Biochem. J. (2016) 473, 347–364 doi:10.

1042/BJ20150942 347

REVIEW ARTICLE
New photosensitizers for photodynamic therapy
Heidi Abrahamse* and Michael R. Hamblin†‡§1
*Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
†Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, U.S.A.
‡Department of Dermatology, Harvard Medical School, Boston, MA 02115, U.S.A.
§Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, U.S.A.

Photodynamic therapy (PDT) was discovered more than 100 years (boron-dipyrromethene), transition metal complexes, and natural
ago, and has since become a well-studied therapy for cancer products such as hypericin, riboflavin and curcumin have been
and various non-malignant diseases including infections. PDT investigated. Targeted PDT uses PSs conjugated to antibodies,
uses photosensitizers (PSs, non-toxic dyes) that are activated by peptides, proteins and other ligands with specific cellular
absorption of visible light to initially form the excited singlet receptors. Nanotechnology has made a significant contribution
state, followed by transition to the long-lived excited triplet to PDT, giving rise to approaches such as nanoparticle delivery,
state. This triplet state can undergo photochemical reactions fullerene-based PSs, titania photocatalysis, and the use of
in the presence of oxygen to form reactive oxygen species upconverting nanoparticles to increase light penetration into
(including singlet oxygen) that can destroy cancer cells, tissue. Future directions include photochemical internalization,
pathogenic microbes and unwanted tissue. The dual-specificity genetically encoded protein PSs, theranostics, two-photon
of PDT relies on accumulation of the PS in diseased tissue absorption PDT, and sonodynamic therapy using ultrasound.
and also on localized light delivery. Tetrapyrrole structures such
as porphyrins, chlorins, bacteriochlorins and phthalocyanines
with appropriate functionalization have been widely investigated Key words: naturally occurring photosensitizers, photochemical
in PDT, and several compounds have received clinical mechanisms, photodynamic therapy, photosensitizers, synthetic
approval. Other molecular structures including the synthetic dyes, tetrapyrroles.
dyes classes as phenothiazinium, squaraine and BODIPY

INTRODUCTION acknowledged disadvantages including skin photosensitivity that

can last for weeks or months and can be highly troubling for
The concept of photodynamic therapy (PDT) dates back to 1900. patients, and a relatively small absorbance peak at 630 nm making
A medical student, Oscar Raab, working in Munich, Germany it somewhat inefficient in use, especially for bulky tumours
[1], made an accidental discovery that micro-organisms such as where light penetration is problematic [2]. Since then medicinal
paramecia that had been incubated with certain dyes could be chemists have attempted to synthesize and discover molecules
killed when exposed to light, but not when they were kept in that could act as improved PSs, and several hundred compounds
the dark. When it was subsequently discovered that oxygen have now been proposed as potentially useful to mediate PDT
in the air was also necessary for this light-mediated killing effect for tackling cancer, infections and many other diseases. In recent
to occur, the term ‘photodynamic action’ was coined. It was years PDT has returned to its earliest roots, and antimicrobial
not long after these discoveries that the first efforts were made photodynamic inactivation (aPDI) has made something of a
to use this phenomenon as a cancer therapy, by painting dyes comeback. The structures of antimicrobial PSs have some features
on to superficial skin tumours and then exposing them to light. in common with anti-cancer PSs, but there are also major
However, the following two world wars and the impressive rise of differences.
the pharmaceutical industry in the 1950s and 1960s delayed the
further exploration of PDT by over 60 years. The modern era of
PDT started in the 1970s in the U.S.A., largely due to the efforts
Photochemical mechanisms
of Dr Thomas Dougherty working at Roswell Park Cancer
Institute in Buffalo, NY. The first photosensitizer (PS) that The PS molecule is a singlet in its ground state because it has
was introduced by Dougherty and co-workers was a water- two electrons with opposite spins. Absorption of a photon of
soluble mixture of porphyrins that was named ‘haematoporphyrin light with the appropriate quantum energy (wavelength) leads
derivative’ (HpD), and a more purified preparation later became to the excitation of one electron into a higher-energy orbital
known as Photofrin. Although Photofrin is still the most (illustrated by the Jablonski diagram shown in Figure 1). This
frequently used PS throughout the world today, it has many singlet excited-state PS is very unstable and loses its excess

Abbreviations: ALA, 5-aminolaevulinic acid; aPDI, antimicrobial photodynamic inactivation; BODIPY, boron-dipyrromethene; DLI, drug–light interval;
EPR, enhanced permeability and retention; ER, endoplasmic reticulum; HpD, haematoporphyrin derivative; LDL, low-density lipoprotein; 2PA, two-photon
absorption; PCI, photochemical internalization; PDT, photodynamic therapy; PS, photosensitizer; ROS, reactive oxygen species; SDT, sonodynamic
therapy.
1
To whom correspondence should be addressed (email [email protected]).


