Nanophotosensitizers toward advanced photodynamic therapy of Cancer

Cancer Letters xxx (2012) xxx–xxx

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Nanophotosensitizers toward advanced photodynamic therapy of Cancer Chang-Keun Lim a, Jeongyun Heo a, Seunghoon Shin b, Keunsoo Jeong a,b, Young Hun Seo a,c, Woo-Dong Jang c, Chong Rae Park b, Soo Young Park b, Sehoon Kim a,⇑, Ick Chan Kwon a a

Center for Theragnosis, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea Department of Material Science and Engineering, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-744, Republic of Korea c Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea b

a r t i c l e

i n f o

Article history: Available online xxxx Keywords: Photodynamic therapy Photosensitizer Nanomedicine Nanotherapeutics

a b s t r a c t Photodynamic therapy (PDT) is a non-invasive treatment modality for selective destruction of cancer and other diseases and involves the colocalization of light, oxygen, and a photosensitizer (PS) to achieve photocytotoxicity. Although this therapeutic method has considerably improved the quality of life and life expectancy of cancer patients, further advances in selectivity and therapeutic efficacy are required to overcome numerous side effects related to classical PDT. The application of nanoscale photosensitizers (NPSs) comprising molecular PSs and nanocarriers with or without other biological/photophysical functions is a promising approach for improving PDT. In this review, we focus on four nanomedical approaches for advanced PDT: (1) nanocarriers for targeted delivery of PS, (2) introduction of active targeting moieties for disease-specific PDT, (3) stimulus-responsive NPSs for selective PDT, and (4) photophysical improvements in NPS for enhanced PDT efficacy. Ó 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction With advances in the early diagnosis of cancer and increased interest in the conservation of normal tissue during cancer surgery, the rising demands for non-invasive or minimally invasive therapeutic methods for cancer have led to the accelerated development of medical technologies such as radiation therapy [1,2], ultrasound treatment [3,4], cryotherapy [3,5], and photodynamic therapy (PDT) [6–8]. PDT, a non-invasive and alternative method for the treatment of cancer, is a light-activated treatment modality for several types of cancers [9–11]. Destruction of cancerous cells by PDT is achieved by a combination of photosensitizer (PS) and light of an appropriate wavelength for the PS. PS is a type of lightabsorbing dye and plays a role as a PDT drug by transferring the absorbed photon energy to oxygen molecules or other substrates in the vicinity, to generate cytotoxic reactive oxygen species (ROS). Typically, the success of PDT is governed by several parameters, among which selective accumulation of the PS molecules in malignant cells and selective colocalization of light irradiation are prerequisites to avoid collateral damage to healthy tissues. By virtue of this inherent dual selectivity, photosensitized cells are eradicated via apoptosis and/or necrosis in a specific area where both requirements are met [12].

⇑ Corresponding author. Fax: +82 2 958 5909. E-mail address: [email protected] (S. Kim).

Most existing PSs are aromatic and hydrophobic in nature with poor or limited solubility in water. Thus, they are apt to aggregate under physiological conditions, significantly reducing the quantum yields of ROS production. Even in the case of water-soluble PSs, the accumulation selectivity at malignant sites is not high enough for clinical use. In this respect, the incorporation of PSs into waterdispersible nanocarriers, the so-called ‘‘nanophotosensitizers (NPSs),’’ can enhance the solubility of PSs as well as the selectivity of treatment by promoting tumor targeting and intracellular delivery of the PS payload, with or without active targeting moieties such as proteins, peptides, and aptamers [13–17]. Unlike typical drug delivery systems, NPSs are not required to release the PS molecules; instead, it is essential that oxygen species (the actual therapeutic agents) can diffuse in and out of the nanoparticle matrix to exert therapeutic efficacy by photosensitization. This feature offers another advantage by allowing for the construction of a solid-structured photosensitizing nanoplatform as a multifunctional nanomedicine that can integrate additional functions (e.g., imaging, active cancer targeting) into the inner matrix or on the outer surface as a whole. In this regard, a number of trials have been conducted to enhance PDT efficacy using the concept of photophysical improvement through the colocalization of enhancing agents and PS within a nanoscopic space. This approach overcomes the limitation of typical NPSs that exhibit inevitably reduced efficiency of ROS generation due to high local concentration of PS molecules. One of the other reinforcing schemes for therapeutic efficacy of PDT has been the progress in the field of activatable PSs that work on the principle of stimuli (e.g., biomarkers

0304-3835/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canlet.2012.09.012

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for cancerous environment), triggering photocytotoxicity of dormant PSs. In the following sections, we review the state of the art in the main strategies of advanced PDT with NPSs, and the modifications of their interior and/or exterior for highly selective and effectual cancer therapy without invasive surgery. 2. Nanocarriers for PS Most hydrophobic PSs require delivery systems because of their poor water solubility and high toxicity-inducing side effects [15,16]. PDT carriers must fulfill several requirements: (1) minimal internal toxicity, (2) tumor selectivity and adequate retention ability, (3) sufficient encapsulation capacity and rapid release property, and (4) protection of the PDT agent from enzymatic or biological degradation. Nano-sized carriers have extensively acted as transporting vehicles for imaging and therapeutic payloads in various biological fields such as optical imaging, magnetic resonance imaging, and cancer therapy [18–20]. One of the advantages of nanocarriers is derived from the unique microenvironment surrounding the tumor tissue. Fast-growing cancer cells exhibit unusual cell sizes and create an acidic environment that is different from that of normal tissue [21,22]. Accordingly, drug entry into tumor cells is determined by the physicochemical and morphological properties of drug carriers, such as material composition, size, shape, and surface properties, considering the pathophysiological aspects of the organism, such as unique tumor microenvironment. Nano-sized carriers have outstanding targeting ability as well as enhanced permeability and retention (EPR) effect in comparison with existing microcarriers [23]. Nanocarriers are extensively used because of their improved performance, simple loading process, and high extensibility. Nanocarriers of PSs are comprised of various materials such as phospholipids and cholesterol, polymers, silica materials, and metals (Fig. 1) [16]. 2.1. Liposomes Liposomal carriers are constantly investigated as drug vehicles owing to their simple archetypal structures, controllable sizes, and convenient preparation procedure [13,24]. Uni- or multilamellar lipid bilayer liposomes exhibit appropriate retention of drugs and excellent and rapid accumulation/release characteristics in tumor cells. Liposome selection can be optimized according to the physical properties of PSs, such as hydrophobicity [25–30]. However, conventional liposomes are sometimes characterized

