ISSN 1519-6984 (Print)

ISSN 1678-4375 (Online)

THE INTERNATIONAL JOURNAL ON NEOTROPICAL BIOLOGY

THE INTERNATIONAL JOURNAL ON GLOBAL BIODIVERSITY AND ENVIRONMENT

Original Article

Photodynamic therapy in cancer treatment: properties and

applications in nanoparticles
Terapia fotodinâmica no tratamento de câncer: propriedades e aplicações em
nanopartículas

L. A. Younusa, Z. H. Mahmoudb, A. A. Hamzac, K. M. A. Alazizd, M. L. Alie, Y. Yasinf, W. S. Jihadg, T. Rasheedh,

A. K. Alkhawaldehi, F. K. Alij and E. Kianfark,l,m* 
a
Jabir Ibn Hayyan Medical University, Faculty of Pharmacy, Department of Clinical Laboratory Sciences, Al Najaf Al Ashraf, Iraq
b
University of Diyala, College of Sciences, Department of Chemistry, Diyala, Iraq
c
University of Al-Ameed, Faculty of Pharmacy, Department of Pharmaceutics, Karbala, Iraq
d
Al-Noor University College, Department of Pharmacy, Nineveh, Iraq
e
Al-Mustaqbal University College, Department of Dentistry, Babylon, Iraq
f
Al-Farahidi University, College of Medical Technology, Baghdad, Iraq
g
Mazaya University College, Department of Medical Technology, Dhi-Qar, Iraq
h
Prince Sattam Bin Abdulaziz University, College of Science and Humanities, Department of English, Al-Kharj, Alkharj, Saudi Arabia
i
Al-Balqa Applied University, Zarqa University College, Department of Medical Allied Sciences, Zarqa, Jordan
j
University of Diyala, College of Sciences, Department of Chemistry, Diyala, Iraq
k
Istanbul Medeniyet University, Faculty of Engineering and Pure Sciences, Mechanical Engineering Department, Istanbul, turkey.
l
Arak Branch, Islamic Azad University, Department of Chemical Engineering, Arak, Iran
m
Islamic Azad University, Young Researchers and Elite Club, Gurcharan Branch, Gachsaran, Iran

Abstract
Most of the treatment strategies for tumors and other disorders is photodynamic therapy (PDT). For several years,
increasing the efficiency of nanostructured treatment devices, including light therapy, has been considered in
different treatment methods. Light Dynamics The use of nanomaterial in this method’s production and progress.
The use of nanoparticles as carriers is a promising accomplishment, since all the criteria for an ideal photodynamic
therapy agent can be given with these nanomaterials. The kinds of nanoparticles that have recently been used
in photodynamic therapy are mentioned in this article. Latest advancements are being explored in the use of
inorganic nanoparticles and biodegradable polymer-based nanomaterial as carriers of photosynthetic agents.
Photosynthetic nanoparticles, self-propagating nanoparticles, and conversion nanoparticles are among the
successful photodynamic therapy nanoparticles addressed in this report.
Keywords: photodynamic therapy, nanostructured, photosensitizer, photosynthesis, polymer.

Resumo
A maioria das estratégias de tratamento para tumores e outros distúrbios consiste na terapia fotodinâmica (PDT).
Por vários anos, observou-se o aumento da eficiência de dispositivos de tratamento nanoestruturados, incluindo
terapia de luz, que tem sido considerada em diferentes métodos de tratamento. Desse modo, este trabalho visa
analisar a utilização de nanomateriais na produção e evolução deste método. A utilização de nanopartículas como
carreadores é uma conquista promissora, pois todos os critérios para um agente de terapia fotodinâmica ideal
podem ser obtidos com esses nanomateriais. Os categorias de nanopartículas que têm sido utilizados recentemente
na terapia fotodinâmica são mencionados neste artigo. Os últimos avanços estão sendo explorados na utilização
de nanopartículas inorgânicas e nanomateriais à base de polímeros biodegradáveis como portadores de agentes
fotossintéticos. Nanopartículas fotossintéticas, nanopartículas autopropagantes e nanopartículas de conversão
estão entre as nanopartículas de terapia fotodinâmica bem-sucedidas abordadas neste trabalho.
Palavras-chave: terapia fotodinâmica, nanoestruturada, fotossensibilizador, fotossíntese, polímero.

*e-mail: ehsan_kianfar2010@yahoo.com
Received: October 23, 2022 – Accepted: April 06, 2023
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

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Younus, L.A. et al.

