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ESIPT‑, AIE‑, and AIE + ESIPT-Based Light-Activated Drug Delivery

Systems and Bioactive Donors for Targeted Disease Treatment
Amit Kumar Singh,‡ Asha V Nair,‡ Sk. Sheriff Shah, Souvik Ray, and N. D. Pradeep Singh*

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ABSTRACT: Targeted release of bioactive molecules for ther-

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apeutic purposes is a key area in the biomedical field that is growing

quickly, where bioactive molecules are released passively or actively
from drug delivery systems (DDSs) or bioactive donors. In the past
decade, researchers have identified light as one of the prime stimuli
that can implement the efficient spatiotemporally targeted delivery
of drugs or gaseous molecules with minimal cytotoxicity and a real-
time monitoring ability. This perspective emphasizes recent
advances in the photophysical properties of ESIPT- (excited-state
intramolecular proton transfer), AIE- (aggregation-induced emis-
sion), and AIE + ESIPT-attributed light-activated delivery systems
or donors. The three major sections of this perspective describe the
distinctive features of DDSs and donors concerning their design,
synthesis, photophysical and photochemical properties, and in vitro and in vivo studies demonstrating their relevance as carrier
molecules for releasing cancer drugs and gaseous molecules in the biological system.

1. INTRODUCTION excimer and exciplex formation, aggregation-induced emission

In the last few decades, the concept of an on-demand drug (AIE), and excited-state intramolecular proton transfer
delivery system has potentially emerged to target various (ESIPT).49−54 Among these photophysical processes, we will
diseases in the human body, where the drugs are passively or focus on delivery systems and donors induced by ESIPT, AIE,
actively released from the conjugated device (drug delivery) and AIE + ESIPT. ESIPT is a process where photoexcited
systems.1−6 To date, several stimuli-responsive drug delivery molecules relax their energy via the proton exchange between
systems and bioactive donors based on pH,7−10 temper- the proton-donating and proton-accepting groups in the
ature,11−15 light,16−20 enzymes,21−29 electric fields,30,31 mag- molecule through the formation of intramolecular hydrogen
netic fields,32−36 and ultrasound37,38 were developed. Among bonds, which help to increase the rate of photorelease and
them, light-induced drug delivery systems (DDSs) and hence lead to faster drug delivery. In the case of AIE, it is a
bioactive donors have gained more attention, since they utilize phenomenon that causes chromophore aggregation, leading to
nonionizing radiation to release bioactive drugs or gaseous enhanced fluorescence of the delivery systems and donors.
molecules at the point of action with spatial and temporal Interestingly, the delivery systems and donors with the coupled
control.39−44 Light-activated delivery systems are mainly AIE and ESIPT photophysical properties are preferred for
classified into three categories: (i) photochemical-induced biological purposes due to their added advantages such as large
delivery systems, where the absorbed light with suitable energy Stokes shifts, minimized dissipation of excitation energy via
directly breaks the covalent bonds or, via a photochemical self-absorption, enhanced photorelease rates, and direct
reaction, releases the drug; (ii) delivery systems induced by quantified drug release.55−58 The biological applications of
photoisomerization, where the excess energy causes reversible the DDSs and donors mentioned here include the delivery of
or irreversible changes in the structure of the carrier molecule, cancer drugs or agents that can spatiotemporally release
which leads to the release of the active ingredient; and (iii)
photothermal delivery systems, where the light energy
absorbed is dissipated via vibrational motion to deliver the Received: September 6, 2022
bioactive molecules.45−48 Many photophysical properties are Published: March 13, 2023
utilized in the design of light-activated DDSs and donors,
including photoinduced electron transfer (PET), intermolec-
ular charge transfer (ICT), fluorescence resonance energy
transfer (FRET), ligand to metal charge transfer (LMCT),

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Scheme 1. Schematic Representation of ESIPT-, AIE-, and AIE + ESIPT-Based Light-Activated Drug Delivery Systems and
Bioactive Donors