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348 H. Abrahamse and M.R. Hamblin

Figure 1 Jablonski diagram

When light (hv ) is absorbed by the PS, the electron moves from a non-excited low-energy singlet state into a high-energy singlet state. This excited state can lose energy by emitting a photon
(fluorescence) or by internal conversion (non-radiative decay). The process known as intersystem crossing involves flipping of the spin of the high-energy electron, leading to a long-lived excited
triplet state. In the presence of molecular oxygen, superoxide and hydroxyl radicals are formed in Type I reactions and singlet oxygen in a Type II reaction. These ROS can damage most types of
biomolecules (amino acids, lipids, nucleic acids).

energy either as emission of light (fluorescence) or production Properties of ideal PSs

heat (internal conversion). However, the excited singlet PS may Most of the PSs used in cancer therapy are based on the
undergo a process known as ‘intersystem crossing’ to form tetrapyrrole backbone, a structure similar to that contained in
a more stable excited triplet state with parallel spins. The the protoporphyrin prosthetic group contained in haemoglobin.
triplet- state PS molecule can decay back to the ground state Depending on the precise structure, effective PSs can be
(by emitting a phosphorescent photon) but this is a ‘forbidden synthesized with absorbance bands between 600 and 800 nm.
process’ by the quantum selection rules, so the triplet state is Since the penetration of light into tissue increases with
much more stable than the singlet state having a lifetime of wavelength, agents with strong absorbance in the deep-
microseconds compared with only nanoseconds for the excited red spectral region such as chlorins, bacteriochlorins and
singlet. This long lifetime of the triplet state allows it sufficient phthalocyanines tend to make much more efficient PSs although
time to transfer its energy by colliding with molecular oxygen many other factors are also important.
(O2 ), which is unique in being a molecular triplet in its A PS should ideally be a single pure compound to allow
ground state. This energy-transfer step leads to the formation manufacturing under good manufacturing practice (GMP)
of singlet oxygen (1 O2 ) (and ground-state PS), and the reaction is conditions with quality control and low manufacturing costs,
referred to as a Type II photochemical process [3]. A Type I and leading to better stability in storage. It should have a
photochemical process can also occur whereby the excited- strong absorption peak in the red to near-infrared spectral
state PS undergoes electron transfer reactions that eventually region (between 650 and 800 nm) because absorption of single
forms reactive oxygen species (ROS). This mechanism may photons with wavelengths longer than 800 nm does not provide
involve either acquisition or donation of an electron to form enough energy to excite oxygen to its singlet state. PSs should
the radical cation or radical anion. The radical anion can react possess a substantial triplet quantum yield leading to good
with oxygen to produce the superoxide radical anion (O2 • − ). production of ROS upon irradiation. It should have no dark
Dismutation or one-electron reduction of O2 • − gives hydrogen toxicity and relatively rapid clearance from normal tissues,
peroxide (H2 O2 ), which in turn can undergo another one-electron thereby minimizing the side effects of phototoxicity [4]. Although
reduction to form the powerful oxidant hydroxyl radicals (HO• ). it used to be considered desirable for the interval between drug
ROS generation via Type II chemistry is mechanistically much administration and irradiation (drug–light interval, DLI) to be
simpler than via Type I, and most PSs used for anti-cancer PDT as long as possible (up to 4 days), so that the PS was given
are believed to operate via the Type II rather than the Type I sufficient time to clear from normal tissues, while remaining
mechanism. concentrated in tumours, many reports now suggest that the


c 2016 Authors; published by Portland Press Limited
 New photosensitizers for PDT 349

Figure 2 Cell death mechanisms

The subcellular localization of the PS in different organelles (mitochondria, lysosomes, endoplasmic reticulum, plasma membrane, etc.) plays a major role in the type of cell death mechanism that
dominates, but other factors such as the overall PDT dose (PS concentration × light fluence) and DLI also play a role.