A

Antibiofouling coat

by short plasma half-life, which is insufficient time for tumor cell uptake given the rapid elimination by the reticuloendothelial system (RES) and decomposition due to lipid exchange from molecular interaction with liposome components. Among liposomes of similar composition, smaller liposomes exhibit more efficient accumulation and retention because larger ones are easily eliminated by macrophages or complement proteins [31,32]. The influence of size on pharmacokinetics and biodistribution was investigated with STEALTHÒ liposomes of different diameters (82–241 nm). The results indicate a size dependence of the therapeutic effect such that smaller liposomes are more efficient than larger ones. Therefore, careful size control in conjunction with PS is an important factor in the use of liposomal carriers. Recently, specifically modified liposomes have been developed for prolonged circulation in the bloodstream and structural stability [33,34]. By modifying the surface property, the circulation time was also increased [35]. Thus, a higher concentration of liposomes can accumulate in the tumor, resulting in an increase in the delivered amount of available PSs [36]. 2.2. Polymer nanoparticles Polymer nanoparticles (PNPs) emerge as more attractive drug delivery systems than liposomes due to their high stability and small/uniform particle size distribution, which contributes to their passive targeting delivery via the EPR effect, and prevents recognition by macrophages and proteins, with prolonged circulation time in the blood [37–39]. A major drawback of nanoparticles is their propensity to be taken up by the RES after intravenous administration and accumulation in the spleen and the liver. Size reduction and antifouling coating with poly(ethylene glycol) (PEG) can increase the blood circulation time and subsequent accumulation of nanoparticles in tumors. Hydrophobic drugs such as PSs can be physically entrapped in the core of PNPs with a hydrophilic periphery for efficient delivery to tumor cells in an aqueous environment. Usually, PSs are confined by hydrophobic or electrostatic interactions between the drug and the polymer. The size of PNPs can be controlled in the nanometer range for transport into tumor cells, by altering the polymer composition. Polyglycolide (PGA), polylactide (PLA), and their copolymer poly(D,L-lactide-co-glycolide) (PLGA) have been particularly used because of their versatility, physical robustness, biocompatibility, high drug-loading efficiency, and controlled drug release [40–42]. The effect of copolymer composition on particle size, drug-loading

C

Lipid bilayer Hydrophilic PS

Hydrophobic PS

Hydrophobic PS

B

Colloidal stabilizer Polymer/silica nanoparticle

Hydrophobic inner multicore

Hydrophilic shell

D

Colloidal stabilizer PS Gold nanorod

Hydrophobic PS

Fig. 1. A schematic diagram of exemplary nanoscale photosensitizer formulations (NPSs): (A) liposome, (B) polymer/silica nanoparticle, and (C) self-assembled nanogel, and (D) gold nanorod.

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efficiency, and PDT effect has been investigated with the selected polyesters, PLGA (50:50 PLGA and 75:25 PLGA) and poly(D,L-lactide) (PLA), having similar molecular weights but different copolymer molar ratios. The influence of the copolymer molar ratio and the tendency of payloads were investigated with respect to particle size, drug loading, and surface characteristics. In every polymer system, sub-150 nm-sized nanoparticles were produced with narrow size distributions regardless of polymer composition. A PS, meso-tetra(hydroxyphenyl)porphyrin (p-THPP), was incorporated into these polymers, resulting in sub-130-nm-sized nanoparticles. The 50:50 PLGA nanoparticles showed relatively low drug concentrations and short incubation periods necessary to induce a satisfactory PDT effect, resulting in superior photoactivity. The use of the PLGA polymer improves PDT performance, including higher payloads, narrow size distribution, and preserved bioactivity. Compared to biodegradable polymeric carrier systems, nonbiodegradable PNPs have several advantages, including their facile synthesis, ease of functionalization, and the robustness of structure integrity [15]. Polyacrylamide (PAA) polymers can also be used in non-degradable PNPs [43,44]. The PAA polymer has been used in preparing multifunctional biomedical nanoparticles (30–60 nm in size) containing PS for successfully delivering ROS to cancer cells. The PDT results indicate successful localization in the tumor by crossing the blood–brain barrier. The PSs encapsulated are not extruded from the nanoparticles, maintaining their PDT performance in cells. Consequently, multidrug resistance (MDR) can be avoided. The attachment of PEG to the surface of PAA nanoparticles prolonged the plasma residence time [45]. 2.3. Polymer nanogels To improve the selective uptake and retention of PSs, hydrophilic nanogels based on chitosan have also been investigated [46]. Photodynamic experiments revealed excellent photocytotoxicity of the PSs that are entrapped in the nanogels. In a mouse model of rheumatoid arthritis, injection of free PSs led to the rapid clearance from the joints, whereas PSs encapsulated in nanogels were retained in the inflamed joints for a longer duration. Photodynamic treatment of the inflamed joints resulted in a reduction in inflammation comparable to that of a standard corticoid treatment. Polymeric nanogels (diameter < 150 nm) composed of a lowmolecular-weight hyaluronic acid (HALM)/PS conjugate were also formulated in aqueous solution [47]. The formed nanogels were rapidly internalized into HeLa cells via an HA-induced endocytosis mechanism. The autoquenched photoactivity of the nanogel was activated when incubated with cells, indicating the enzymatic degradation of the HA backbone. The consequently recovered phototoxicity of the nanogel against cancer cells is similar to that of free PS, with very low dark toxicity. This indicates that HA-based nanogels can potentially be applied in PDT. 2.4. Silica nanoparticles Compared to organic polymeric systems, inorganic silicate (SiO2) carriers have several merits, including their non-toxic nature, inert and stable properties, and potential non-reactivity toward microbials and enzymes [15,39]. They are also insensitive to fluctuations in temperature and pH. Consequently, the physical characteristics of SNPs, such as particle size, shape, and surface property, are maintained during the carrying and therapy procedure. Since they are not biodegradable, the particle size needs to be carefully controlled as small as possible to ensure avoidance of the RES capturing as well as body clearance through the kidney. Biological applications of porous silica nanoparticles (SNPs) have been investigated in various fields such as cell marking, bioimag-