gasotransmitters like H2S, CO, or NO and gaseous molecules of NO includes its ability to disperse biofilms and hence reduce
like H2S2.59−63 In the case of cancer treatment, the major biofilm growth. In the case of cancers, high concentrations of
drawbacks associated with the chemotherapeutic drugs are (i) NO (≥500 nM) are observed to be cytotoxic and kill cancer
high dose requirements, (ii) poor bioavailability, and (iii) cells, whereas, at lower concentrations (≤100 nM) they
severe side effects. Light-activated delivery systems can facilitate tumor suppression and antibacterial activity.67−69
overcome some of the above-mentioned limitations due to The easiest method of administering gasotransmitters is via
their unique features like (i) their noninvasive nature, (ii) the direct inhalation of small quantities of the particular
spatial and temporal control over the release, (iii) ease of use gaseous species. However, to obtain the maximum therapeutic
and portability, and (iv) ability to maintain the required drug effects, precise control over the release and the concentration
concentration at a specified site for a longer time, resulting in of the gasotransmitter is required, which is very difficult to
improved therapeutic efficacy with fewer side effects.64 To achieve. Hence, research groups are interested in developing
date, several light-activated systems have been developed using donor molecules for the controlled release of gasotransmitters.
phototriggers, namely o-nitrobenzyl,39 phenacyl,40 benzoyl,41 In recent years, researchers have been more focused on light-
quinolinyl,46 anthracenyl,47 and coumarinyl48 derivatives. responsive gasotransmitter donors because of their spatial and
In the human body, gaseous molecules play a significant role temporal control over the release of gasotransmitters. Hence,
in cellular processes and pathological conditions. For example, several light-activated gasotransmitter donors for CO (e.g.,
hydrogen sulfide (H2S), hydrogen persulfide (H2S2), carbon cyclic aromatic α-diketone, 6-hydroxy-3-oxo-3H-xanthene-9-
monoxide (CO), and nitric oxide (NO) are important carboxylic acid, flavonols, carbazole-fused 1,3-dioxol-2-one,
signaling molecules.60,62 Endogenously produced H2S and and meso-carboxy BODIPY),50,52,63−65 NO (e.g., 4-nitro-3-
H2S2 have important roles in several physiological processes, (trifluoromethyl)aniline, derivatives of N-nitrosoaminophenol,
like protecting the cells from oxidative stress, in the protein S- dimethylnitrobenzene, and NO photocages of BODIPY and
persulfidation pathway, glyceraldehyde-3-phosphate dehydro- rhodamine),17,55,68 and H2S (e.g., geminal-dithiols, ketoprofen-
genase (GAPDH) activity, etc., and pathological processes, like ate-caged H2S donors, o-nitrobenzyl-caged thiocarbamates, and
neurodegenerative diseases, heart problems, and diabetes.65,66 a m-amino benzyl-caged H2S donor)6,59,66,67 have been
Carbon monoxide has essential roles in the human system as a reported. To improve the photophysical and photochemical
vasodilator and a blood pressure regulator.63 It is also properties of the above-designed light-activated DDSs and
important in smooth muscle cell proliferation and anti- bioactive donors, researchers are interested in incorporating
inflammatory, antiapoptotic, and anticoagulation actions. CO photophysical properties like ESIPT, AIE, and AIE + ESIPT in
exhibits antibacterial efficacy against both Gram-positive and their design.
Gram-negative bacteria, and carbon monoxide-releasing Hence, this perspective is intended to focus on the state-of-
molecules form a new class of antimicrobials. Nitric oxide the-art developments in the photophysical properties of light-
also has a significant role in biological processes and activated DDSs and donors used to efficiently release bioactive
therapeutic functions. It is a well-known vasodilator that molecules (Scheme 1). This perspective is mainly divided into
modulates blood pressure, which plays a role in heart disease three parts: section 2 deals with the ESIPT-based DDSs and
and pulmonary hypertension.62 Moreover, NO is a potent bioactive donors, their photophysical properties, and biological
antioxidant and anti-inflammatory agent. The therapeutic role applications; section 3 discusses the fundamental concepts of
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AIE-based DDSs and donors and their photophysical proper- behavior. Hence, the spectral characteristics of the ESIPT-
ties; and section 4 focuses on the incorporation of AIE + based fluorophores are mainly influenced by hydrogen
ESIPT-coupled photophysical properties in DDSs and bonding, the surrounding medium’s acidity or basicity, and
bioactive donors, along with their design, synthesis, and substituents on the donor and acceptor species. As a result, the
biomedical applications.68,69 Finally, we summarize the uses fluorescence characteristics of ESIPT-based fluorophores can
and performances of DDSs and donors discussed here, along be tuned by altering these parameters, making them advanta-
with the prospects in this continually growing field of research. geous and desirable tools for fluorescent probes and imaging
agents.74
2. ESIPT-BASED DDSS AND BIOACTIVE DONORS In biological investigations, ESIPT-based fluorophores
The concept of ESIPT was first introduced by Weller in the benefit significantly from detecting physiologically necessary
1950s using salicylic acid.70 Thereafter, this concept has been metal ions, such as zinc (Zn2+) and copper ions (Cu2+), the
widely explored in different fields of biology, physiology, and two crucial transition metal ions in human metabolism.75,76
pharmacology and for the selective detection/imaging of The abnormalities of these metal ions act as predictive
biologically or environmentally relevant analytes. ESIPT biomarkers for various types of diseases.
includes a rapid four-level photocycle (E → E*→ K* → K) The general strategy for developing ESIPT-based fluorescent
process, where E is the enol form and K is the keto form. For probes is based on a design that involves blocking the
ESIPT, an intramolecular hydrogen bond (H-bond) between hydrogen-bond donor of the ESIPT fluorophore with a specific
the proton acceptor (�N� and �C�O) and proton donor reactive unit that prevents the ESIPT process.
(−OH and −NH−) groups close to each other within a As a result, there will be no exchangeable protons available;
molecule (Scheme 2) is required.71−73 Besides, ESIPT is an hence, only enol emission is recorded. Additionally, the ESIPT
process is activated when a reactive unit in the probe is
Scheme 2. Schematic Representation of the ESIPT Process exposed to a specific analyte, allowing access to the keto form.
Furthermore, the ESIPT process is widely used in the design of
light-activated delivery systems and donors to release bioactive
molecules due to its salient features such as (a) rapid and clean
release, (b) high photochemical efficiency, (c) large Stokes
shift, and (d) real-time monitoring ability.77,78
2.1. Light-Responsive ESIPT-Induced DDSs for Cancer
Treatment. Inspired by the aforementioned unique properties
of the ESIPT phenomenon, an ESIPT-based drug delivery
system, the coumarin−benzothiazole−chlorambucil (Cou-
Benz-Cbl) conjugate, was developed using the 7-hydroxy-
coumarin moiety as a phototrigger.43 However, this mentioned
DDS released the anticancer drug chlorambucil upon
irradiation with UV light (λ ≥ 365 nm), a major limitation
for biological applications. Overcoming this limitation, the
Singh group developed a visible-light-activated drug delivery
system, namely, p-hydroxyphenacyl-benzothiazole-chlorambu-
cil (pHP-Benz-Cbl, Figure 1A), which delivers anticancer drug
extremely fast process (kESIPT > 1012 s−1) that involves chlorambucil (Cbl) upon exposure to light of wavelengths
transient changes, where its emission is easily affected by the greater than 410 nm.55 This DDS was synthesized from the
microenvironment, resulting in a change in the fluorescence core unit of salicylaldehyde, which contains a p-hydroxyphe-

Figure 1. (A) ESIPT-assisted photorelease of the drug from pHP-Benz-Cbl-based DDS. (B) ESIPT-induced photorelease mechanism of pHP-
Benz-Cbl-based DDS. (C) Dual-step surveillance in the release of an anticancer drug-based DDS from nano pro-drug-X (ANPD-X). (D) TEM (a−
c) images of ANPD-X, and (d) DLS data of ANPD-X nanoparticles. (E) Fluorescence images of HeLa cells after cellular internalization with
ANPD-X: 1(a) bright-field picture, 1(b) fluorescence picture, 1(c) blend of bright-field and fluorescence images, 2(a) ANPD-X-treated cells, 2(b)
ANPD-X-pretreated cells after H2O2 treatment and incubation for 12 h, and 2(c) cells upon visible light (λ ≥ 410 nm) exposure. Panels D and E
were reprinted with permission from ref 57. Copyright 2017 American Chemical Society.

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Figure 2. (A) ESIPT-assisted visible-light-activated H2S donor. (B) Real-time monitoring of a pHP phototrigger-based H2S donor during
photolysis at regular intervals (0−20 min). (C) Confocal microscopy images of the internalization of a pHP phototrigger-based H2S donor in HeLa
cells. Panels B and C were reprinted with permission from ref 45. Copyright 2018 Royal Society of Chemistry. (D) ESIPT-induced visible-light-
triggered H2S2 donor. (E) Overlay HPLC chromatograms of the H2S2 donor at various time intervals (0−30 min) of photoexcitation (≥410 nm).
(F) Fluorescence microscopy images of the ESIPT-induced hydrogen persulfide donor upon light irradiation (λ ≥ 410 nm) in MDA-MB-468 cells.
Panels E and F were reprinted with permission from ref 61. Copyright 2019 Royal Society of Chemistry. (G) ESIPT-induced light-triggered
ratiometric carbon monoxide donor. (H) Visible-light-triggered nitric oxide donor.