tumour response may be substantially better when light is Tumour-targeting in PDT

delivered at a much shorter DLI (minutes or hours) when most The most effective PSs tend to be relatively hydrophobic
of the PS is still present in the blood vessels, thus producing compounds that rapidly diffuse into tumour cells and localize
marked vascular damage [5]. Some reports have suggested that in intracellular membrane structures such as mitochondria and
a pronounced inflammatory response resulting from necrotic endoplasmic reticulum (ER). More polar compounds tend to
cell death after PDT is important because it aids the immune- be taken up by the active process of adsorptive or fluid phase
stimulating function of PDT, whereas other reports have suggested endocytosis, and this process is slower than passive diffusion,
that PDT regimens that produce more apoptosis and less necrosis necessitating a longer DLI. Many hypotheses have been proposed
and inflammation are suitable for applications such as PDT of to account for the tumour-localizing properties that have long been
brain tumours where swelling is undesirable. Previous findings, observed in PDT [9]. These explanations include the occurrence
however, show that certain PDT-induced apoptotic cell death of leaky and tortuous tumour blood vessels that are typical of the
mechanisms are also highly immunogenic and can stimulate neovascularization process occurring in tumour angiogenesis, and
antitumour immunity [6]. The light-mediated destruction of the together with the absence of lymphatic drainage in tumours are
PS (known as photobleaching) was thought to be undesirable, collectively known as the ‘enhanced permeability and retention
but some reports now suggest that this phenomenon may make (EPR) effect’ [10]. Some of the most effective PS compounds
light dosimetry during PDT less critical, as over-treatment have been found preferentially to low-density lipoprotein (LDL)
is avoided when the remaining PS is destroyed during the among various serum proteins, and it has been proposed that over-
illumination [7]. expressed LDL receptors that are sometimes found on tumour
The discovery that 5-aminolaevulinic acid (ALA) could cells could be important in tumour localization [11].
function as a biosynthetic precursor of the PS protoporphyrin
IX [8] has led to many applications in which ALA or ALA-
esters can be topically applied to tissues, or even administered
orally. These ALA derivatives are considered to be ‘pro- Mechanisms of PDT-mediated cytotoxicity
drugs’, needing to be metabolically converted into protoporphyrin The lifetime of singlet oxygen (1 O2 ) is very short (∼10–320 ns),
IX in order to become active PSs. Successes in treatment limiting its diffusion to only approximately 10–55 nm in cells
of skin cancer and other dermatologic indications have been [12]. Thus, photodynamic damage is likely to occur very close
reported. to the intracellular location of the PS [13]. PDT can kill


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350 H. Abrahamse and M.R. Hamblin

Figure 3 Structure and absorption spectra of tetrapyrrole photosensitizers

Tetrapyrrole absorption spectrum showing porphyrins, chlorins and bacteriochlorins.

cells via the three main morphologies of cell death: apoptotic, much less important as infections that will be treated by PDT tend
necrotic and autophagy-associated cell death (Figure 2). It is to be rather superficial in nature.
thought that the subcellular localization of the PS in different
organelles (mitochondria, lysosomes, endoplasmic reticulum,
plasma membrane, etc.) plays a major role in the type of cell death TETRAPYRROLE STRUCTURES
mechanism that dominates, but other factors such as the overall
PDT dose (PS concentration × light fluence) and DLI also play a Tetrapyrrole structures make up the largest group of PSs that have
role. Overall it is accepted that apoptosis is the principal modality been employed for anti-cancer applications. Tetrapyrrole back-
of cell death when cells are treated with PDT in vitro. bones occur naturally in several important biomolecules such as
haem, chlorophyll and bacteriochlorophyll. In fact, tetrapyrroles
have been termed the ‘pigments of life’ [14]. As the double-
Antimicrobial photoinactivation bonds are successively reduced when moving from backbones
that are porphyrins to chlorins to bacteriochlorins the Q-band is
It is somewhat ironic that the origins of PDT over 100 years substantially red-shifted and the height of the band also increases
ago were in the killing of micro-organisms, but throughout the (Figure 3). Phthalocyanines also have a large band in the 670 nm
period from the 1970s to 2010, cancer was the overwhelming most region. Broadly speaking, tetrapyrrole PSs (with the exception of
popular target disease in PDT research. Now with the inexorable bacteriochlorins) tend to produce predominantly Type II singlet
rise of multi-drug-resistance among pathogenic microbes, a PDI oxygen, compared with the Type I ROS (such as hydroxyl
has made something of a comeback. radicals) that are often produced by PSs with other structures.
The ideal PS structure is very different between anti-cancer The number of tetrapyrrole compounds used as PSs in PDT is too
drugs and antimicrobial drugs. Anti-cancer PSs tend to be high to even list them all, but in Table 1 we have tried to list the
lipophilic with little or no overall charge (either positive or most important compounds and the newest examples.
negative). Antimicrobial PSs, on the other hand, should have
pronounced cationic charges, and in many cases the more charges
the better especially for targeting Gram-negative bacteria. Anti-
Porphyrins
cancer PSs are usually expected to have long wavelength (far-
red/near-infrared) absorption bands for good tissue penetration of As mentioned above, HpD and Photofrin were the first PSs to
the exciting light, whereas for antimicrobial PSs, this property is receive regulatory approval, and these and similar preparations


c 2016 Authors; published by Portland Press Limited
 New photosensitizers for PDT 351