1. Introduction Hematoporphyrin derivative photosynthesizer -

HPD American-Canadian drug Photofrin (Pf) was first
Light therapy has been a non-invasive, effective and
used in bladder, esophageal, and lung cancers (Néel,
modern treatment for about two decades that has opened
1947; Herzer, 1996). This is the first-generation Ps of
its place in the treatment of some cancer and non-cancer
a mixture of multicopying, which due to the limited
diseases (Yoo et al., 2016; Ling and Hyeon, 2013; Nie et al.,
selective accumulation in the tumor tissue, the ratio of
2013; Yamada et al., 2014; Meisen and Kathrein, 2000).
its accumulation in the target tissue to healthy tissue is
This method is based on the interaction of two factors,
negligible (Ogi et al., 2016, 2017; Kartikowati et al., 2016a).
the first factor is sensitive to Light (Ps) which has two
It is a relatively long time (one month) after treatment
basic properties (Yavuz et al., 2006; Lee et al., 2015a;
that the patient is forced to endure a certain light regimen,
Wang et al., 2007). The first characteristic is the ability to
something that is significantly reduced in second-
selectively absorb in atypical cancer cells ​(tumor tissue),
generation drugs (chlorines) with 48-hour urination
while in adjacent healthy cells, absorption is almost
(Ogi et al., 2016; Suhendi et al., 2015). Bio nanotechnology
non-existent (or so low that it is not considered) and the
has opened up new avenues for photodynamic therapy.
second characteristic is the formation of photo biochemical
Photodynamic therapy is the use of a light-sensitive
interactions due to long-term radiation (Jun et al., 2005;
drug (a photosynthesizer), along with light at visible
Huber, 2005; Ozel and Kockar, 2015). A specific wave
wavelengths, to destroy target cells (Kreibig and Vollmer,
(depending on the type of substance Ps) of radiation
1995; Mie, 1908). Therapeutic photodynamics, or PDT, is
(mainly laser) is the basis of occupational therapy. In this
now recognized as the hallmark of clinical treatment for
way, with irradiating light with appropriate wavelength
various diseases, such as cancer, and especially for the
(as a second factor) to Ps, the light molecule absorbs and
treatment of superficial tumors. Because the efficiency of
is excited and then returns to the ground state to emit
PDT is attributed to the amount of unique 1O2 production,
radiation, but most Ps have a weak fluorescence, so with
an electron spin conversion to triple and this causes the two different nanoparticle utilization strategies can be
transfer of energy to oxygen or surrounding molecules that pursued. One of these two strategies is biodegradable
later react with oxygen (Butler and Banerjee, 1975; Leslie- nanoparticles, from which the photosynthesize is released
Pelecky and Rieke, 1996; Kim et al., 2009; Ma et al., 2004; (Lee and El-Sayed, 2005; Gans, 1915; Her et al., 2017;
Iida et al., 2007). These reactions lead to the formation of Gomez et al., 2014). They are free. Another remaining
free radicals or radical ions (Santoyo Salazar et al., 2011; limitation of PDT is the limited penetration of light into
Upadhyay et al., 2016; Lee et al., 2015a; Noh et al., 2012). tissues. The absorption of two photons raises hopes for
These substances then react with molecular oxygen at light penetration, as this allows two photons of laser
the ground state to produce the superoxide anion radicals energy to be used to generate excitation.selected studies
of hydrogen peroxide and hydroxyl (Yoo et al., 2016). of localized cancer or precancerous disorders are shown
Interactions mentioned that this element is naturally in Table 1.
present in body tissue conditions (Figure 1).
Non-toxicity, selective harvesting and maintenance with
tumor tissue, adequate production of oxygen free radicals 2. Treatment Mechanism with Photodynamic
with absorbing wavelengths that can easily pass through Therapy
the tissue, are the most important properties of the ideal
Photodynamic therapy’s molecular mechanism is
photosynthesize (Sun and Zeng, 2002; Baumgartner et al.,
based on the three non-toxic components that achieve
2013; Klokkenburg et al., 2004). Reactive oxygen species
the desired effects inside pathological tissues only with
(ROS) have a half-life of 3.5 microseconds and only have
reciprocal interactions between (Petryayeva and Krull,
a motility of 0.01 to 0.02 micrometers (Goya et al., 2003),
2011; El-Sayed, 2001; Link and El-Sayed, 1999; Pérez-
so damage occurs depending on where ROS is produced.
Juste et al., 2005):
The nucleus usually remains intact and DNA damage is rare
• Photosensitizer (PS);
(Caruntu et al., 2007; Kovalenko et al., 2007; Kandasamy
• Light with the required wavelength;
and Maity, 2015).
• Oxygen dissolved in cells.
The photodynamic reaction has two major pathways.
Both are closely dependent within cells on oxygen
molecules (Liu et al., 2014; Chen et al., 2008; Pitsillides et al.,
2003). There is a common first step to both processes.
After entering the cell, a photosensitizer is irradiated
with a light wavelength coinciding with the spectrum of
PS absorption and is transformed from the singlet specific
energy state S1 due to the absorption of the photon into the
excited singlet state S1 (Karakoçak et al., 2016; Pan et al.,
2007; Misawa and Takahashi, 2011). Part of the energy is
radiated in the form of a fluorescence quantum, and the
remaining energy is guided to the excited triplet state
T1 with a photosensitizer molecule - the proper therapeutic
Figure 1. Photodynamic therapy process. form of the compound (Figure 2).

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 Photodynamic therapy in cancer treatment

Table 1. Trials selected for localized cancer or precancerous conditions.