3

ing, and drug and gene delivery. Owing to their small particle size and high pore volume, SNPs have a high PS-loading capacity that contributes to PDT efficacy [16]. Organically modified silica (ORMOSIL) nanoparticles (ca. 30 nm) with an entrapped photosensitizing anticancer drug have been investigated [48]. The resulting ORMOSIL nanoparticles are monodispersed, spherical, and stable in aqueous media. Singlet oxygen is efficiently generated by suitable light irradiation, causing significant damage to tumor cells via the inherently porous surface. The fine pores in the ORMOSIL nanoparticles, which are 0.50–1.00 nm in diameter, are small enough to block drug release, but permeable to molecular oxygen and the generated singlet oxygen. 3. Active targeting of NPSs The goal of PDT is to selectively kill tumor cells with minimal collateral damage to surrounding normal cells. For this, selective uptake of PSs into the tumor is a prerequisite. To improve tumor selectivity, studies have been conducted to design and develop NPSs with specific targeting moieties [49]. These moieties, which have a specific affinity for appropriate receptors overexpressed on the tumor cells and their vasculature but not on normal cells, facilitate the effective accumulation of PSs in tumor tissue and increase the overall efficacy of PDT with low collateral damage. In this section, the recent approaches to increase the efficiency of PDT using tumor-targeting moieties are summarized (Table 1). 3.1. Tumor vasculature and neo-angiogenesis targeted PDT Vessels that develop in and around tumors function as channels to transport nutrition and oxygen for tumor survival. The tumor vasculature has been mainly targeted in the eradication of vascularized tumors using PDT [66]. However, secondary angiogenic and inflammatory responses occur after single PDT application for cancer, which results in revascularization of the treated lesions and contributes to tumor recurrence [66,67]. Angiogenesistargeted PDT, which interacts with target blood vessels, destroys reforming vasculature, and increases the therapeutic efficacy of PDT, has been used to suppress tumor recurrence after single PDT [68]. Another advantage of angiogenesis-targeted PDT is the reduction in secondarily acquired drug resistance due to the limited susceptibility of neovascular endothelial cells to undergo phenotypic variations. Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) are the most potent and specific regulators of angiogenesis, which trigger tumor regrowth by promoting the proliferation, migration, and tube formation of endothelial cells. VEGFR is overexpressed in many cancers, including ovarian, colorectal carcinoma, head and neck, lung, and pancreatic cancers among others, and is correlated with poor prognosis. Therefore, VEGFR and its ligand VEGF are used as a targeting pair. Many studies have shown that the use of VEGF or VEGFR for angiogenesistargeted PDT is effective in enhancing the therapeutic efficacy of PDT [50,69–73]. Photoimmunoconjugates, which are PS-conjugated angiogenesis-targeting antibodies, represent a useful dual strategy for the selective destruction of cancer cells, and exert the receptorblocking biological function of the antibody [51,74]. Small synthetic peptides are relatively easy to prepare and store compared to antibodies, which are fragile materials that can easily lose their tertiary structure and biological activity during the conjugation process [73,75]. Furthermore, their chemical synthesis is almost impossible. Small synthetic peptides are very effective in selectively targeting tumor vessels and angiogenesis even though they lack a functional tertiary structure [51,67,70,71]. A PS, 5-(4carboxylphenyl)-10,15,20-triphenyl-chlorin (TPC), coupled to a VEGFR-specific heptapeptide (ATWLPPR) via 6-aminohexanoic acid (Ahx) (TPC-Ahx-ATWLPPR), bound exclusively to neutrophilin-1

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Table 1 Target specificity of active tumor-targeting NPSs. Targeting moiety

Target

Cell types

Photosensitizer

Nanocarrier

Ref.

Cyclic Arg–Gly–Asp-(D)–Tyr–Lys (c(RGDyK)) Ala–Pro–Arg–Pro–Gly (APRPG)

Integrin amb3

U87-MG

Pyropheophorbide A (Ppa)

[50]

Angiogenic endothelial cell pKi-67 (nuclear) Folate receptor

Meth-A sarcoma Benzoprophyrin derivative monoacid ring A (BPD-MA)

Chitosan-wrapped NaYF4:Yb/Er upconversion nanoparticle PEG modified liposom

Ki-67 antibody (TuBB-9) Folic acid

Haluronic acid

Mannose/galactose

OVCAR-5

Fluorescein isothiocyanate (FITC)

Photoimmunoconjugate encapsulating liposome

[52]

HT29

5-ALA

Alginate conjugated chitosan nanoparticles

[53]

Chlorin e6 (Ce6) Pheophorbide A Chlorin e6 (Ce6)

Graphene oxide nanoparticle Pullulan nanoparticle 5b-Cholanic acid conjugated hyaluronic acid nanoparticles Mesoporous silica nanoparticle coated with poly-(L-lysine) and hyaluronic acid (HA) NLS conjugated BSA

[54] [55] [56]

PEGylated phtofrin/iron oxide encapsulated acrylamide nanoparticle Methylene blue conjugated polyacrylamide nanogel F3, Cyanine dye and HPPH conjugated polyacrylamide nanogel Mesoporous silica nanoparticle