Table 1 PSs based on tetrapyrrole backbone

Class Name Structure λmax Application Reference

Porphyrin Photofrin (NB actual structure of 630 nm Cancer, in vitro , [135]

Photofrin is a complex mixture of in vivo , clinical
ester- and ether-linked dimers and
oligomers)

Porphyrin ALA-induced protoporphyrin IX 635 nm Cancer, in vitro , [136]

in vivo , clinical

Porphyrin 5,10,15,20-Tetrakis(1- White Cancer, antimicrobial, [137]

methylpyridinium-4-yl) porphyrin in vitro , in vivo
tosylate

Porphyrin XF70 White Antimicrobial, in vitro , [138]

in vivo


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352 H. Abrahamse and M.R. Hamblin

Table 1 Continued

Class Name Structure λmax Application Reference

Chlorin Foscan, m-tetrahydroxyphenylchlorin 652 nm Cancer, in vitro , in vivo , [139]

clinical

Chlorin Verteporfin, benzoporphyrin derivative 690 nm Cancer, ophthalmology, [18]

mono acid ring A in vitro , in vivo , clinical

Chlorin Chlorin(e6) 660 nm Cancer, in vitro , in vivo , [19]

clinical

Chlorin Monoaspartyl chlorin(e6), 660 nm Cancer, cardiology, in vitro , [140]

talaporfin sodium in vivo , clinical


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 New photosensitizers for PDT 353

Table 1 Continued

Class Name Structure λmax Application Reference

Chlorin HPPH 660 nm Cancer, in vitro , in vivo , [141]

clinical

Bacteriochlorin TOOKAD Soluble, WST-11 753 nm Cancer, in vitro , in vivo , [142]

clinical

Bacteriochlorin LUZ11 748 nm Cancer, in vitro , in vivo , [27]

clinical

Bacteriochlorin BC19 732 nm Cancer, in vitro , in vivo [28]

Bacteriochlorin BC21 732 nm Antimicrobial, in vitro [143]


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354 H. Abrahamse and M.R. Hamblin

Table 1 Continued

Class Name Structure λmax Application Reference

Phthalocyanine Liposomal ZnPC 670 nm Cancer, in vitro , [144]

in vivo , clinical

Phthalocyanine Chloroaluminium 670 nm Cancer, in vitro , in vivo [145]

sulfonated
phthalocyanine
(CASP)

Phthalocyanine Silicon phthalocyanine 675 nm Cancer, in vitro , [33]

(PC4) in vivo , clinical

Phthalocyanine RLP068 690 nm Antimicrobial, in vitro , [146]

in vivo


c 2016 Authors; published by Portland Press Limited
 New photosensitizers for PDT 355

are still in widespread use around the world [4]. ALA-induced SYNTHETIC DYES
protoporphyrin IX is, of course, a porphyrin and this methodology
is widely used around the world, mainly by dermatologists [15]. Structures that can be classified as synthetic dyes account for a
There have been some new porphyrin compounds proposed as sizeable fraction of the molecules that are being studied for a PDI
PSs, but these have been tested mainly in the PDI field [16]. and a selection are listed in Table 2.
Although porphyrins are most efficiently activated at the Soret
band (∼400 nm), the presence of several Q-bands extending as
Phenothiazinium salts
far as the 630 nm region means that red light is most often used
to activate porphyrins in vivo, although blue, green or white light The two most popular phenothiazinium dyes (Methylene Blue
has been used for more superficial applications. [37] and Toluidine Blue [38]) have been widely studies for both
antimicrobial applications [39] and less often for anti-cancer
[40]. There are some new phenothiazinium dye structures that
have been recently prepared mostly for antimicrobial use. PP904
was clinically tested for infected non-healing leg ulcers [41].
Chlorins The benzophenothiazinium dye EtNBS has been studied for both
Chlorins include several of the most important clinical antimicrobial [42] and anti-cancer [43] PDT.
PSs, namely m-tetrahydroxyphenylchlorin (Temoporfin or
Foscan) [17], benzoporphyrin derivative (Verteporfin) [18] and
Radachlorin (now Bremachlorin) [19]. Chlorin(e6) is derived Rose Bengal
from naturally occurring chlorophyll and it has been used on Rose Bengal is a member of the xanthene class of fluorescent dyes
its own (formulated either as the trisodium salt known as that includes fluorescein (the most popular synthetic fluorophore).
photodithazine [20] or dissolved in polyvinylpyrrolidone [21]). The introduction of heavy atoms into the rings, such as the
The monoaspartyl derivative (laserphyrin, taloporphin sodium or halogen atoms bromine and iodine, increases the triplet yield
LS11) [22] has been used in Japan. Other PSs that have advanced of the molecule by facilitating intersystem crossing. Rose Bengal
to clinical trials can also be classified as chlorins, including the has a long history as a photoactive dye and has been explored for
pyrophaeophorbide derivative HPPH [23] and tin(II) etiopurpurin antimicrobial applications [44], tissue bonding applications [45]
[24]. Red light between 650 and 700 nm is used to activate chlorins and anti-cancer applications [46].
depending on the exact structure.