Condition Photosensitisers Treatment Trial type Patients

Carcinoma of the lip Temoporfin Temoporfin (0·15 mg/kg) 96 h before Non-randomised 25

20 J/cm2 light (652 nm) phase II trial

Barrett’s oesophagus Aminolevulinic acid 30 mg/kg oral aminolevulinic acid or Randomised, 36

placebo 4 h before laser Endoscopy. double blind
Total light dose 60 J/cm2 (514 nm) placebo controlled
trial

Barrett’s oesophagus Porfimer sodium 2 mg/kg porfimer sodium 48–72 h Multicentre, 208
before laser treatment (630 nm) partially blinded
randomised study

Cervical intraepithelial Aminolevulinic acid Topical application of 3% Randomised, 25

neoplasia aminolevulinic acid gel to cervix for double blind
3 h, followed with 100 J/cm2 635 nm placebo controlled
laser light trial

Figure 2. The Photodynamic reaction mechanism.

2.1. Form I of photodynamic reaction mechanism state). Since they have the same spins, direct energy
The photosensitizer will transfer energy to the transfers between molecules (PS x O2) is possible. This
biomolecules from its surroundings in the excited creates excited particles of oxygen, so-called singlet oxygen,
triplet state T1 (Chithrani et al., 2006; Fang et al., 2011; characterized with exceptionally high oxidizing properties.
Paciotti et al., 2006; Choi et al., 2003). A hydrogen or The bulk of organic compounds are in the simple state
electron is exchanged between the photosensitizer in of singlet. However, their triplet state (as the basis) and
the T1 state and the cancerous tissue (substrate), which excitation into the singlet describe oxygen molecules.
Because of this, excited photosensitizer particles do not affect
contributes to the creation of the photosensitizer and
the structures of organic cells and only react with oxygen
substrate free radicals and anion radicals (Chen et al.,
molecules dissolved in the cytoplasm (Salimi et al., 2017a).
2015; Patra et al., 2010; Kim et al., 2017). Electrons interact
The most important method for conditioning the
with molecules of oxygen that stay in their underlying
performance of PDT is believed to be the type II system.
energetic state. This approach leads to the development
However, the contribution ratio of both pathways depends
of reactive oxygen species (ROS) - initially in the form
on several factors, including: the concentration of oxygen,
of anion radical superoxide (O2•-), which produces more
the dielectric constant of the tissue and the composition
ROS generation within the cells. The initiated cascade of
of pH and photosensitizer. The first type of process starts
reactions leads to the death of cancer cells with oxidative
to prevail when the oxygen runs out.
stress (Smaisim et al., 2022a; Isola et al., 2022; Salimi et al.,
In the photosensitized area, highly reactive oxygen
2017b; Kianfar et al., 2018a).
species cause photographic damage to proteins, fats and
other molecules. In the apoptosis and/or necrosis process,
2.2. Form II of photodynamic reaction mechanism this leads to the direct death of tumor cells (Kianfar et al.,
Energy is passed directly to the oxygen molecule in the 2020a; Liu and Kianfar, 2020). The reciprocal contribution of
simple energetic state as a result of the photosensitizer’s multiple cell death forms is based on the photosensitizer’s
transition into the excited triplet state (the basic triplet intracellular position. Mitochondrial damage can lead to

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Younus, L.A. et al.

Figure 3. Photodynamic Reaction mechanism.

apoptosis, necrosis can be triggered with cell membrane

degradation and loss of integrity, and autophagy can be caused
with lysosome or endoplasmic reticulum damage (Figure 3).

3. Superiority of PDT Method

Due to the selective absorption of Ps substance,

malignant lesion destruction is selective and healthy
tissue adjacent to the irradiated tumor is not damaged
(Kianfar et al., 2018a, b). In addition, with using the
adjunctive method of PDD diagnosis, which is based on
Figure 4. General principles and stages of photodynamic therapy.
spectrophotometry (spectroscopy). The PS is absorbed
into the tissue, it is possible to objectively and accurately
identify the border of cancerous and healthy tissue and
irradiate only the cancerous part (similar to what surgeons only limited amounts, there with mitigating adverse side
do during such biopsies, with removing a margin from effects in healthy tissues (Chen et al., 2023; Kianfar et al.,
healthy tissue and is a relative and inaccurate method. 2020a, b). To achieve this goal, there are two major hurdles.
Figure 4 shows the general principles and stages of Second, most PSs have expanded π-conjugation structures
photodynamic therapy. that make the molecules highly planar, although the
• The treatment is very simple and almost non-invasive molecules appear to be highly hydrophobic, so most PSs
(Kianfar et al., 2020b). stack up in an aqueous atmosphere to form aggregates
• Compared to other treatment methods, this group (Kianfar et al., 2020a. This process of aggregation
of patients, namely surgery, chemotherapy and decreases the PSs’ performance, which must be highly
radiotherapy, has much fewer side effects. photoactive in monomeric form. Second, the PSs tested so
• It is more economical for both the general treatment far generally do not have a high tumor cell specificity or a
system and the patient. pronounced tumor-localizing effect, rendering it difficult
to target only the diseased tissue when PDT is applied
3.1. Benefits photodynamic therapy cancer (Faghih and Kianfar, 2018.Therefore, several attempts
✓ Selectivity (Kianfar et al., 2017). have been aimed at developing delivery mechanisms
✓ Little to no scar following regeneration. that can integrate PS in monomeric form without limiting
✓ Lower prices relative to other treatments. its operation and without having any in vivo adverse
✓ Impossible for new technologies to treat metastatic effects. The ability of Nano-carriers to target tumors is
cancers. also of great importance in PDT using nanoparticles due
to the improved permeability and retention (EPR) effect.
Figure 5 illustrates how the PDT effects can be potentiated
with encapsulation of PS in nanoparticles. Many various
4. Nanotechnology for Photodynamic Therapy
lipid and detergent nanostructures are used in these Nano-
In order for PDT to be both efficient and protected, delivery systems (liposomes and micelles). In fact, before
it is important that PS be administered to target cells nanotechnology became a distinct and rapidly growing field
(such as tumor cells) at therapeutic amounts, whilst at of specialization , these Nano carriers were routinely used in
the same time being consumed with non-target cells in PDT. (Kianfar, 2019; Kianfar, 2021). In the other side, before