[59]

Mesoporous silica nanoparticles

[63]

Jacalin (a lectin) -PEG phthalocyanine gold nanoparticles

[64]

TMPyP4 incorporated AS1411-functionalized

[65]

MGC803 HeLa CD44 receptor HT29

Simian virus SV40 large T antigen Nucleus (nuclear localization signal (NLS)) Vascular homing peptide (F3) Nucleolin

Lectin

[51]

HCT116

Anionic porphyrin

PLC/PRF/5

Chlorin e6 (Ce6)

MDA-MB-435/ 9L 9L/MDA-MB435/F98/MCF-7 9L/MDA-MB435/F98/MCF-7 MCF-7/MDAMB-231/HTC116 Y-79

Photofrin

T antigen-specific lectin (Jacalin)

Lectin

HT-29

Aptamer (AS1411)

Nucleolin

Overexpressed in tumor cells

Methylene blue 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide (HPPH) Banana-shaped biphotonic quadrupolar chromophores 13 Camptothecin delivery and PDT anionic porphyrin Octaalkyl-substitued zinc(II) phtalocyanin (C11Pc) photosensitizer 5,10,15,20-tetrakis(1methylpyridinium-4-yl)porphyrin (TMPyP4)

and exhibited significantly enhanced photodynamic activity compared to free TPC in human umbilical vein endothelial cells (HUVECs) as well as in nude mice xenografted with U87 human malignant glioma cells [67,71]. In an NPS system, angiogenic endothelial cells targeted with the pentapeptide (APRPG)-conjugated liposomal PS exhibited strong suppression of tumor growth compared to those targeted with a non-APRPG NPS [51]. Another major biomarker of tumor angiogenesis is integrin avb3, which is widely overexpressed on actively proliferating endothelial cells of neovessels in and around malignant tumors such as osteosarcomas, neuroblastomas, and lung carcinomas, and extensively interacts with the extracellular matrix (ECM) on other tumor cells via the Arg–Gly–Asp (RGD) motif of ECM proteins. This interaction is associated with deregulated angiogenesis, tumor growth, and metastasis [50,76–78]. A PS and RGD peptide-comodified chitosan-wrapped NaYF4:Yb/Er upconversion NPS (UCNP-Ppa-RGD) exhibited strong targeting to integrin avb3-positive U87-MG cells with near-infrared (NIR) PDT [50]. Taken together, photodynamic technology using tumor vessel/angiogenic-targeting moieties and NPS seems to be a promising and powerful approach not only to increase tumor selectivity but also to enhance the anti-tumor efficacy of PDT with suppressed malignant tumor recurrence. 3.2. Tumor-specific cellular biomarker targeted PDT During the transformation of healthy cells to malignant cells, aberrations occur in the glycosylation of cell-surface glycoproteins. For example, cancer cells frequently display glycans at different levels or with fundamentally different structures from those observed on normal cells. To improve the therapeutic efficacy of PDT in cancer, efforts have been made to use the glycosylation differences between cancer and normal cells as a targeting factor [79].

[57] [58]

[60] [61] [62]

Fe3O4–SiO2 ðRuðbpyÞ2þ 3 ) core–shell nanoparticle

T-antigen disaccharide, one of the most attractive cancer-associated carbohydrate biomarkers, is expressed in more than 90% of primary human carcinomas. Recently, gold-NPS-conjugated jacalin, a kind of lectin, which was covalently conjugated to specifically target the T-antigen disaccharide, exhibited significantly greater cellular uptake and exceptional photodynamic efficacy with respect to cell death rate than non-conjugated nanoparticles in HT29 colon adenocarcinoma cells [64]. In addition to directing PSs specifically to tumor cells, direct targeting of PSs to hypersensitive subcellular sites within tumor cells, such as nucleus, should enable more effective PDT without harming normal healthy cells [80]. Nucleus is more sensitive to 1O2 damage than other organelles. Considering that the average intracellular diffusion distance of 1O2 produced during PDT is approximately 50 nm, the smaller the distance between PSs and nucleus, the greater is the phototoxicity in tumor cells [80,81]. Nuclear localization signal peptide (NLS peptide)-conjugated PSs exhibit 100- to 1000-fold enhanced phototoxicity compared to nonconjugated PSs [58,82]. F3, a vascular-homing peptide, selectively binds to nucleolin overexpressed on the surface of actively growing endothelial cells, such as tumor blood vessel cells and tumor cells, and the F3-nucleolin bound complex is transported from the cell membrane to the nucleus [83]. F3-targeted iron oxide-based NPS was selectively distributed in the nucleus of MDA-MB-435 cells and exhibited significantly improved phototoxicity and contrast in magnetic resonance imaging in a rat model of brain tumors [59]. As a result, the survival rate of the group with F3-targeted NPS was also significantly increased. Similar to a small peptide, an aptamer, which is an oligonucleotide that selectively binds to molecular targets with high affinity, can be an effective tool for targeting anti-tumor PDT [84]. Pegaptanib and AS1411 are representative aptamers that are currently un-