nacyl (pHP) group, a well-known phototrigger, by incorporat- 5 μM to 1 mM). This sensing of ROS leads to an ESIPT-
ing a benzothiazole ring that makes the molecule ESIPT-active. induced drug release accompanied by a color change from blue
Furthermore, a possible mechanism for the photoinduced to green. Experiments conducted have shown that upon the
release of Cbl from pHP-Benz-Cbl (1) in an aqueous specific exposure of identified tumor sites to light (λ ≥ 410
acetonitrile solution is presented in Figure 1B. Upon nm), almost 90% of the drug got released (within 15 min) and
irradiation of light λ ≥ 410 nm, the pHP-Benz-Cbl was a fluorescence color change occurred, enabling the monitoring
excited to the singlet excited state, which underwent a rapid of the drug release. In vitro studies of ANPD-X offered the
ESIPT process from the pHP species to the benzothiazole two-step surveillance of anticancer drug delivery with high
group 2, producing the deprotonated pHP moiety to form the sensitivity and more than 90% cell viability with real-time
compound 3. Then, the zwitterionic product 3 underwent monitoring (Figure 1E).
effective intersystem crossing (ISC) to its excited triplet state 2.2. Light-Responsive ESIPT-Induced Hydrogen Per-
with a photo-Favorskii rearrangement, leading to the formation sulfide (H2S2)/Hydrogen Sulfide (H2S) Donors. The first
of putative spirodiketone 4 with an associated uncaging of Cbl. light-activated ESIPT-based H2S donor reported was 2,2′-
This spirodiketone 5 then underwent hydrolytic ring opening thiobis(1-(3-(benzo[d]thiazol-2-yl)-4-hydroxyphenyl)-
and rearrangement to produce pHP-Benz-COOH 6. Interest- ethanone), which used p-hydroxyphenacyl as the phototrigger
ingly, this ESIPT-activated DDS exhibited several unique (pHP) (Figure 2A).45 This H2S donor was designed in such a
features such as (i) an excitation wavelength greater than 410 way that the phototrigger group pHP in the excited state forms
nm, (ii) faster release of the drug (released up to 90% of the intramolecular H-bonds with the benzothiazole ring (which is
drug within 15 min of light exposure) with a good attached to salicylaldehyde), enabling the ESIPT process and
photochemical quantum yield (0.46), and (iii) a distinctive driving the release of H2S. The ESIPT behavior enabled the
change in fluorescence during photolysis. In addition, in vitro self-monitoring of H2S uncaging by an emission (lowest singlet
studies of the DDS in the tumor cell line MDA-MB 231 excited state of the keto form) color change from green to blue
showed that the DDS exhibited excellent properties, such as (Figure 2B). The donor released more than 90% of H2S after
photoregulated drug delivery, high cell viability, and good being excited by visible light (λ ≥ 410 nm) for 20 min, with a
biocompatibility coupled with real-time monitoring. photochemical quantum yield of 0.16 ± 0.05 based on the
Later on, a new type of dual-step surveillance H2O2- decomposition of the H2S donor, using potassium ferrioxalate
mediated and ESIPT-induced photoactivatable nano pro-drug- as an actinometer. In vitro studies conducted to understand the
X (ANPD-X) DDS was reported (Figure 1C).57 This DDS was biological effects of the donor in HeLa cells demonstrated
synthesized from p-hydroxyphenacyl-benzothiazole-chloram- good biocompatibility, cellular internalization, and real-time
bucil using the previously reported synthetic scheme with a monitoring (Figure 2C).
final step of borate ester incorporation, leading to the In continuation, another visible-light-activated (λ ≥ 410
formation of ANPD-X. Furthermore, the nanoparticles of the nm) ESIPT-based H2S2 donor (2,2′-disulfanediylbis(1-(3-
DDS were prepared via the reprecipitation technique. A TEM (benzo[d]thiazol-2-yl)-4-hydroxy phenyl)ethane-1-one) was
image of the synthesized nano pro-drug-X (ANPD-X) showed reported (Figure 2D).61 The ESIPT process in this designed
an average diameter of ∼78 nm (Figure 1D), enabling effective system exhibited excellent properties, like (i) intense
penetration and accumulation within the cancer cell. ANPD-X fluorescence with a large Stokes shift, (ii) a minimum self-
uses borate ester to sense the reactive oxygen species (ROS) in quenching process along with the real-time monitoring during
cancer cells (cancer cells have higher H2O2 concentration from the uncaging process via the fluorescence color change, and
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(iii) a reduced inner-filter effect. Further, the donor ability of light exposure a complete color change from green to blue was
2′-thiobis(1-(3-(benzo[d]thiazol-2-yl)-4hydroxyphenyl)- exhibited (Figure 2H), specifying the complete decomposition
ethanone) was examined by exposing it to visible light (λ ≥ of the delivery agent and NO release. Hence, this ESIPT-
410 nm) for 30 min in PBS buffer. The photodecomposition of induced NO donor efficiently releases NO in tumor cells and
the donor was monitored by RP-HPLC. The HPLC profile enables potent tumoricidal activity and real-time monitoring.
showed that the peak at a retention time (tR) of 3.25 min
gradually disappeared with an increase in the exposure time, 3. AIE-BASED DDSS AND BIOACTIVE DONORS
showing the photodecomposition of the H2S2 donor.61 In AIE is a novel photophysical process associated with the
addition, a gradual appearance of a new peak at a tR of 2.35 aggregation of a chromophore and was first reported by the
min due to the formation of the photoproduct, pHP-Benz- Tang group in 2001.81,82 AIE-active luminophores are
COOH (Figure 2E), was noticed. The time-dependent essentially nonemissive at low concentrations, whereas when
photodecomposition of the H2S2 donor followed the first- aggregated they emit enhanced fluorescence. According to the
order photodecomposition with a photochemical quantum Tang group’s findings, the restriction of intramolecular
yield of (Φp) 0.12 ± 0.05 with respect to the decomposition of rotations (RIRs) is the fundamental reason for AIE effects
the starting material using potassium ferrioxalate as an and is the most widely used mechanism to create AIE-active
actinometer. In vitro studies of the H2S2 donor using molecules.83 Thereafter, AIE-active molecules have been
fluorescence microscopy in breast cancer cells (MDA-MB- widely developed for a variety of applications, including
468) showed a green color (from the keto form, which is the sensing, imaging, drug delivery, and material design. In sensing
lowest singlet excited state) due to the uptake of the DDS. applications, AIE molecules can be used to detect changes in
After 15 min of excitation with visible light (λ ≥ 410 nm), both the environment, such as temperature, pressure, humidity, and
green and blue emission colors were observed, implying the pH. In imaging, AIE molecules can be used to create high-
partial decomposition of the H2S2 donor. Finally, after 30 min resolution images of biological processes. In drug delivery, AIE
of exposure, the fluorescence color changed completely to molecules can be used to target specific cells or tissue and
blue, suggesting the complete release of H2S2 (Figure 2F). The deliver drugs with improved efficacy and accuracy. In material
reported H2S2 donor revealed its good biocompatibility, design, AIE molecules can be used to create materials with
cellular internalization, and cytoprotective capability in the unique properties, such as being optically active or having a
highly oxidizing microenvironment of the MDA-MB-468 cell high refractive index.81,83 Thus, the understanding of
line. structure−property relationships of aggregates can be used to
2.3. Light-Responsive ESIPT-Induced Carbon Mon- develop new materials or processes with specific properties. By
oxide (CO) Donors. Feng and co-workers for the first time analyzing the structures of the aggregates and understanding
reported an ESIPT-based visible-light-activated CO-releasing how various factors like size, shape, and composition affect the
molecule (CORM), Cou-Flavone (Figure 2G).79 The reported properties of the aggregates and materials, researchers can
DDS was synthesized via the condensation reaction of 2- develop materials or processes that are tailored to the specific
hydroxy acetophenone with an extended conjugated coumarin. needs of a given application. In addition, understanding these
This new CORM exhibited a ratiometric fluorescence color relationships can lead to an improved understanding of the
change when exposed to visible light, along with a large Stokes stability and reactivity of these materials, which can be
shift (due to ESIPT). Before irradiation, Cou-Flavone showed leveraged to design materials that are better suited for a given
yellow fluorescence. After irradiation with 460 nm (Φfl = 0.03) application. In consequence, AIE-active molecules have made
light, the color changed from yellow to blue-green due to the significant progress in material design, mechanistic experi-
release of CO. In vitro experiments in MCF-7 cells and in vivo ments, high-tech drug delivery, and imaging applications in the
studies in zebrafish and mice using the CORM showed a last 20 years The AIE-active molecules have made significant
similar color change. These biological studies also demon- progress in material design, mechanistic experiments, high-tech
strated that the CORM has properties like the efficient and drug delivery, and imaging applications in the last 20 years.84
trackable release of CO and low cytotoxicity. Hence, it is an Several functions and physiological behaviors absent in
excellent light-activated system to employ in both live cells and molecular species are found in molecular aggregates, as the
animals. behavior of molecular ensembles is similar to those of
2.4. Light-Responsive ESIPT-Induced Nitric Oxide macroscopic materials, thus providing a tool for better
(NO) Donors. A NO donor molecule that can release the understanding biological problems. Some of the most common
gasotransmitter when triggered by both UV (365−400 nm) applications of AIE-active molecules include fluorescence
and visible light (λ ≥ 410 nm) was developed (Figure 2H).80 sensors (for ions, pH, temperature, pressure, viscosity, etc.)
The molecule of interest was synthesized from O2-(4- biological probes (for DNA, RNA, protein, sugar, etc.),
hydroxyphenacyl) diazeniumdiolates by attaching the benzo- multistimuli-responsive phospholipids, immunoassay markers,
thiazole-2-yl group to the ortho-position of the hydroxyl group PAGE visualization agents, layer-by-layer assembly monitors,
on the aryl ring to produce O2-(3-(benzothiazole-2-yl)-4- polarized light emitters, reporters for micelle formation, and for
hydroxyphenacyl) diazeniumdiolates. The synthesized mole- photodynamic therapy (PDT).83 Quain and his colleagues
cule exhibited an ESIPT effect that produced a distinct reported the nanoparticle-assisted AIE-active molecule tetra-
fluorescent color change that enabled the monitoring of the phenylethylene (TPE-red), a red-emissive photosensitizer (PS)
NO release. The NO donor, after light irradiation (λ ≥ 410 with AIE properties, which was designed, processed, and
nm), formed the photoproduct [(benzothiazole-2-yl)-4- decorated with poly(styrene-co-maleic anhydride) (PSMA) to
hydroxyphenylacetic acid] accompanied by the release of create nanoparticles.85 The PSs were found suitable for deep
NO. Real-time monitoring of NO release in HL60 cells tissue image-guided therapy, whereas the TPE-red-PSMA
showed that the cells initially exhibited a green color due to the nanoparticles were studied for two-photon-induced reactive
internalization of the NO delivery agents, but after 15 min of oxygen species (ROS) production and two-photon fluores-
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Figure 3. (A) AIE-active photorelease of an anticancer drug from a TPE(Cbl)4 nanoparticle conjugate-based DDS. (B) Real-time monitoring of a
nanoparticle-based DDS (1 × 10−4 M) at different intervals of light exposure (0−25 min) in CH3CN−PBS buffer of pH 7.4. (C) Confocal
microscopy images of TPE(Cbl)4 NPs in tumor cells: (a) bright-field image and images after (b) 0, (c) 10, and (d) 25 min of light irradiation.
Panels B and C were reprinted with permission from ref 87. Copyright 2019 American Chemical Society. (D) AIE-photoinduced nitric oxide
delivery from a TPT(NOD)4-based system. (E) Real-time monitoring of nitric oxide. (F) Confocal images of U87MG cells treated with DAPI for
nuclear staining and 6 μM TPT-(NOD)4 NPs during irradiation: (a) DAPI nucleus staining; (b) 0 min, excimer emission (red fluorescence); (c)
30 min, monomer emission; and (d) a merged image. Panels E and F were reprinted with permission from ref 51. Copyright 2018 Royal Society of
Chemistry.