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 Photodynamic therapy in cancer treatment

the nanoparticles have a chance to aggregate in the tumor, of fully localized interstitial PDT procedures (Kianfar et al.,
the PS may be released prematurely in the serum, which 2022a; Ansari et al., 2022; Hachem et al., 2022; Smaisim et al.,
is hypothesized to occur with the improved permeability 2022b). the mixture of the injection of medications with
and retention impact (Kianfar, 2021). If biodegradable, the light irradiation. The 2nd generation photosensitizers are
structure of the substance may be limited to lipids or such called porphyrin derivatives or synthetics of established
polymers, while no degradable nanoparticles may stay in chemical structures made since the late 1980s. The light
the body for long periods of time, and this may contribute avoidance length of certain photosensitizers of the 2nd
to questions about the toxicity caused with the delivery generation has been substantially decreased (e.g.<2 weeks).
vehicle rather than the drug (Syah et al., 2021). Photosensitizers of the third generation typically apply to
improvements such as biological conjugates (e.g. antibody
4.1. Photosynthesize (PS) for cancer conjugate, liposome conjugate) and built-in capabilities for
A crucial factor is known to be the photosensitizer. photo quenching or bleaching (Kianfar, 2022; Salahdin et al.,
The excessive photosensitization of the skin following 2022; Kianfar et al., 2022b; Isola et al., 2022; Fattah et al.,
systematic administration of photosensitizer and the need for 2023).The target-specific PDT uses photosensitizers that
patient avoidance of sunlight for many weeks are a significant combine the sensitivity of an over-expressed cell marker
drawback of PDT. However, light avoidance is tolerable for with the phototoxic properties of the conjugated PDT
the majority of cancer patients (Abdelbasset et al., 2022). photosensitizer with the antibody-or antisense-conjugated
Nonetheless, there is also a need to investigate drug delivery photosensitizers (Kadhim et al., 2023; Al-Awsi et al., 2023).
methods for localized tumors to administer photosensitizer A quick analysis of the advantages and deficiencies of each
locally, while enhancing clinical effectiveness, shortening is worthwhile (Table 2).
therapy time, and finally removing skin photosensitization In general, the optimal photosensitizer for solid tumor
(Jasim et al., 2022; Kianfar et al., 2022a). Progress in injection PDT should fulfill at least some of the following criteria
techniques, particularly in endoscopic needle injection, can (Abderrahmane et al., 2023; Wang et al., 2022; Xiao and
be anticipated to reinvigorate interest in the advancement Smaisim, 2022):

Figure 5. From in vitro trials, nanotechnology could hasten the advancement of PDT science, moving on to in vivo tests, and eventually
to clinical applications.

Table 2. Photosensitizers in Photodynamic Pulmonary Therapy.

Wavelength Dose Drau to illumination

Name
nm Mg/kg Interval, hr

Photofrin 630 2.0 48

ALA 630 30.0 48

Foscan 660 0.15 96

MACE 664 3.0 6

Fotosens 675 1.0 24

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Younus, L.A. et al.