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der clinical trials. Pegaptanib sodium is a Food and Drug Administration (FDA)-approved RNA aptamer directed against VEGF-165, which is the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability [85]. AS1411 is a 26-mer guanine-rich DNA aptamer in phase II clinical trials for relapsed or refractory acute myeloid leukemia and renal cell carcinoma. It is stable in the G-quadruplex form, which binds to nucleolin with high affinity [86]. The PS, 5,10,15,20-tetrakis(1methylpyridininium-4-yl)porphyrin (TMPyP4)-incorporated Gquadruplex of AS1411, exhibited substantially higher affinity and phototoxicity toward MCF7 breast cancer cells than normal cells [87]. When TMPyP4-AS1411 was conjugated to Fe3O4– SiO2 ðRuðbpyÞ2þ nanoparticles (FMNs), the phototoxicity of 3 ) AS1411-TMPyP4-FMN NPS was higher than that of the TMPyP4FMN conjugate at high concentrations of TMPyP4 [65]. However, the production cost for nucleic acid therapeutics remains relatively high, particularly for long nucleic acids such as aptamers. Improvements in chemical synthesis will prove relevant to the development of aptamer therapeutics [88]. The folate receptor is frequently overexpressed on the surface of cancer cells, especially in ovarian, kidney, lung, breast, and brain carcinomas, whereas it is highly regulated in most normal tissues. Furthermore, it is efficiently internalized into cells after binding with its ligand, folic acid. Folic acid is stable in the plasma compartment, inexpensive, and non-immunogenic, compared with proteins such as antibodies, and has a very high affinity for its receptor (Kd  1 nM) [89]. For these reasons, folic acid offers

advantages as a PDT-targeting agent. Folic acid-conjugated NPSs [53–55] demonstrated enhanced cellular uptake and phototoxicity in KB cells and MGC803 cells, respectively. 4. Activatable NPSs Activatable PSs are advanced PDT agents that are turned on by various stimuli in or around diseased environments, resulting in cytotoxic singlet oxygen generation (SOG) with high selectivity for the disease [90,91]. In addition to light irradiation and selective accumulation of PSs in the diseased tissue, molecular activation offers the third level for enhancing the specificity of the targeted PDT toward diseased cells. In this regard, various approaches for deactivation and reactivation of SOG have been extensively researched. This switching modulation is often achieved by sealing the PS in a quenched state of photosensitizing process. As shown in Fig. 2, NPSs that are specially designed to exhibit photocytotoxicity in a stimuli-responsive manner modulate their SOG quantum yields in response to changes in pH and enzyme concentrations. 4.1. Environment (pH)-activatable NPSs The SOG of PSs can be controlled by environmental properties such as pH and polarity [92–96]. Given the more acidic environment around tumor than normal tissues, smart probes comprising pH-sensitive components may be associated with a change in the conformation of the nanostructures or photo-induced electron

A

D

B

E

C

F

photosensitizer

pH indicator

quencher

SiO2 nanoparticle

gold nanorod

pullulan nanogel

PEG

peptide linker

cationic polymer

hydrophilic polymer

anionic polymer

Fig. 2. Schematic representation of activatable NPSs: (A) Micellar probe, the components of which are molecularly dissociated at low pH, (B) pH Indicator-embedded silica nanoparticles. Activation of PS is observed at low pH because of a change in the indicator absorption at the excitation wavelength, (C) silica nanoparticle-based probe. The quenched PSs on the surface are detached and activated at low pH, (D) protease-activatable gold nanorods. Phototoxicity is turned on by the cleavage of specific peptide linkers by protease, (E) pullulan-based nanogels. Self-quenched photoactivity is recovered by the enzymatic release of PSs in cancer cells, and (F) quencher-containing polymeric NPS. Photoactivity is recovered following the proteolytic release of quenchers from the NPS.

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transfer (PET) properties, especially under tumoral conditions. To increase the PDT selectivity toward cancer cells, pH-activatable PSs based on the modulation of electron transfer phenomenon were developed. McDonnell et al. designed a series of pH-responsive supramolecular PSs based on reversible off/on switching by attaching PET-based quenchers, resulting in PSs that are only active in the protonated state at low pH [97]. Urano et al. synthesized acidic pH-activatable BODIPY probes based on the N,N-dialkylated aniline structure capable of PET [98]. When N,N-dialkylated aniline-substituted BODIPY probes were deprotonated at neutral pH, the BODIPY fluorophore did not exhibit fluorescence. However, these probes were changed to a protonated form at low pH, and the fluorescence of the probes appeared in the lysosomes due to the prevention of PET from the aniline moiety to the fluorophore. This approach can provide highly specific optical imaging of diseased cells with minimal background intensity. Taking advantage of this principle, Jiang et al. synthesized a variety of silicon (IV) phthalocyanine-substituted aryl polyamine moieties as pH-activatable PSs via amine protonation [99]. The smart PSs exhibited enhanced quantum efficiencies of ROS generation as well as enhanced fluorescence at pH 6.0 compared to pH 7.4. To examine the intracellular pH sensitivity, HT29 cells were incubated with the PSs, followed by solutions of the ionophore nigericin at different pH, resulting in the selective appearance of fluorescence in the acidic environment. Modification of photosensitizing porphyrin derivatives is also an effective method to obtain a highly selective accumulation of the PS in tumor cells. Zhu et al. reported an imidazole-substituted pH-activatable PS, 5,10,15,20-tetrakis (N-(2-(1H-imidazol-4-yl)ethyl)benzamide)porphyrin (TIEBAP), and its pH-dependent modulation of hydrophilicity [100]. The weak fluorescence due to the face-to-face aggregation of the porphyrins caused by their poor water solubility at pH 8.0 was altered to a strong fluorescence with an increase in hydrophilicity at pH 5.3. Furthermore, in the SK-BR-3 cancer cell viability test, photocytotoxicity was also enhanced when the pH was reduced from alkaline to acidic pH. Activatable NPSs with micellar structures formed by the physical or chemical introduction of a hydrophobic PS into a waterdispersible polymer have been used in PDT. A pH-sensitive micelle-encapsulated m-THPC, a clinically approved PS, was reported for smart PDT [101]. The pH-sensitive micelles, based on poly(2-ethyl-2-oxazoline)-b-poly(D,L-lactide) diblock copolymer, more effectively released the PSs at pH 5.0 than at pH 7.4. When free m-THPC was compared with the m-THPC-loaded micelles, the latter exhibited less skin phototoxicity in vivo. A smart NPS based on 3-diethylaminopropyl isothiocyanate (DEAP)-conjugated glycol chitosan was designed in such a way that it converts from a 3-dimensional supramolecular nano-assembly into extended random molecules via a change in the charge on the substituted DEAP at low pH. The SOG became detectable when these smart NPSs underwent a conformational change into freely extended molecules at pH 6.8 (see Fig. 2A) [102]. To improve both photosensitization efficiency and specific targeting to tumor cells, ORMOSIL nanoparticles have been developed by several research groups [103,104]. Because ORMOSIL nanoparticles, which are well-known water-dispersible and biocompatible materials, have a number of advantages as nanocarriers for optically active materials, they are suitable for light-activated theranostic applications [48,105–107]. Wang et al. proposed a pH-sensitive silica-based NPS consisting of a PS and a pH indicator for activatable PDT. Through competitive light absorption with PSs, the pH indicator as an ‘‘inner filter’’ adjusts the excitation of the PSs. At low pH, the hypsochromic shift in the absorption of the pH indicator allows the expeditious excitation of the sensitizer, whereas the excitation light for the PSs is competitively absorbed by the pH indicator at high pH (see Fig. 2B) [108]. Due to pH dependence of the ionic strength and