Squaraines
The squaraine dye structure has a delocalized system of molecular
Bacteriochlorins orbitals providing good absorption in the visible range. The four-
The bacteriochlorin group of compounds also contains clinically membered carbon ring is usually stabilized against nucleophilic
important PSs. The lead-containing bacteriophaeophorbide attack by surrounding it with a rotaxane structure [47,48]. In
derivative known as TOOKAD [25] and its newer water-soluble a similar manner to xanthenes (see above), the introduction of
derivative known as TOOKAD Soluble have been tested in iodine substituents into the ring increases the triplet yield by the
clinical trials for prostate cancer [26]. The new bacteriochlorin heavy atom effect.
derivative known as LUZ11 [27] recently entered clinical trials for
head and neck cancer in Portugal (Photodynamic Therapy With
LUZ11 in Advanced Head and Neck Cancer, Clinical Trials.Gov BODIPY dyes
NCT02070432). Other bacteriochlorin structures have been tested The BODIPY (boron-dipyrromethene) dye structure usually
as PSs for both anti-cancer [28] and antimicrobial applications contains a BF2 bridging unit, and constitutes a popular class
[29]. Near-infrared light between 700 and 800 nm is used to of fluorophores [49]. Addition of heavy halogen atoms in the
activate bacteriochlorins and this was shown to be particularly pyrrole rings increases the triplet yield and allows the molecules
effective against pigmented tumours such as malignant melanoma to function as PSs [50].
[30].

Phenalenones
The parent compound phenalenone was often used as a reference
Phthalocyanines standard for generation of 1 O2 [51]. Maisch and co-workers
Phthalocyanines were some of the earliest compounds studied in have recently synthesized a quaternized cationic derivative of
the 1980s and 1990s. It should be noted that phthalocyanines are phenalenone as an antimicrobial PS [52,53].
also synthetic dyes and could have also been included in the next
section. There used to be a mixture of sulfonated chloroaluminium
phthalocyanines known as CASPs that received considerable Transition metal compounds
attention in the PDT field [31]. Unmodified zinc-phthalocyanine Transition metal co-ordination compounds are a relatively new
was tested in a liposomal formulation in both animal models class of PS. Ruthenium(II) polypyridyl complexes are perhaps the
and in clinical trials [32]. The silicon-substituted phthalocyanine most studied [54], although other ruthenium ligands [55], rhodium
PC4 has also been tested in vivo [33] and in clinical trials [34]. [56] and cyclometalated iridium [57] complexes have also been
Cationic phthalocyanines such as RLP068 have been studied for studied. Rhodium compounds are often in the form of Rh(II)–
antimicrobial applications, both in vivo [35] and in clinical trial Rh(II) bridged dimer compounds [58]. There is also evidence that
for infected diabetic foot ulcers [36]. Phthalocyanines are some luminescent platinum(II) and gold(III) compounds can act
activated by far-red light in the 670 nm range. as PSs [59].


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356 H. Abrahamse and M.R. Hamblin

Table 2 PSs classed as synthetic dyes

Class Name Structure λmax Application Reference

Phenothiazinium salt Methylene Blue 660 nm Cancer, antimicrobial, [37]

in vitro , in vivo , clinical

Phenothiazinium salt Toluidine Blue O 630 nm Antimicrobial, in vitro , [147]

in vivo , clinical

Phenothiazinium salt PP904 630 nm Antimicrobial, in vitro , [41]

in vivo , clinical

Benzophenothiazinium salt EtNBS 670 nm Cancer, antimicrobial, [148]

in vitro , in vivo , clinical

Halogenated xanthene Rose Bengal 540 nm Cancer, antimicrobial, [149]

tissue bonding, in vitro ,
in vivo , clinical

Squaraine ASQI 610 nm Antimicrobial, in vitro [150]