✓ A pure chemical which is commercially available, 2022). Specific and direct localization of sensitizers is
✓ Low toxicity of darkness, but high photocytotoxicity also available through active targeting of Ps-containing
✓ Excellent selectivity against tumor cells, nanoparticles (conjugating the receptor and other
✓ A longer wavelength enables greater penetration of light, components). Therefore, the combination of these factors
✓ Rapid removal from the body, as well as reduces the effective dose of light sensitizers for the
✓ Many routes for administration (oral, intravenous, treatment of PDT (Figure 6).
intratumoral or inhalational).
These requirements include a general reference guide. 4.4. Nanoparticles used in PDT
Although all or any of these requirements are fulfilled with The criteria for nanoparticle classification in PDT
some photosensitizers, there are currently only a few PDT are very different. In a review article written by Kumar,
photosensitizers that have earned official clearance around nanoparticles are divided into active and inactive types
the world. Those may, but are not restricted to (Mourad et al., depending on their involvement in the PDT process
2022; Smaisim et al., 2022a; Abderrahmane et al., 2022; (Figure 7) (Mozafarifard et al., 2022):
Tan et al., 2022; Mir et al., 2023; Ruhani et al., 2022; Cai et al., A) Biodegradable polymer nanoparticles.
2022; Moarrefzadeh et al., 2022): B) Non-destructible nanoparticles are divided like ceramic
✓ Photofrin-like (630 nm, Axcan Pharma, Inc.) and metal nanoparticles.
✓ Levulanan (predrug of protoporphyrin IX; 630 nm, Active nanoparticles according to the activation
DUSA Pharmaceuticals, Inc.) mechanism in the process of photodynamic therapy into
✓ Metvixa (predrug of protoporphyrin IX; 630 nm, 3 groups:
PhotoCure ASA.) A) Photosynthesizes: Nanoparticles that transfer energy
✓ Foscan-Foscan (652 nm, Biolitec AG) from incident light to ambient oxygen, such as CdSe
✓ Laserphyrine (664 nm, Meiji Seika Kaisha, Ltd. semiconductor nanoparticles
✓ Visudyne’s (693 nm, Novartis Pharmaceuticals B) Self-illuminating nanoparticles: These nanoparticles
are activated with x-ray radiation and activate the light
4.3. Properties of NPT for delivery of light sensitizers sensitizers attached to them with light fluorescence.
Different nanoparticles each have their own Like nanoparticles BafBr: Er +, Mn+.
characteristics in terms of the type of function, but in C) Up converting: These nanoparticles convert low energy
general should (Hai et al., 2022; Fadhil Smaisim et al., light into high energy light to sensitively stimulate the
2022; Smaisim et al., 2022b): attached optical stump, including NaYF4 nanoparticles:
1. Have the ability to functionalize the surface for different Yb, Er / Tm.
chemical and biochemical groups, for example, with
peeling (adding to the surface of PEG nanoparticles
(polyethylene glycol) can prevent enzymatic degradation 5. Inactive nanoparticles in dynamic light therapy
and microbial attacks on the sensitizer (Yang et al., 2020).
2. The surface of nanoparticles should have good porosity 5.1. Biodegradable nanoparticle carriers
3. It has a suitable size to be able to use the enhanced However, the results of degradation of these
permeability and retention effect (EPR). nanoparticles in exogenous conditions have been reported
4. be non-immunological. differently from the in vitro conditions (Sharba et al.,
5. be optically transparent. 2022; Smaisim et al., 2022a; AbdulHussein et al., 2022;
6. Optically more stable than in-body sensitizers (PS). Ahamad et al., 2022; Doss et al., 2022). The main advantages
7. Have the ability to create a multifunctional system of this type of nanoparticles are high loading of the drug,
such as multiple therapies or diagnostics. the possibility of controlling the release of the drug and
Since the efficiency of photodynamic therapy depends the high diversity of particles and their synthesis processes
on the amount of oxygen produced, two strategies for (Lefteh et al., 2022; Al-Madhhachi and Smaisim, 2021).
nanoparticles in photodynamic therapy are proposed. As expected, deforming the surface of these nanoparticles
(A) Degradable nanoparticles that release Ps into target with PEG increases their circulation time. In one study,
tissues and then Ps produce unique oxygen. B) Non- PLGA nanoparticles were used to create a sterile drug
degradable nanoparticles in which a single oxygen is delivery system for Vertoporin, a sensitizer suitable for
produced and then diffused (Jiang et al., 2022; Tian et al., the treatment of several types of cancer, including skin.
2022a; Alharbi et al., 2022). Nanoparticles were first It is generally accepted that the mean size of nanoparticles
defined by Birrenbach and Speiser as nanoparticles and can play an important role in drug therapeutic activity
Nano spheres with a diameter of less than 100 nm. Interest (via cell and tissue sampling depending on the size
in nanoparticles as drug carriers has increased in recent 370 and 167 nm). In this study, it was found that smaller
years because they can easily transport hydrophobic drugs particles have a greater therapeutic effect (Smaisim,
into the bloodstream, and their high effective levels can 2017a, 2017b, 2018 Smaisim et al., 2016a). Other light-
be used to add chemical agents. These substances have sensitive compounds studied for PLGA nanoparticles
a high volume of distribution and are effectively picked include hypericin and indomethacin green (ICG). ICG is
up with cells. In addition, they enable controlled drug an FDA-approved dye used to create contrast in diagnostic
release and have a variety of synthetic strategies for them procedures for superficial cancers, including breast and skin
(Wu et al., 2022; Tian et al., 2022a, b; Brontowiyono et al., (Farahani et al., 2023; Mir et al., 2023; Wang et al., 2023a).

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Figure 6. Schematic diagram of fluorescence trimodality/thermal/photoacoustic imaging-guided photo thermal/photodynamic cancer

synergistic treatment with photosensitizer (Ce6)-encapsulated plasmatic gold vesicles (GVs).

Figure 7. Schematic Polymeric Nanoparticles and Photodynamic Therapy.