zeta-potential of silica colloids, their surface charge becomes more negative via deprotonation of silanol protons as the pH increases [109,110]. On the basis of this phenomenon, Li et al. prepared a pH-activatable smart NPS via electrostatic interactions between a cationic PS, meso-tetra(N-methyl-4-pyridyl)porphine, and bare SiO2 nanoparticles. In acidic solution, the attached PSs are separated from the surface of the silica nanoparticles, resulting in increased fluorescence and SOG (see Fig. 2C) [111]. 4.2. Enzyme-activatable NPSs Enzymes are proteinaceous biological materials that act as catalysts in chemical reactions, with extremely high specificity for their substrates. Given that enzyme overexpression is highly correlated with specific diseases, the use of enzymes as biomarkers of specific diseases, and simultaneously, as stimuli for smart PSs can be an excellent strategy for highly selective PDT. Recently, various protease-activatable smart probes have been selectively activated by proteolysis. These probes are optically deactivated by a FRET-based quenching process elicited by proximity between the PS and quencher molecules, which often can be the same PS for self-quenching [112]. During selective cleavage of the peptide linker connecting the PS and quencher (or PS) in the diseased tissue, where the linker-specific proteases are abundant, the photosensitizing process is activated by the removal of the quenching moiety from the PS. Various approaches employing enzyme-activatable smart sensitizers have been developed to utilize the selective proteolytic activity in specific tissues. Peptide-based activatable smart probes have been constructed using either polymeric peptide backbones or short peptide sequences. An enzyme-activatable smart sensitizer was reported based on the polylysine-conjugated chlorin e6 (Ce6) as a PS [113,114]. After enzymatic cleavage of the polylysine backbone in the tumor tissue, the PSs were separated from other PSs. As a result, both the SOG and fluorescence of the PSs were enhanced at tumor sites. However, because cross-reactivity of the polylysine residues with various proteases is a disadvantage of these probes, enzyme-specific peptides with higher specificity are required for highly selective PDT [115–118]. Zheng et al. synthesized an enzyme-sensitive PS that specifically responded to matrix metalloproteinase-7 (MMP7) to regulate PDT activity [116]. By conjugating the PS and BHQ-3 quencher to the opposite ends of the MMP7-specific peptide linker, fluorescence and singlet oxygen generation of the PS were perfectly quenched by FRET. Using this smart PS, MMP7-activated PDT efficacy was demonstrated in cells as well as in vivo. A similar approach involving the use of a PS and a quencher fused by an enzyme-specific cleavable linker sequence has been used to detect other proteases, including caspase-3 and fibroblast activation protein [117,118]. Recently, some studies on enzyme-activatable PDT have been conducted using NPSs such as nanorods, nanogels, and nanoparticles [106–108]. Jang et al. reported gold nanorod (GNR)-based NPSs, in which the PSs were conjugated to the surface of the GNR via an MMP2-cleavable peptide linker [119]. The fluorescence and phototoxicity of the NPSs were suppressed by the surface plasmon resonance of the GNR and activated following release from the GNR surface by MMP2 (see Fig. 2D). A nanogel-based activatable PS was demonstrated to selectively target tumor cells by efficient activation [120]. The nanogel-based probe that was formed by pullulan-PS conjugation via an ester bond was degraded by lysosomal enzymes in tumor cells as well as tumor tissue in vivo, resulting in the occurrence of photoactivity (see Fig. 2E). Another type of SOG-quenched polymeric NPS was designed and prepared by using the electrostatic interaction between a cationic PEG–polyethylenimine–chlorin e6 (PEG–PEI–Ce6) and an anionic polysaccharide quencher (BHQ-3-CS) [121]. The quenched photoactivity derived from the colocalization of the PS and quencher in

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the nanoscopic space was recovered by the enzymatic degradation of the quencher after esterase treatment (see Fig. 2F). Furthermore, when the NPS was injected into both the tumor-inoculated and normal regions of tumor-bearing mice, the fluorescence in the tumors was efficiently enhanced compared to that of the normal region.

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electron or hydrogen-atom transfer between the excited triplet PS and a substrate to generate free radicals. The Type II reaction, the main process occurring in PDT, involves energy transfer between the excited triplet PS and the ground triplet oxygen, to generate singlet oxygen [127]. Accordingly, the efficiency of singlet oxygen generation (SOG) that governs the phototoxicity can be enhanced by improving the photophysics of PSs. NPS-based strategies for photophysics improvement are exemplified in Fig. 4.