cence. In continuation, polymeric micelles for anticancer drug tumor-cell-targeting, dual-responsive drug delivery, and out-
delivery and imaging of cancer cells were reported, which standing AIE behavior.
gained ample attention due to their systemic low toxicity, 3.1. Light-Responsive AIE-Induced DDS for Cancer
increased therapeutic efficacy, and better tumor detection.86 Treatment. Light-responsive fluorescent organic nanopar-
Then, for stimuli-responsive drug release and AIE-active ticles (NPs) based on tetraphenylethylene (TPE) (Figure 3A)
imaging, a multifunctional polymeric micelle system based on were developed for cancer diagnosis and treatment.87 The TPE
pH and a redox dual-responsive mPEG-P(TPE-co-AEMA) molecule conjugated with Cbl (DNA alkylating agent) acts as a
copolymer was developed. The biocompatibility and emission photosensitizer upon exposure to light. For this purpose, the
properties of these micelles were outstanding, suggesting their TPE unit was functionalized by an acylation reaction with
excellent cellular imaging ability.86 Furthermore, during the bromoacetyl bromide and made a conjugate ester of anticancer
self-assembly process, the anticancer drug doxorubicin (DOX) drug, producing tetraphenylethylene-chlorambucil TPE(Cbl)4.
was encapsulated with a high loading efficacy, producing a 68.2 TPE(Cbl)4 nanoparticles were synthesized using reprecipita-
nm DOX-loaded micelle system and a narrow size distribution. tion techniques. These TPE(Cbl)4 NPs released 4 equiv of the
DOX-loaded micelles suppressed tumors effectively in vitro anticancer drug sequentially and generated singlet oxygen in
and tracked the intracellular drug release. DOX-loaded micelles the aggregated state. The photochemical quantum yield for the
had a superior anticancer impact due to their aggregation at release of Cbl was influenced by the volume of the water
the cancer site and much fewer side effects than free DOX. fraction (ACN−water binary mixture). With an increase of the
Finally, the polymeric micelle was identified as an excellent volume of water fractions, the photorelease of Cbl was
cancer therapy and detection tool because of its efficient increasingly likely at f w = 80% (Φ= 0.06), 90%, (Φ= 0.12), and
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Figure 4. (A) AIE + ESIPT-coupled photorelease of H2S from a TPE-pHP-H2S NP-based H2S donor. (B) Real-time monitoring of the nano-H2S
donor during photolysis within a different time interval (0−20 min). (C) Cell viability assay of the TPE-pHP-H2S NP donor in the HeLa cell line
(a) before and (b) after photolysis for 20 min. Panels B and C were reprinted with permission from ref 91. Copyright 2018 Royal Society of
Chemistry. (D) AIE + ESIPT-induced photorelease of the dual anticancer drug by NDDS. (E) (1a) Change in fluorescent spectra during
photolysis (0−5 min) and (1b) Comparison of the fluorescent spectra of the DDS and NDDS before and after photolysis (0−15 min). (F) Real-
time monitoring of the NDDS during photorelease using visible light (λ ≥ 410 nm) exposure. Panels E and F were reprinted with permission from
ref 56. Copyright 2018 Royal Society of Chemistry.