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 New photosensitizers for PDT 357

Table 2 Continued

Class Name Structure λmax Application Reference

BODIPY Zinc(II)-dipicolylamine di-iodo-BODIPY 540 nm Antimicrobial, in vitro [151]

BODIPY DIMPy-BODIPY 530 nm Antimicrobial, in vitro [152]

Phenalenone Cationic 380 nm Antimicrobial, in vitro [52]

Transition metal complex Ruthenium 450 nm Antimicrobial, in vitro [153]

Transition metal complex Rhodium 450 nm Cancer, antimicrobial, in vitro [154]

Transition metal complex Iridium 600 nm Cancer, antimicrobial, in vitro [155]


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358 H. Abrahamse and M.R. Hamblin

Table 3 Naturally occurring compounds as PSs

Class Name Structure λmax Application Reference

Perylenequinone Hypericin 570 nm Cancer, antimicrobial, in vitro , in vivo [60]

Perylenequinone Hypocrellin 470 nm Cancer, antimicrobial, in vitro , in vivo , clinical [63]

Flavin Cationic riboflavin UVA/440 nm Antimicrobial, in vitro [68]

Curcuminoid Curcumin 420 nm Antimicrobial, in vitro , in vivo , clinical [156]

NATURAL PRODUCTS Hypericin

The idea to use a naturally occurring compound as a PS inherently Hypericin is a perylenequinone isolated from St John’s wort, a
contains possible contradictions. If plants have evolved over long-known medicinal plant [60]. Hypericin is a hydrophobic
millennia to grow in sunlight, then surely they cannot contain molecule that requires formulation in a drug-delivery vehicle
a highly active PS molecule or they would have burned up in the (liposomes, micelles, nanoparticles) [61]. The peak absorption
sun? Nevertheless, there are several natural product isolates that band of hypericin is 600 nm, so orange light is used. Hypericin
have been extensively explored as PSs and some of these are listed has been found to efficiently localize in the endoplasmic reticulum
in Table 3. and to cause ER stress after light application, that can produce


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 New photosensitizers for PDT 359

Table 4 Targeting ligands in PDT

Class Ligand Target PS Application Reference

Monoclonal antibody OC125 Ovarian cancer Chlorin(e6) Cancer, in vitro , in vivo [157]
Peptide Octreotide Somatostatin receptor Chlorin(e6) Leukaemia, in vitro [81]
Peptide RGD tripeptide αvβ3 integrin Phaeophorbide a Cancer, in vitro [76]
Lipoprotein Low-density lipoprotein LDL receptor Tetra-t-butyl silicon phthalocyanine Cancer, atherosclerosis, in vitro , in vivo [158]
Serum protein Transferrin Transferrin receptor Hematoporphyrin Cancer, in vitro [77]
Serum protein Modified albumin Scavenger receptor Chlorin(e6) Atherosclerosis, in vitro , in vivo [159]
Vitamin Folic acid Folate receptor Phaeophorbide a Cancer, in vitro [76]
Steroid Oestradiol Steroid receptor Phaeophorbide a Breast cancer, in vitro [160]
Carbohydrate Mannose Mannose receptor Meso-tetraphenylporphyrin Cancer, in vitro [161]

‘damage associated molecular patterns’ that efficiently activate most effective PSs tend to be insoluble, hydrophobic molecules
the immune system [62]. with a high propensity to aggregate means that encapsulation in
nano-drug carriers may make a big difference to their performance
Hypocrellin [84]. Moreover many other nanostructures such as plasmonic gold
nanoparticles, mesoporous silica nanoparticles, carbon nanotubes,
Hypocrellins A and B are another group of perylenequinone graphene and upconversion nanoparticles have found uses in PDT
pigments which have been isolated from the parasitic fungi [85]. There is another group of nanostructures where the actual
Hypocrella bambuase sacc and Shiraia bambusicola P. Heen nanoparticle itself acts as the PS absorbing light and producing
found in China and other parts of Asia including Sri Lanka [63]. ROS, as in the case of fullerenes [86], titanium dioxide [84] and
These compounds have been used in PDT and can also benefit some types of quantum dots [87].
from encapsulation in liposomes [64].