5. Photophysical improvements in PDT 5.1. Heavy-atom effect Singlet oxygen is the dominant mediator of phototoxicity in PDT, which causes apoptosis or necrosis of malignant cells [10,11,122,123]. The photophysical processes related with singlet oxygen generation are illustrated in a Jablonski’s diagram (Fig. 3). The photosensitization is initiated by the absorption of light by the PS causing a transition of the PS from its ground state to the excited singlet state. The PS’s excited triplet state is subsequently generated as a result of intersystem crossing (ISC) from the excited singlet state. With the longer lifetime, the excited triplet PS interacts with surrounding molecules to elicit a Type I or Type II photo-oxidative reaction [124–126]. The Type I reaction involves

In the process of SOG during PDT, the ISC governs the amount of singlet oxygen produced (see Fig. 3), and the rate of ISC can be elevated as a result of enhanced spin–orbit coupling via internal or external incorporation of heavy atoms into the PS [128–130]. Generally, the heavy-atom effect (HAE) for SOG is generated by directly/covalently incorporating heavy atoms such as halogens [131–136] and metals [137–141] into the PS, making use of the so-called internal heavy-atom effect (IHAE). Comparative studies on the IHAE phenomenon for advanced PDT have been conducted with halogen substituted porphyrin derivatives (PDs) as PSs

Fig. 3. Simplified Jablonski’s diagram of single and two-photon absorption-induced excitation for singlet oxygen generation.

Fig. 4. A schematic diagram of NPSs showing improved photosensitization by photophysical modulation: (A) Iodine-rich NPSs with intraparticle heavy-atom effect. (B–D) NPSs capable of FRET-mediated enhanced excitation by single/multi-photon (visible, near-IR) or X-ray.

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[136]. The efficiency of ISC of the halogenated PD (uD.hal = 0.56– 0.64) was higher than that of non-halogenated PD (uD.nonhal = 0.49), and large decreases in fluorescence quantum yield (uf.hal = 0.002–0.006 and uf.non-hal = 0.065, in ethanol) were observed, indicating the IHAE. Similarly, various chromophores, including boron-dipyrromethene (BODIPY), polypyrrole macrocycle, squaraine, and bacteriochlorin, have been used to generate the IHAE during ISC by direct/covalent halogenation [131– 134,136]. In the same manner, metal-incorporated chromophores have been used to generate the IHAE in SOG. For this approach, various metals such as selenium [137], copper [138], palladium [138,139,141], magnesium [140], tin, and platinum [141] have been incorporated into the chromophore. The approaches to generate the IHAE by intramolecular incorporation of heavy atoms into the PS involve complicated synthetic procedures that elicit undesirable modifications in the photophysical properties of the PSs. In this respect, the external heavy-atom effect (EHAE) generated by intermolecular incorporation of heavy atoms is suggested to be another possible approach to enhance the efficiency of SOG in PDT. An organically modified SNP colocalizing iodines and a PS [142], for example, was prepared using a mixture of an iodine-substituted silicate precursor, (3-iodopropyl)trimethoxysilane, and a PS, 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide. The PS molecules in the iodine-concentrated nanoparticles were surrounded by a large quantity of iodine within a nanoscopic distance, producing an increased population of the excited triplet PS due to enhanced spin–orbit coupling, and thus showing the enhanced efficiency of SOG. Similarly, pluronic nanoparticles containing iodine-substituted aromatic molecules as a rigid core matrix and chlorin e6 as a PS was shown to have almost doubled efficiency of SOG, compared to free chlorin e6 [143]. Diatrizoic acid was used as the iodine-substituted aromatic matrix, which has been shown to be safe in vivo and is being used clinically as a radiocontrast agent for X-ray imaging and computed tomography (CT). Further, it has recently been reported that iodinated glycol chitosan nanoparticles conjugated with chlorin e6 and diatrizoic acid exhibited the combined merits of intraparticle EHAE and high-specificity tumor targeting in vitro and in vivo [144]. In addition to EHAE, the iodine-concentrated NPSs offer another advantage of enhanced hydrophilicity and appropriate small size for passive targeting to tumor tissues via the EPR effect, as discussed above [37,145]. Given benefits of the combined merits, heavy atom-rich nanoplatforms of PS provide a promising pathway to enhanced PDT. 5.2. Energy transfer (ET) Commonly used PSs for PDT are mostly activated by visible light absorption. Therefore, the clinical use of PSs are limited to the treatment of topical lesions, such as skin and breast cancers, due to the low penetration depth (a few millimeter) of visible light. Even with the use of a light dose with relatively long penetration depth in the NIR region, the efficacy of PDT is still limited by the weak absorption of PSs in the NIR spectral region [146]. To overcome this problem, Förster (fluorescence) resonance energy transfer (FRET) is often suggested as a possible approach to improve the SOG efficiency of PSs, where FRET is the non-radiative energy transfer from the initially excited donor to an acceptor. FRET has been widely used in most applications of fluorescence, including PDT [147]. The main idea behind the efforts to use FRET-based SOG is the chemical/physical incorporation of a donor having high absorption coefficient and fluorescence quantum efficiency with an acceptor PS, within nanoscopic distance for effective ET, resulting in SOG following donor activation. Given their extremely high absorption coefficient and fluorescence quantum yield, and long-term photostability, as well as tun-