99% (Φ= 0.52, maximum value). In addition, the singlet tation techniques, (iii) a single TPT molecule provides four
oxygen generation of DDS and the photoproduct were found covalent linkages to yield a four-armed NO photodonor, (iv)
to be Φ = 0.31 and 0.27, respectively. Therefore, the perylene aggregates showed a transformation from excimer to
requirement of RIR was essential to initiate the photophysical monomer fluorescence in the event of a π−π stacking
and the photochemical process. In vitro studies demonstrated disruption (AIE), and (v) visualization of the NO release
the synergistic effect of the improved cell-killing mechanism in (Figure 3E). Further, in vitro studies of the nanoparticles in
HeLa cells accompanied by self-tracking, as per the cell U87MG cells established the efficacy of the nitric oxide donor,
imaging studies with real-time monitoring (Figure 3B and C). where the NO photorelease was associated with the AIE
3.2. Light-Responsive AIE-Induced Nitric Oxide (NO) transition, which aided in the real-time reporting of NO
Donors. The first AIE-active nitric oxide photodonors release. The nanoparticles also exhibited efficient cellular
(NODs) reported were the conjugated perylene tetracarbox- internalization and negligible cytotoxicity (Figure 3F).
ylate ester (TPT) based organic fluorescent TPT-(NOD)4
nanoparticles (Figure 3D).51 The reprecipitation approach was 4. AIE + ESIPT-COUPLED DDSS AND BIOACTIVE
employed to produce the photoresponsive TPT-(NOD)4 NPs. DONORS
The NPs were globular in shape, with good stability and a ζ- In the last few decades, researchers have been keen to develop
potential of +58 mV. The photophysical properties of the fluorophores exhibiting AIE + ESIPT phenomena by
TPT-(NOD)4 conjugate and TPT-(NOD)4 NPs were suppressing the aggregation-caused quenching (ACQ) effect
analyzed. The absorption and emission maxima of the TPT- in the excited state to achieve coupled (AIE + ESIPT)
(NOD)4 conjugate (10−5 M in ACN) were found to be at 380 emission.88 For this purpose, the most popular models of RIMs
and 492 nm, respectively, while the absorption and emission and RIRs were incorporated into ESIPT molecules to enhance
spectra of TPT-(NOD)4 NPs (10−5 M in water) exhibited a the emissive response in aggregate states.89,90
redshift, with the maxima at 385 and 627 nm, respectively, due Consequently, unique features of AIE + ESIPT provided the
to RIR. Consequently, the distinct features associated with the DDSs or bioactive donors with synergistic photophysical
development of TPT-(NOD)4 NPs are (i) easy synthesis, (ii) properties like (i) AIE properties that favor ESIPT emission via
perylene-derived substrates form spherical NPs by reprecipi- aggregate formation, which is advantageous for assisting the
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Figure 5. (A) AIE + ESIPT-coupled photorelease of an anticancer drug from a TPE-pHP-Cbl-based DDS. (B) Real-time monitoring of TPE-pHP-
Cbl (1 × 10−4 M) at different intervals of photoexcitation (0−5 min). (C) MTT assay of TPE-pHP-Cbl NPs in the HeLa cell line (a) before and
(b) after photolysis and (c) at different time intervals of light irradiation. Panels B and C were reprinted with permission from ref 58. Copyright
2018 American Chemical Society. (D) AIE + ESIPT-coupled photorelease of an anticancer drug from a pHP-Naph-Cbl-based DDS in the
phototherapeutic window. (E) (a) Real-time monitoring of a DDS, pHP-Naph-Cbl (1 × 10−4 M), in CH3CN-PBS buffer of pH 7.4 at various
intervals of photoexcitation (0−15 min) and (b) HPLC overlay chromatogram of pHP-Naph-Cbl at different time intervals of light irradiation with
a laser of wavelength 700 nm with 100 fs pulses at an 85 MHz rate. (F) Confocal fluorescence cellular uptake images of pHP-Naph-Cbl in breast
cancer cell line MCF-7: (i)a bright-field image at 0 min, (i)b bright-field fluorescence image at 475−550 nm, (i)c bright-field fluorescence image in
the blue channel (range of emission wavelengths of 420−450 nm), (i)d merged bright-field images of the blue and yellow-green channels, (ii)a
bright-field image at 0 min, (ii)b bright-field fluorescence image at 475−550 nm after 15 min of light exposure, (ii)c bright-field fluorescence image
in the blue channel after 15 min of exposure (range of emission wavelength of 420−450 nm), and (ii)d merged bright-field images of the blue and
yellow-green channels of pHP-Naph-Cbl. Panels E and F were eprinted with permission from ref 92. Copyright 2020 Royal Society of Chemistry.