Of course, this dye is absorbed in solution at 800 nm and higher optical activity of hypersin loaded in nanoparticles
has an emission peak of 820 nm, so it has great potential than free hypersin. However, increasing the drug load on
for photodynamic therapies. Recently, the bio-dispersion of these nanoparticles reduces the optical toxicity at high
ICG embedded in PLGA nanoparticles (300 nm in diameter concentrations (Figure 8).
and loaded 20%) and free ICG in C57BL / 6 mice was shown
and found that drug-containing nanoparticles were two 5.2. Non- Biodegradable nanoparticles carriers
to eight times more precipitated than free ICG They had a The function of these nanoparticles is different in PDT
tumor. Therefore, the use of nanoparticles has increased and they are not usually used for drug delivery because
the shelf life of light-sensitive compounds in tumor tissue. they are not destroyed and therefore cannot release the
Hypersin-containing PLA nanoparticles have been used for drug (Figure 9). Therefore, the Ps itself carried in the corn
photodynamic treatment of ovarian cancer and showed cannot be toxic, but produces toxic products of non-toxic

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Younus, L.A. et al.

Figure 8. Schematic Biodegradable nanoparticle carriers.

environmental molecular oxygen and acts as a catalyst and encapsulation of HPPH and Fe3O4 nanoparticles. In this paper,
can be applied continuously with excitatory light. A small a magnetic core is used to guide the carrier to the target cells.
hole (pore) in a ceramic particle with a diameter of 0.1 to Wieder has recently developed drug delivery systems based
0.5 nm is very small for the drug to leave, but it is very on gold nanoparticles that have Ps attached to the surface of
suitable for the entry of O2 and the exit of 1O2. In order to gold nanoparticles. Phthalocyanine derivatives attached to
be effective, these nanoparticles must be small in order to nanoparticles (phthalocyanine nanoparticles) were created
have a volume distribution parallel to the drug, and this with a diameter of 2 to 4 nm. Phthalocyanine monomer in the
requires precise size control so that the size is less than form of covalently on the surface of gold nanoparticles with
100 nm and preferably less than 50 nm (Wang et al., 2023a; absorbing a wavelength of 685 nm catalytically increases
Farahani et al., 2023). Ceramic nanoparticles that hold the production of ROS with high efficiency. Incubation of
Ps non-covalently have several advantages over organic nanoparticles with Hela cells showed good cell harvest and
polymer particles, including resistance to pH-temperature 0.43 more cell death than free phthalocyanine (probably
changes, microbial and enzymatic attacks. Particle size- due to a 50% increase in ROS production in phthalocyanine
shape-prosthesis and their particle size distribution index nanoparticles compared to free phthalocyanine). Wieder
(PDI = Poly dispersity index) can be easily controlled during and colleagues also made a comparison between gold and
fabrication . They are produced in ambient temperature silica nanoparticles. He expected that the photosynthesizer
conditions. Their surface can be easily changed for selective on the surface of gold nanoparticles was more efficient
targeting (Targeting) and these Ps particles protect the than the photosynthesizer inside silica particles (regardless
environment well.It should be noted that although of the 1O2 emission from the particles) (Bahadoran et al.,
biodegradable polymer nanoparticles easily release the 2022; Mahmood et al., 2022). Metal nanoparticles smaller
drug, the efficiency of PDT depends on the production in size than silica particles. Can be produced, therefore due
of 1O2, so drug release is unnecessary (Mir et al., 2023; to the high active surface, high photosynthesizers can bind
Abderrahmane et al., 2023; Wang et al., 2023a; Chen et al., to them and produce higher cytotoxicity. In a study with
2023a; Narayanasamy et al., 2023). The half-life of 1O2 in Oo​, 5-ALA electrostatic bonding was used on the surface
aqueous medium is in the microsecond range because of gold nanoparticles (30 nm in diameter) and observed
1
O2 reacts rapidly. Probably the first paper published on a 50% increase in cell death compared to free 5-ALA.
ceramic nanoparticles to encapsulate Ps in PDT was on Increased ROS production with this researcher was also
the use of silica nanoparticles containing the drug HPPH observed. It was observed and stated that this is due to
(2-devinyl-2- (1-hexyloxyethyl) pyropheophorbide. the transfer of near field energy from gold nanoparticles
This study demonstrates the high potential of ceramic to protoporphyrin nanoparticle surface due to the effect of
nanoparticles in PDT. HPPH is currently in phases one and SPR. Also, in a study conducted with our group, in addition
two of esophageal cancer clinics (Tahmasebi et al., 2021; to observing the catalytic role of gold nanoparticles in the
Taifur Rahman and Evgeny, 2014; Suryatna et al., 2022). production of ROS, the optimal conditions for the use of gold
In 2002, a group showed that pegylated silica (binding nanoparticles in the ALA-PDT process were determined and
of polyethylene glycol polymer (PEG) to the nanoparticle characterized (Bokov et al., 2022; Mansoor Al Sarraf et al.,
surface) (which increases carrier biocompatibility) with 2022; Mahmoud et al., 2022a, b; Raya et al., 2022).
small sizes has wide applications in biology. The team
compared the spectroscopic properties between (mTHPC
(meta-tetrahydroxyphenylchlorin) prepared with sol-gel
5. Two–photon Excitation in PDT
method and examined free mTHPC. Among the current topics
of interest is the combination of PDT method with other The death of cells is mediated with singlet oxygen in
therapeutic and diagnostic methods. Among these studies, PDT. Owing to its short life span (~3.5 ms in the aqueous
we can mention the polymer micelle system for simultaneous environment) and its failure to diffuse longer distances