able emission bands, quantum dots (QDs) are attractive donors for FRET [148,149]. Various QD-PS conjugates, in which PS molecules are covalently conjugated to the surface of QDs, have been used for FRET-mediated SOG [150–152]. CdSe QD-phthalocyanine conjugates, for example, were prepared as a FRET probe, in which the efficiency of the FRET process could be modulated by different QD surface chemistry conditions [150]. CdSe/CdS/ZnS QD-chlorin e6 (or Rose Bengal) conjugates exhibited high SOG efficiency via indirect excitation through FRET from QDs to PSs [151]. However, light delivery into deep tissues for PDT remains an inherent limitation, because QDs absorb light of shorter wavelengths than PSs. Generally, porphyrin derivatives have a strong absorption at around 400 nm (Soret band) and a weak absorption at around 600–800 nm (Q band) [153]. The excitation of the PS at the Soret band can be much more efficient than that at the Q-band if the UV/blue light is delivered into deep tissues. However, due to the limited penetration depth of the UV/blue light, the NIR/red light is commonly used to activate the weak Q-band of PS, which results in lower SOG efficiency for PDT. In this respect, a combination of radiotherapy and PDT using PS-conjugated X-ray luminescent nanoparticles (XLNPs), such as LaF3:Ce3+ and LaF3:Tb3+ nanoparticles, has been considered as a new approach to facilitate excitation at the Soret band of PSs for high PDT efficacy [154–156]. In this manner, PS-XLNP conjugates can be activated at targeted tumors by X-rays during radiotherapy, following the effective ET from excited XLNP to PS. Therefore, by virtue of the combined merits of radiotherapy and PDT, the therapeutic effect will be further improved even in the case of deep tumor treatment. Alternatively, to overcome the low penetration depth of a higher-energy (shorter wavelength) light dose, upconversion nanoparticles (UCNPs), such as NaYF4:Yb3+/Er3+ nanoparticles, have served as effective energy donors for PSs [157–161]. UCNP absorbs more than two low-energy pump photons in the NIR region in a cascade manner and converts them into a higher-energy photon in the visible region. Therefore, NaYF4 nanoparticles emit visible light in the green and red spectral regions, enabling effective activation of PSs via transfer of the upconverted energy. For PDT use, UCNP has been conjugated with PSs such as merocyanine [157], zinc phthalocyanine [158,160,161], chlorin e6 [159], and pyropheophorbide a [162], and exhibits efficient SOG after exposure to NIR light, resulting in enhanced therapeutic effects in vitro and in vivo. This approach has to be distinguished from simultaneous two-photon absorption-induced excitation of PSs, which will be discussed in the next section. For all ET-mediated PDT agents, a nanoscopic distance is required between the donor and acceptor, and therefore most of the ET-mediated approaches are facilitated by colocalization of donors and acceptors in a nanoplatform. As mentioned above, nanoplatforms also offer the benefit of high accumulation selectivity in tumor tissues via the EPR effect, making them clinically more useful. 5.3. Two-photon absorption Two-photon absorption (TPA)-induced excitation is based on the absorption of two NIR photons (normally in the range of 750–1000 nm), providing the same level of energy to a single photon of visible light (Fig. 3). Therefore, TPA-mediated approaches are regarded as another promising strategy to overcome the limitation of low penetration depth of light, and have been exploited by the design of new PSs or chemical modification of existing PSs to enhance the quantum efficiency of TPA-induced excitation for SOG [163–168]. As mentioned previously, nanoplatforms have facilitated TPAmediated approaches by offering the benefits of efficient twophoton energy transfer for SOG as well as selective accumulation

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in tumor tissues for higher PDT efficacy. The strategies have generally been proposed using the combined concepts of TPA- and FRETbased approaches and generated by incorporating a TPA dye (an energy donor) and a PS (an energy acceptor) into the nanoplatform [169–171]. Therefore, complicated synthetic steps are no more necessary to raise the two-photon absorptivity. Indeed, energy harvesting by the TPA donor in the recently reported ORMOSIL nanoparticle [169] co-encapsulating a TPA dye and a known PS strongly enhanced the SOG efficiency of the PS after exposure to NIR light, resulting in enhanced phototoxicity in cancer cells even in water. Similarly, aqueous micelles colocalizing a TPA dye and a PS [171], prepared by combining a water-soluble, amphiphilic, TPA-chromophore-containing, block copolymer and a hydrophobic porphyrin as a PS acceptor in aqueous media, exhibited efficient ET from the TPA chromophore to porphyrin, following the effective SOG from the porphyrins. 6. Conclusion PDT has been clinically applied to various tumors such as skin, esophageal, lung, head and neck, liver, bladder, and prostate tumors; age-related macular degeneration; refractory liver metastasis; breast metastasis; chest wall metastasis; and Kaposi’s sarcoma, given its advantages over current treatments [7,11]. However, there are several technical difficulties in the application of classical PS-based PDT to the treatment of a wide range of tumors, especially those developed in deep tissues. Most classical PSs have limitations such as poor solubility under physiological conditions, uncertain selectivity between tumor and normal tissues for clinical use, and limited light penetration of tissues. A nanoplatform-based PS could solve these problems. NPS can make hydrophobic PS soluble in water and exhibit an appropriate size for passive targeting to tumor tissue. Selective accumulation can be further enhanced by conjugating antibodies or specific tumor-targeting moieties to the NPS surface. Incorporation of two-photon absorbing or upconverting components to NPS enables PDT in deep tumor tissues, and the acceleration of ISC with HAE enhances SOG quantum efficiency. Moreover, as a multimodality nanoplatform, NPSs provide theranostic advantages when they are constructed with diagnostic agents such as magnetic nanoparticles, fluorophores, and quantum dots, or their own fluorescence is used as an imaging signal [43,59,61,172–174]. Although NPSs are still in the initial stages of clinical trials, the exploitation of innovative NPSs may attract the attention of clinicians. Nevertheless, light-activatable therapy continues to suffer from limitations caused by the intrinsic drawbacks of light in vivo (e.g., absorption by biological materials and scattering in tissue). We believe that a combination of improved technologies in light delivery, endoscopic devices, and PS may eventually propel the application of PDT to the forefront of oncological diagnosis and intervention of various tumors in the near future and finally overcome the limitation of PDT for clinical application. Combinations of PDT with surgery, radiotherapy, and/or chemotherapy are being used in a much more precise fashion to minimize morbidity and maximize tumor control. Further, PDT can be performed under relatively primitive conditions and in a cost-effective manner so that patients may have the opportunity to avoid an invasive surgery. Welldesigned clinical trials will allow the realization of this possibility. Acknowledgements This work was supported by grants from the Korea Ministry of Education, Science and Technology (MEST) (Nos. 2012-0001082 and 2012-0006061) and by the Intramural Research Program of KIST.

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Please cite this article in press as: C.-K. Lim et al., Nanophotosensitizers toward advanced photodynamic therapy of Cancer, Cancer Lett. (2012), http:// dx.doi.org/10.1016/j.canlet.2012.09.012