ESIPT process with significant Stokes shift, especially in strong conjugate and the photoproduct of the DDS, respectively).
H-bond donor or highly polar solvents.90 (ii) The ESIPT The nano-H2S donor released H2S only in the aggregated state
increases aggregate fluorescence by enhancing the AIE effect upon irradiation with visible light (λ ≥ 410 nm) in different
via intramolecular hydrogen bonds and enhancing the volumes of ACN−H2O. Interestingly the photochemical
photorelease rate after exposure to a particular wavelength of quantum yields progressively improved as the volume of
light. Conclusively, the DDSs or donors based on the water fractions increased and at f w = 99 vol % found a
combination of the AIE + ESIPT process have shown maximum value of the quantum yield (Φ= 0.18). Further, in
promising advantages over single ESIPT- or AIE-based DDSs vitro studies of the nano-H2S donor in HeLa cells showed that
or bioactive donors, such as avoidance of self-quenching at the H2S donor was highly biocompatible at the given
higher concentrations, strong fluorescence with a large Stokes concentrations (0−20 μM, Figure 4C). After irradiation by
shift, and elimination of hydrophilic modification, that endow visible light, the TPE-pHP-H2S nanoparticle-based H2S donor
them with potential practical applications in biological exhibited excellent properties like photoregulated H2S release
studies.57,58 inside the cell.
4.1. Light-Responsive AIE + ESIPT-Induced Hydrogen Concurrent with these emerging breakthroughs in the
Sulfide (H2S) Donor/Anticancer DDSs. Photoresponsive research of AIE + ESIPT-based DDSs, a dual (different)
single-component organic-nanoparticle-based TPE-pHP-H2S drug release photoresponsive DDS was developed by
(Figure 4A), an H2S donor molecule exhibiting both ESIPT incorporating a salicylaldazine group to a p-hydroxyphenacyl
and AIE phenomena, was synthesized.91 The photoactivated (pHP) phototrigger (Figure 4D).56 The developed nano-DDS
single-component organic fluorescent nanoparticles, TPE- (nanobased drug delivery system, NDDS) was highly
pHP-H2S, provided the following advantages: (i) an increase fluorescent in the aggregated state (due to RIRs) and exhibited
in the AIE property, (ii) a large Stokes shift, (iii) the extension a large Stokes shift (because of ESIPT). The coupled
of the irradiation wavelength up to λ ≥ 410 nm, (iv) the photophysical properties of ESIPT and AIE extended the
photorelease of H2S in the aggregated state, (v) efficient H2S absorption wavelength to over 400 nm, and the drug was
release, and (vi) real-time monitoring (Figure 4B) due to a released only in the aggregated state accompanied by a distinct
fluorescence color change (λem = 549 and 486 nm for the ester fluorescent color change of yellow to blue (Figure 4E),
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Figure 6. (A) Green-light-activated DDS [DAN-bis(HO-Naph-VPA)] for the release of two equivalents of an anticancer drug. (B) Increase in the
emission intensity with increasing volumes of water fractions. (C) TEM images of nano-DDS [DAN-bis(HO-Naph-VPA)] (i) before and (ii) after
photolysis. (D) Cellular internalization of the nano-DDS in HeLa cell lines. Panels B−D were reprinted with permission from ref 93. Copyright
2022 American Chemical Society. (E) Lysosome-targeted two-photon responsive Lyso-Naph-Cbl-based DDS. (F) Open aperture z-scan curves
recorded at different wavelengths of the Lyso-Naph-Cbl (10−4 M) based DDS. (G) Cellular uptake experiments of Lyso-Naph-Cbl NPs and the
drug uncaging ability via light irradiation. Panels F and G were reprinted with permission from ref 94. Copyright 2022 American Chemical Society.