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 Photodynamic therapy in cancer treatment

Figure 9. As regulated with hormones and nutrients, and as postulated in reaction to nanoparticles, autophagy pathways. (A) Graphical
diagram of the simplified form of control of autophagy. PI3K1 stimulates PDK1, Akt, and mTOR, which in turn prevents autophagy and,
for protein synthesis, activates p70S6K.(B) Schematic diagram of the pathway MEK1/Erk and its relations to mTOR and Akt. Poor may be
dephosphorylated with Akt and p90RSK, resulting in apoptosis. Akt can also phosphorylate eNOS, resulting in apoptosis. Apoptosis can
be caused with phosphorylated JNK. In nanoparticle studies where apoptosis is being studied, these causes are starting to be confirmed.
(C) Graphical diagram of the impact on mTOR of fasting, generation of ROS and oxidative/osmotic tension. All three inhibit mTOR and
induce autophagy in these situations. This is believed to occur through ULK1, Atg13, and FIP200, but other autophagic pathways that
with pass mTOR have been observed. Once activated, autophagy involves the sequestration into organelles called autophagosomes of
a subset of the cytoplasm, which can be partly recognized with LC3-II and p62. The autophagosomes combine with lysosomes to form
autolysosomes where, with the action of membrane permeases, the contents are degraded and released back into the cytoplasm.(D)
Schematic diagram of a lysosome bearing spherical nanoparticles to form an autolysosome combining with an autophagosome. How
the existence of nanoparticles in lysosomes modulates the mechanism of autophagy is unclear.

beyond 100 nm in vivo, the region affected with singlet sensitizers overcomes the above-mentioned drawback
oxygen is spatially limited to a small volume. PDT is thus with specifically controlling the amount of therapy in three
considered a comparatively safe, targeted modality of non- dimensions. A closely focused femtosecond laser beam is
invasive therapy (Meena et al., 2016; Dhanalekshmi et al., used to get high fluxes of light as a light source for TPE.
2019a; Dhanalekshmi et al., 2022). Currently, PDT In this process, a PS molecule is concurrently excited with
treatment requires PS excitation through absorption of the absorption of half the energy of two incident photons
one photon. The key drawback of one photon excitation, or twice the wavelength of one excitation photon. In order
with the excitation of photosensitizer present there, is the to excite a molecule from the ground state to a higher
potential photodamage of the over and underlying tissues energy electronic state, TPE is the mutual absorption
adjacent to the treated area (Dhanalekshmi et al., 2019b, of two photons at equal or separate frequencies. Two-
2021). The new two-photon excitation (TPE) system of photon absorption at low light intensity is a third-order

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Younus, L.A. et al.

Figure 10. (a) Graphical illustration with type I and type II pathways of one or two-photon excitation mediated PDT. (b) The five distinct
forms of PDT cancer TPE nanoparticles that will be presented in this study.

mechanism and several orders of magnitude slower than

linear absorption. Without modifying the photophysical and
photochemical properties of the photosensitizer, the two
photon absorption excites the molecule, meaning that the
excited states achieved with one or two photon absorption
are similar. Awareness of the cross section value of PS for
two photon absorption helps to determine its suitability
for biological applications. For PDT applications, high
TPA cross-section values are favorable since the ratio of
the radiation consumed to the tumor input-energy flux
will be high, reducing the potential photodamage to the
neighboring normal cells. In 2003, with zinc-imidazolyl
coordinations, Kobuke and co-workers reported a self-
assembled conjugated porphyrin exhibiting a broad two
photon absorption cross-section value (s(2)) of 7,600 GM, Figure 11. Possible mechanisms of optical light generation in the
photodynamic process with quantum dots.
which was the largest of the reported values calculated
using femtosecond pulses. This importance is greater than
that of protoporphyrin IX or Photofrin with three or four
orders of magnitude. Furthermore, the development of
dots can also transfer energy to ambient molecular
singlet oxygen with high toluene efficiency was found,
oxygen and lead to cell death, and recently articles
suggesting a suitable candidate for TPE-PDT. For effective
have been published on their potential for Ps (Hameed
two-photon absorption, Collins and co-workers developed
Mahmood et al., 2022). In a study, two-phase energy
porphyrin dimmers with polar functional groups. They also
transfer of quantum dots of CdSe to Ps attached to these
demonstrated its in vivo PDT efficiency. Figure 10 show (a)
particles is expressed (Huang et al., 2021). The group also
Graphical illustration with type I and type II pathways of
predicted the interaction of phospholipid-coated (water-
one or two-photon excitation mediated PDT. (b) The five
soluble) quantum dots (Figure 11). They hypothesized
distinct forms of PDT cancer TPE nanoparticles that will
that the triplet state is the lowest energy level of the
be presented in this study.
CdSe quantum dots and that the triplet energy transfer
(TET) is responsible for producing 1O2 from 3O2, but in
any case, the 1O2 production efficiency is about 5% (with
6. Active Nanoparticles in Photodynamic Therapy 65% efficiency). Quantum fluorescence emission has
(Mir et al., 2023) limited their use (Mir et al., 2023). Many efforts have been
made to improve the efficiency of 1O2 production with
6.1. Photosynthetic nanoparticles quantum dots. These include connecting the covalent Ps
Quantum dots have long been considered as a to the quantum dots CdSe and ZnS via an organic bridge.
nanoparticle optical probe with high quantum efficiency, These attempts had common problems, including the
high optical stability, and size-dependent fluorescence low solubility of the designed system in water, while the
properties. These nanoparticles can be soluble in water ability of quantum dots to produce toxic oxygen was not
or specific to specific areas and malignancies. Quantum used in these cases (Kianfar et al., 2020a).