Riboflavin Nanoparticle PS delivery

Riboflavin (vitamin B2 ) has been explored as an antimicrobial There has been an astonishing variety of nanoparticles used to
PS. It has been tested for antimicrobial [65] and blood product solubilize, encapsulate and deliver PSs to both tumours [88] and
sterilization [66] applications, and also as a photoactivated cross- microbial cells [89]. As mentioned above, the planar conjugated
linker for corneal stiffening [67]. Riboflavin has two peaks in structures of PSs that are needed to absorb the light means the
the UVA (360 nm) and blue (440 nm) regions. Maisch et al. [68] molecules tend to be hydrophobic and prone to aggregation.
have synthesized a cationic version of riboflavin designed as an Liposomes, micelles, nanoemulsions can all be constructed out
antimicrobial PS. of lipids or amphiphilic polymers that self-assemble into delivery
vehicles for PSs [90]. These nanovehicles have many advantages,
the most important of which are providing a big increase in
Curcumin photochemical efficiency, and the ability to localize in tumours
Curcumin is a relative newcomer in the PDT field, although it after IV injection due to the EPR effect [91].
has been known as a spice and medicinal compound for centuries
[69]. Again curcumin is a very hydrophobic molecule and requires
some kind of formulation vehicle to allow it to be used as a PS Fullerenes
[70]. Curcumin is activated by blue light [71]. Curcumin has found Fullerenes are closed-cage all-carbon nanostructures composed
most applications as an antimicrobial PS in dentistry to eradicate of sp2 hybridized carbon atoms (C60 , C70 , C84 , etc.) and with
oral pathogens [72]. a large molar absorption coefficient and high triplet yields. In
organic solvents or hydrophobic environments, fullerenes are
TARGETED PDT very efficient in producing photoexcited 1 O2 , whereas in aqueous
environments, fullerenes switch the photochemical mechanism
There have been a large number of targeting studies in which to Type 1 producing HO• [92]. Pristine fullerenes are insoluble
PSs are covalently attached to various molecules that have some in water, but the cage can be readily functionalized with polar
affinity for neoplasia or to receptors expressed on specific tumours groups such as carboxylic acids and quaternary amino groups
[73]. The intention is to rely on the ability of the targeting vehicle that improve solubility and biological compatibility. Fullerenes
to control localization so that the PS can be chosen based on have been used to mediate PDT of cancer cells [93] and microbial
its photochemical properties rather than on its tumour targeting cells [94] in vitro, to treat tumours [95] and infections [96] in vivo,
properties, which are often unimpressive. These targeting vehicles and there is even one case report of a clinical application.
include monoclonal antibodies [74], antibody fragments [75],
peptides [76], proteins such as transferrin [77], epidermal growth
factor [77] and insulin [78], LDL [79], various carbohydrates [80], Titanium dioxide
somatostatin [81], folic acid [82] and many others. Table 4 lists
It has long been known that titanium dioxide (TiO2 ) or titania
some of these targeting ligand–PS conjugates.
acts as a large band gap semiconductor. When excited with
UVA light, an electron is excited from the valence band into
the conductance band leaving behind a positively charged hole.
NANOTECHNOLOGY
The electron can produce superoxide from oxygen, whereas the
The nanotechnology revolution has had a major impact on PDT hole can produce hydroxyl radicals from water. These ROS have
as it also has had in other areas of biomedicine [83]. The fact that been used in the process of photocatalysis which is used to kill


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360 H. Abrahamse and M.R. Hamblin