providing real-time drug monitoring. The DDS released up to of the ESIPT process. Further, the photolysis of TPE-pHP-Cbl
90% of the drug (Cbl) within 5 min of exposure to visible light. NPs (1 × 10−4 M in aq acetonitrile) released ≥90% of the drug
Additionally, the photolysis of the nano-DDS in the within 5 min of visible light (λ ≥ 410 nm) irradiation and
acetonitrile−water solvent systems reported no prominent generated singlet oxygen simultaneously, along with the
drug release in pure CH3CN. However, the value of the fluorescence color change from yellow to green (Figure 5B).
photochemical quantum yield increased with the volume of In addition, to understand the drug release in the aggregated
water fractions in ACN−water binary mixtures (at f w= 60%, state, the photolysis of TPE-pHP-Cbl NPs was carried out with
70%, 80%, and 90%, Φ= 0.03, 0.10, 0.14, and 0.19, different volumes of water fractions in ACN−water binary
respectively). The above results suggested that the aggregation mixtures. No significant drug release was observed below f w =
of the DDS initiated the drug delivery process. Additionally, 70% (Φ = 0.09), and with further increase in the volumes of
the highest photochemical quantum yield for the nano-DDS water fractions the value of photochemical quantum yield
observed was 0.48 at f w = 99%. Further, the in vitro activity of reached a maximum Φ= 0.51 (at f w= 99%). This clearly shows
NDDS was investigated in the HeLa cell line and revealed a that the aggregation process initiates the drug release. Thus, for
homogeneous distribution within the cells, specifying its good the first time, a DDS has utilized the coupled photophysical
cellular uptake. The tracking of drug release by NDDS using properties, resulting in increased cancer killing due to the
confocal microscopy showed that the cells first showed yellow synergistic effect of combination therapy. In vitro studies of the
fluorescence due to the internalization of DDS. And after 3 DDS in HeLa cells revealed the real-time cellular imaging of
min of light exposure, yellow and blue fluorescence was drug release and effective anticancer activity because of
observed, indicating the partial release, and finally, after 5 min synergistic combination therapy (Figure 5C).
the fluorescence color changed completely to blue (Figure 4F), Further, the development of a two-photon (TP) induced
indicating the delivery of both the drugs (chlorambucil and DDS has been achieved, which combines the features of ESIPT
ferulic acid). and AIE and has high tissue penetration for the spatiotemporal
Next, a light-induced single-component fluorescent organic delivery of anticancer drugs. The reported DDS, p-hydrox-
nanoparticle-based DDS (TPE-pHP-Cbl NPs, Figure 5A) for yphenacyl-naphthalene-chlorambucil (pHP-Naph-Cbl, Figure
synergistically (anticancer drug delivery + photodynamic 5D), has a two-photon absorption (TPA) cross-section of ≥20
therapy) killing cancer cells was synthesized.58 The photo- GM in the phototherapeutic window (700 nm).92 Upon
physical properties of TPE-pHP-Cbl conjugate showed an exposure to light (>365 nm) in a ACN−PBS buffer mixture,
absorption maximum at 382 nm, and the TPE-pHP-Cbl NPs the DDS released 95% of the drug in 15 min, with a
showed broadband emission at 382 nm. The emission fluorescence color change from greenish-yellow to blue (Figure
spectrum of TPE-pHP-Cbl conjugate exhibited two emission 5E(a)). Besides, the DDS delivered the anticancer drug only in
maxima at 460 (enol form) and 549 nm (keto form) because the aggregated state a maximum quantum yield of 0.49 when
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the volume of water fraction reached ∼90%. However, after the viability of the Lyso-Naph-Cbl NP at the studied concen-
single-photon release of the DDS, the two-photon uncaging trations (0−40 μM). These promising features make this DDS
was performed using a laser with a 100 fs pulse at an 80 MHz an excellent choice for the future design and synthesis of DDSs
repetition rate and a wavelength of 700 nm, which released to target different organelles.
25% of the drug after 3 h of irradiation (Figure 5E(b)). Cell In Table 1, we have summarized representatives of the light-
viability studies showed more than 95% cell survival at various induced DDSs and bioactive donors discussed in this work
concentrations (4 to 500 μM) of the DDS in the MCF-7 cell along with their photophysical and photochemical properties,
line. In vitro studies also demonstrated the higher cytotoxicity advantages, and applications in biological systems.
of the DDS (pHP-Naph-Cbl) under light exposure than the
free drug (Cbl), making it an efficient tool for killing cancer 5. CONCLUSIONS
cells (Figure 5F).
Very recently in 2022, a green-light-activated nanodrug This perspective briefly discussed the importance and
delivery system for the dual release of the active molecule for relevance of photophysical properties like ESIPT, AIE, and
cancer treatment was developed by combining the properties AIE + ESIPT (coupled) in the reported DDSs and bioactive
of ESIPT and AIE.93 This DDS [DAN-bis(HO-Naph-VPA)] donors. Here we have elaborated on the features of the delivery
(Figure 6A) was prepared by attaching 2-hydroxy-6-naphthacyl systems and donors for the targeted release of anticancer drugs
(phototrigger) on both sides of the 1,5-diaminonaphthalene and other biologically relevant gaseous molecules like H2S,
(DAN) chromophore. The DDS released two equivalents of CO, NO, and H2S2. We have also discussed the development
the anticancer drug, valproic acid, in a spatial and temporally of AIE + ESIPT-based DDSs and bioactive donors and their
controlled manner. The two emission maxima exhibited by the relevance in the biological field. Among them, AIE + ESIPT-
DDS were at 525 and 550 nm, showing its ESIPT property. based systems have superior features due to the synergistic
The DDS had a low emission intensity in pure acetonitrile properties of both ESIPT and AIE phenomena, which include
improved fluorescence performance, better sensitivity, bio-
solution and showed increased emission intensity with
compatibility, and greater effectiveness in the spatiotemporally
increasing water fractions (Figure 6B). The maximum emission
targeted delivery of the drugs/bioactive molecules. Hence, the
intensity was achieved at 90% volume of f w with a fluorescence
use of ESIPT-, AIE-, and AIE + ESIPT-based systems for light-
quantum yield (Φf) of 0.29. The photolysis of DDS (1 × 10−4
activated drug delivery and as bioactive donors for targeted
M) in an ACN−PBS buffer mixture (1:9, v/v) at the
disease treatment is a promising area of research with great
physiological pH (pH = 7.4) by exposure to green light (λ
potential. The ability to precisely control the release of
≥ 500 nm) led to 90% VPA release after 40 min of light
therapeutic agents and biological compounds and the potential
excitation. Furthermore, we formulated the [DAN-bis(HO-
for improved specificity are key advantages of these systems. In
Naph-VPA)] DDS as nanoparticles. The shape and size of the
addition, the ability to use a single light source to activate
nano-DDS were determined by transmission electron micros-
multiple devices in a single system is also an attractive feature.
copy. The nano-DDS was globular and ∼48 nm in size (Figure
As the technology and understanding of these light-activated
6C). In vitro experiments were performed in HeLa cell lines
systems improve, the potential for further development and
using the nano-DDS. After 2 h of incubation, nano-DDS was
applications of these DDSs and bioactive donors will become
internalized, showing a reddish-orange color, which after
more apparent.
exposure to light resulted in cellular death (Figure 6D),
establishing the nano-DDS as an excellent green-light-
responsive drug delivery system. 6. FUTURE PERSPECTIVE
Furthermore, a two-photon active lysosome-targeted AIE + Even though significant progress has been achieved in the field
ESIPT-based nanocarrier DDS was developed (Figure 6E).94 of light-activated DDSs and bioactive donors, there are still
The designed DDS, a lysosomotropic-naphthalene-chlorambu- certain limitations that need to be addressed: (i) damage to
cil conjugate (Lyso-Naph-Cbl), has a TP-responsive 2- healthy cells due to the UV−vis light, (ii) the limited
hydroxy-6-napthacyl backbone with an imine side arm inserted penetration ability of the light into the live tissue, (iii) the
at the 1-position of naphthalene and the caged alkylating agent moderate photochemical quantum yield for the release of the
chlorambucil. The DDS had a TPA cross-section of 142 GM at active molecule, and (iv) the formation of unwanted additional
850 nm (Figure 6F). ESIPT enabled the two absorption and photoproducts. Hence, in the future, synthetic chemists,
emission maxima in Lyso-Naph-Cbl. The absorption and pharmacologists, and biomedical scientists need to join forces
emission maxima for the enol form were exhibited at 390 and to develop more innovative and efficient light-activated drug
460 nm. Additionally for the keto form, the absorption and delivery systems (DDSs) and bioactive donor molecules. Such
emission maxima were observed at 480 and 530 nm. systems could provide improved biological screening, delivery
Interestingly, after exposure to light, the DDS Lyso-Naph- of drugs, gasotransmitters, and other bioactive molecules for
Cbl ratiometrically uncaged the Cbl. Further, the two-photon the treatment of various diseases while also minimizing damage
uncaging study of DDS was carried out using a 100 fs pulsed to healthy cells and avoiding the formation of unwanted
laser with a 50 μm size focused beam with a power of 800 mW photoproducts. Combining ESIPT and AIE with other
at 850 nm, and the drug release was found to be 24% and 29% photophysical properties, such as vibration-induced emission
at pH 7.4 and 5.4, respectively. In vitro studies of the DDS (VIE), could enable the construction of improved systems via
were conducted in the cancerous and normal cell lines by various combinations of AIE + ESIPT + VIE, ESIPT + VIE, or
converting the DDS to a nanocarrier (Lyso-Naph-Cbl NPs). AIE + VIE. Such advancements could allow for the greater
The NPs showed localization in the lysosome and a reduction penetration of light into live tissue, higher photochemical
in the fluorescence intensity when irradiated with light, quantum yields for the release of active molecules, and more
showing the light-dependent drug release in the lysosome efficient drug delivery, leading to improved treatments and
(Figure 6G). The MTT assay showed that more than 80% cell better quality of life for patients.
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■ AUTHOR INFORMATION

