Intracellular Uptake
Cellular Uptake (%)

10

5-Fold
5

1.2
0
ZnPc ZnPc-peptide
1.0
Relative Fluorescence Intensity

0.8
Ex Vivo Data (72 h post-injection)
(Counts mm )
-2

0.6

0.4

0.2
Chem. Eur. J. 2012, 18, 4225
0.0
Tumor Skin Liver Kidney Stomach Spleen
 Activatable Photosensitizers

(1) Lovell, J. F.; Liu, T. W. B.; Chen, J.; Zheng G. Chem. Rev. 2010, 110, 2839.
(2) Lo, P.-C.; Lovell, J. F.; Zheng G. In Handbook of Biophotonics, Popp, J., Tuchin, V. V., Chiou A.,
Heinemann, S. (eds.), Wiley-VCH, 2011, 2, 295.
 pH-Depentent Photosensitizers for Targeted PDT

IC50 = 50 nM

IC50 = 10 nM

Chem. Eur. J. 2010, 16, 4777

Chem. Commun. 2010, 46, 3188

PET = photoinduced electron transfer

- one of the quenching mechanisms
 A Thiol-Activated Photosensitizer

DTT = dithiothreitol

Chem. Commun. 2013, 49, 4274

 Summary

1. PDT has emerged to be a promising treatment modality for some

localized and superficial cancer, as well as certain non-cancerous
conditions.

2. Various classes of photosensitizers have been studied with a view to

enhancing the photodynamic activities and reducing the side effects.

3. To address the issue of selectivity toward malignant tissues, various

approaches have been explored, which include bioconjugation to tumor-
specific vehicles, encapsulation in colloidal nanocarriers, and
incorporation of an activatable component.
How would you classify this field of research?
a) Organic chemistry
b) Inorganic chemistry
c) Photochemistry
d) Medicinal chemistry