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 Photodynamic therapy in cancer treatment

6.2. Self-lighting nanoparticle

A new method for treating cancer with a combination of
radiotherapy and photodynamic therapy has been proposed,
called SLPDT = Self lighting photodynamic therapy
(Figure 12). In this method, scintillation luminescent
nanoparticle nanoparticles with Ps that are covalently
attached to their surface (such as porphyrins) have been
used for photodynamic treatment in vivo (Mir et al., 2023).
It should be noted that this system reduces the damage of
this beam to healthy tissues around the target tissue with
reducing the dose of ionizing radiation. Direct biological
applications of this method have not yet been used. Among
these nanoparticles, we can mention nanoparticles with
the composition (BaFBr: Eu +, Mn+).
Figure 12. X-ray induced photodynamic therapy for cancer care,
6.3. Up conversion nanoparticle a graphical diagram nanoparticle-porphyrin conjugates. Annex
In general, tri-excitation luminescence materials (called in V is a molecule which can attack tumor cells with certain
phosphors) emit light with more energy than excitation particular antigens.
light through various mechanisms, including up conversion
and spontaneous two photon absorption. In two-photon
absorption, the transition from the ground state to the
excited state takes place with the spontaneous absorption
of two photons. Up conversion relies on discontinuous
discontinuous adsorption and stepwise luminescence,
while at least two unstable components (usually ions) are
involved in the process. The first component is used as the
excitation store and the second component as the radiation
state (Figure 13). Antistox radiation for the up-conversion
process is ten to one hundred times kT (temperature (T)
multiplied with the Boltzmann constant (k) is a measure
of energy at the molecular scale) is greater than excitation
energies, both the up-conversion mechanism and TPA
because with wavelengths High radiation is generated thus
providing the potential for access to tumors and deeper
tissues. The role of nanoparticles in these cases becomes
nanotransformable. These types of nanoparticles cannot
cause the ROS effect, so they need to bind a suitable Ps.
Up converting Nanoparticle (UCN) is a nanoscale compound Figure 13. Structure and mechanism design of Upconverting
that produces photons with energetic energy with nanoparticles. These nanoparticles absorb high-wavelength light
absorbing NIR or IR radiation with metal ions mediated and transmit it to the short-wavelength and appropriate Ps at the
with lanthanides and actinides inside a suitable host. Raises nanoparticle surface.
. Sometimes referred to as Up-converting Phosphorus (UCP),
they are known as sub-micron ceramic particles containing
lanthanides that are visible with IR absorption. Binding of
molecules and surface engineering (Kianfar et al., 2020a). Polyethyleneimine) polymers. The resulting particles were
Various materials are known as dopants in UCNs, some of 50 nm in size and had a positive surface charge. For use
which have real or potential applications in biology. Ionic in photodynamic therapy, a light-sensitive compound
materials are usually rare earth crystals such as lanthanides ZnPc (phthalocyanine tin) was placed on the surface of
and actinides that are doped in a suitable crystalline matrix these nanoparticles. This nanoparticle system had three
(Kianfar et al., 2020b). One of the common nuclei for very interesting functions; Dissolve non-polar ZnPc, help
biological applications is NaFY4, which has recently been low-energy radiation to synthesize the energetic energy
doped with Er3 + / Yb3+or TM3 + / Yb3+ to form micrometer- needed to stimulate ZnPc, and help target ZnPc to target
sized particles Kianfar et al. (2020a).The first report of PDT tumor cells (Smaisim, 2017 a).
use with UCNs is the use of NaYF4: Yb3 + .Er3+ coated with a In general, there are several benefits to using UCNs:
thin porous silica layer containing PsMerocyanine-370 and 1. Ability to examine deeper tissues with NIR light
tumor-specific agents attached to its surface (Meena et al., 2. NIR light cannot cause tissue damage.
2016; Dhanalekshmi et al., 2019a; Dhanalekshmi et al., 3. Nanoparticles tend to deposit in tumor tissues due to
2022). In subsequent studies, NaYF4 nanocrystals the effect of EPR, but this property is intensified with
contaminated with Er and Yb elements were coated the binding of targeting agents on the surface of the
with polyvinylpyrrolidone (PVP) and polyethylene (PEI = particles.

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Younus, L.A. et al.

7. Conclusion of different fluids in microchannels and nanochannels in the

presence of external electric field and external magnetic field
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