B16F10, MDA-MB-
231, CT26, and
Table 1. Representative DDSs and Bioactive Donors from the Perspective: Outlining the Photophysical and Photochemical Properties, Advantages and Applications in

cell line used

Corresponding Author

MDA-MB 231

U87MG cells
N. D. Pradeep Singh − Department of Chemistry,

HEK-293
HeLa cells

HeLa cells

HeLa cells
Photochemistry Laboratory, Indian Institute of Technology
Kharagpur, Kharagpur, West Bengal 721302, India;
orcid.org/0000-0001-6806-9774; Email: ndpradeep@
exhibits excellent cell penetration, high selectivity for ROS
chem.iitkgp.ac.in

shows good biocompatibility, self-tracking ability, good cell

exhibits two-photon activity, good cell viability, lysosome

shows high cell viability, good biocompatibility, and real-

releases H2S only in the aggregated state when triggered

spatiotemporally controlled NO release, real-time mon-

with visible light and real-time monitoring capability

λmax of absorption spectra in nm. bλmax of emission spectra in nm. cFluorescence quantum yield. N.A.= not available. dPhotochemical quantum yield. N.A.= not available.
imaging, and 4 equiv of drug release with real-time
detection, and two-step surveillance with real-time
Authors

localization, and enhanced cytosolic drug delivery

Amit Kumar Singh − Department of Chemistry,
Photochemistry Laboratory, Indian Institute of Technology
Kharagpur, Kharagpur, West Bengal 721302, India
Asha V Nair − Department of Chemistry, Photochemistry
advantages

Laboratory, Indian Institute of Technology Kharagpur,

itoring, and anticancer activity

Kharagpur, West Bengal 721302, India

Sk. Sheriff Shah − Department of Chemistry, Photochemistry
Laboratory, Indian Institute of Technology Kharagpur,
time monitoring

Kharagpur, West Bengal 721302, India

Souvik Ray − Department of Chemistry, Photochemistry
monitoring

monitoring

Laboratory, Indian Institute of Technology Kharagpur,

Kharagpur, West Bengal 721302, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jmedchem.2c01466
0.31 (Cbl uncaging)

Author Contributions
‡
These authors contributed equally.
d
Φ

Notes
0.46

0.16

O2 = 0.27

0.18

0.19
N.A.

The authors declare no competing financial interest.

Biographies
1

Amit Kumar Singh secured his M.Sc. degree from Vinoba Bhave
University Hazaribag, India, in 2015. He started his Ph.D. in organic
0.13
N.A.

N.A.

N.A.

N.A.
Φfl
0.1

photochemistry under the supervision of Prof. N. D. Pradeep Singh at

c

the department of chemistry, Indian Institute of Technology,

and keto forms, respec-

and keto forms, respec-

and keto forms, respec-

and keto forms, respec-

Kharagpur, India. He studies the development of one- and two-

450 and 515 nm (enol

450 and 515 nm (enol

460 and 549 nm (enol

480 and 530 nm (enol

photon-activated systems to release bioactive molecules and design

new photoremovable protecting groups.
b
λfl

Asha V. Nair received her M.Sc. degree in 2009 from the University of
tively)

tively)

tively)

tively)
508 nm

627 nm

Agricultural Sciences, Bangalore, India. She received her Ph.D. in

2014 under the guidance of Prof. Paul Race from the University of
Bristol, UK. Then, she did postdoctoral research at the Department of
and enol forms, respec-

and enol forms, respec-

and enol forms, respec-

Pharmacology, University of Cambridge, UK. At IIT Kharagpur, she

350 and 380 nm (keto

350 and 460 nm (keto

390 and 460 nm (keto

currently focuses on developing light-induced target-specific and

synergistic drug delivery systems to combat bacterial infections and
λabs

cancer in Prof. N. D. Pradeep Singh’s lab.

a

tively)

tively)

tively)

Sk. Sheriff Shah started his research career in chemistry under the
374 nm

385 nm

372 nm

supervision of Prof. N. D. Pradeep Singh at the Indian Institute of

Technology, Kharagpur, India, and received his Ph.D. degree in 2019.
Biological Systems, and Cell Lines Used

properties involved

duced anticancer

His research mainly focused on metallaphotoredox catalysis for C−H

anticancer DDS

AIE-induced anti-

AIE-induced NO

AIE + ESIPT-in-

AIE + ESIPT-in-
photophysical

ESIPT-induced

ESIPT-induced

activation and functional group transformation. Currently, he is

cancer DDS
H2S donor

duced H2S

working on photodynamic therapy (PDT) for cancer treatments.

donor

donor

DDS

Souvik Ray completed his M.Sc. degree in 2017 from the Indian
Institute of Technology, Guwahati, India. He started his Ph.D. in
organic photochemistry under the guidance of Prof. N. D. Pradeep
2,2′-thiobis(1-(3-(benzo[d]thia-
representative DDSs and bio-

Singh at the department of chemistry, Indian Institute of Technology,

zol-2-yl)-4hydroxyphenyl)

Kharagpur, India. He is working on developing one- and two-photon-

active donors

activated drug delivery systems to release biologically relevant

Lyso-Naph-Cbl NPs
TPE-pHP-H2S NPs

molecules and the synthesis of new photoremovable protecting

pHP-Benz-Cbl

groups.
TPT-(NOD)4
ethanone)
TPE(Cbl)4

N. D. Pradeep Singh received his M.Sc. degree in 1996 from the

University of Madras, India, and conducted research with Prof. A.
Anandhan. He completed his Ph.D. in 2001 at the same institute with
a

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Prof. Geetha Gopalakrishnan in organic photochemistry. Currently, (9) Dadsetan, M.; Taylor, K. E.; Yong, C.; Bajzer, Ž .; Lu, L.;
he is a Professor of Chemistry at the Indian Institute of Technology, Yaszemski, M. J. Controlled Release of Doxorubicin from pH-
Kharagpur, India, and has received numerous awards. The Singh lab is Responsive Microgels. Acta Biomaterialia 2013, 9, 5438−5446.
involved in developing new fluorescent photoremovable protecting (10) Jayakumar, R.; Nair, A.; Rejinold, N. S.; Maya, S.; Nair, S. V.
groups for bioapplications and working on visible-light-assisted Doxorubicin-Loaded pH-Responsive Chitin Nanogels for Drug
Delivery to Cancer Cells. Carbohydr. Polym. 2012, 87, 2352−2356.
photocatalysis.
(11) Al-Jamal, K. T.; Al-Jamal, W. T.; Wang, J. T.-W.; Rubio, N.;

■ ACKNOWLEDGMENTS
We acknowledge CSIR (sanction letter no. 02(367)/19/EMR-
Buddle, J.; Gathercole, D.; Zloh, M.; Kostarelos, K. Cationic Poly-l-
lysine Dendrimer Complexes Doxorubicin and Delays Tumor Growth
in Vitro and in Vivo. ACS Nano 2013, 7, 1905−1917.
II) and DST SERB (Grants EMR/2016/005885 and DIA/ (12) Antoniraj, M. G.; Kumar, C. S.; Kandasamy, R. Synthesis and
2018/000019) for funding. Characterization of Poly (N-Isopropylacrylamide)-g-Carboxymethyl
Chitosan Copolymer-Based Doxorubicin-Loaded Polymeric Nano-
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