micro-organisms and degrade organic pollutants [97]. In recent instance KillerRed has been targeted to cell membranes [115],
times TiO2 nanoparticles have been used as PDT agents often as to lysosomes [116], to mitochondria [117] and to the nucleus
composites or hybrids [98–100]. [118]. KillerRed has been used as an optogenetic tool to allow
the light-mediated inactivation of specific groups of neurons in
Caeorhabditis elegans [119] in transgenic zebrafish [120],
Quantum dots in Xenopus laevis embryos [121] and in the mouse retina [122].
Although many researchers have prepared conjugates between Another genetically encoded PS is the flavoprotein ‘miniSOG’
quantum dots and various different PSs to carry out PDT [101– [123].
103], a recent study showed that graphene quantum dots could
mediate PDT on their own without any added PS [87].
Theranostics
The term ‘theranostics’ was coined as a combination of
Upconversion nanoparticles diagnostics and therapeutics [124], but should really combine
Upconversion is a process in which the sequential absorption of more elements than simply an imaging agent that allows a tumour
two or more photons leads to the emission of light at shorter to be visualized (often by fluorescence), and a therapeutic agent
wavelength than the excitation wavelength. The mechanism (often photodynamic) that allows a tumour to be destroyed [125].
relies on absorption of two consecutive photons, where second Theranostic agents could in addition be designed to act as ‘smart
near-infrared photon is absorbed by a ‘virtual excited state’ drug-delivery vehicles’ that could be activated by a change in
to give the actual excited state that can then emit a much the environment of the tumour or the infection such as lower pH
shorter wavelength photon. Lanthanide-doped nanoparticles [126], redox, enzyme activation [127], elevated temperature or
emerged in the late 1990s and the optical transitions from magnetic fields [128]. Furthermore theranostic agents could also
compounds containing yttrium, ytterbium and erbium were be designed to incorporate a method to monitor the effectiveness
found to be suitable for photon upconversion. In contrast with of treatment, possibly in real-time, and in the days following
two-photon absorption (2PA) which needs a very high peak treatment. Porphysomes (self-assembled nanostructures from
power density provided by femtosecond pulsed lasers, photon lipid-conjugated porphyrins) are an interesting example of a
upconversion can operate with reasonable efficiency using a CW theranostic PDT agent [129].
laser (often at 980 nm) [104]. Near-infrared wavelengths are
preferred for their greater tissue penetration, and the shorter
Two-photon excitation
wavelengths emitted are able to excite more different PSs,
that have been attached to the lanthanide-doped nanoparticles. Another way to use long wavelength near-infrared light that
Recently a NaYbF4 :Nd@NaGdF4 :Yb/Er@NaGdF4 core–shell– penetrates deeply into tissue to excite PSs with short wavelength
shell nanoparticle loaded with chlorin(e6) and folic acid for absorptions (in addition to upconversion nanoparticles) is 2-PA.
targeting was reported that could be excited with 808 nm laser Here two separate near-infrared photons have to arrive at the PS
[105]. molecule virtually simultaneously, and if they are absorbed at the
same time they will be equivalent to a single photon of half the
wavelength [130]. However, the need for simultaneous absorption
FUTURE DIRECTIONS of both photons means that an extremely high peak power density
(in the order of GW/cm2 ) is required. Moreover, the efficiency
Photochemical internalization (PCI)
of 2-PA PDT depends strongly on what is known as the 2-PA
The PCI is a new technique in which a highly amphiphilic cross-section of the PS molecule, which is measured in Goeppert-
PS such as aluminium phthalocyanine adjacent disulfonate or Mayer units (1 GM = 10 − 50 cm4 · s · molecule − 1 · photon − 1 ).
Amphinex (meso-tetraphenylchlorin adjacent disulfonate) [106] Most regular PSs have a 2-PA cross-section between 1 and 100,
is administered together with a cytotoxic molecule such as but specially designed PSs can have values as high as 33 000
bleomycin [107] or a ribosome-inactivating protein [108]. The [131]. 2-PA PDT has been tested in vivo when the femtosecond
cytotoxic molecule is taken up by endocytosis into endosomes laser beam was delivered though the whole body of the mouse to
which also have the PS in their membranes. When light is reach the tumour on the other side [132].
delivered, the endosomes are broken open, releasing the cytotoxic
molecule into the cytoplasm where its toxicity is much higher.
This approach has advanced through in vitro studies [109], to Sonodynamic therapy (SDT)
in vivo [110], and into clinical trials for head and neck cancer The ability to activate some kinds of PS molecule with ultrasound
[111]. PCI can also be used for non-viral delivery of DNA and energy instead of light has been known for some years [133]. The
other nucleic acid-based therapeutics as a form of gene therapy ultrasound employed is usually between 1 and 2 MHz delivered
[112]. at power densities between 0.5 and 10 W/cm2 . In fact, although
many sonosensitizers are the same types of molecule as those used
as PSs, this is not always the case, and some chemotherapeutic
Genetically encoded proteins drugs have been shown to be potentiated by ultrasound [134].
It was previously discovered that some modified fluorescent The main proposed mechanisms of actions are: (a) generation of
proteins based on the fundamental chromophore structure present flashes of light (sonoluminescence) from collapse of cavitation
in green fluorescent protein (GFP) can not only emit fluorescence, bubbles that activates the PS to produce singlet oxygen; (b)
but also produce ROS upon excitation with light [113]. The generation of free radicals which initiate chain peroxidation of
most well known of these photodynamically active fluorescent membrane lipids via peroxyl and/or alkoxyl radicals; (c) physical
proteins is called KillerRed [114]. The intracellular location of the destabilization of the cell membrane by the sonosensitizer thereby
expressed protein can be controlled by additional genetic elements rendering the cell more susceptible to ultrasound induced shear
attached to the DNA sequence for the KillerRed molecule. For forces; (d) ultrasound-enhanced drug transport across the cell


c 2016 Authors; published by Portland Press Limited
 New photosensitizers for PDT 361

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Received 27 August 2015/30 November 2015; accepted 4 December 2015

Version of Record published 9 February 2016, doi:10.1042/BJ20150942


c 2016 Authors; published by Portland Press Limited