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DOI: 10.1201/ 9781003426820-12 149
12
Nano-
formulations
of Tempol
Abhishek Tiwari
1*
, Varsha Tiwari
2*
,
and Bimal Krishna Banik
3*
INTRODUCTION
Nanotechnology holds immense importance in the medical realm, par‑
ticularly concerning lipid‑insoluble drugs. Various nano‑formulations have
evolved over the years to address this need. These formulations include
Polymeric particles (1989), PEGylation (1990), lipid disks (1995), Nano/
Microemulsions (1995), Iron oxide nanoparticles (1996), Hydrogels (2002),
Polymeric micelles (2003), Nano‑crystals (2003), albumin nanoparticles
(2005), Cell‑based therapies (2010), viral nanoparticles (2010), Oncolytic
viruses (2015), and Lipid‑based nucleic acid nanoparticles (2018). These
advancements have signicantly impacted the treatment of various disorders,
particularly in delivering both water and lipid‑
soluble drugs and phytocon‑
stituents. Figure12.1 shows various nano‑formulations Tempol in the treat‑
ment of Liver injury, inammation, and ROS.
1
Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Lucknow, Amity
University Uttar Pradesh, Sector 125, Noida‑201313, Uttar Pradesh (India)
2
Department of Pharmacognosy, Amity Institute of Pharmacy, Lucknow, Amity University
Uttar Pradesh, Sector 125, Noida‑201313, Uttar Pradesh (India)
3
Department of Mathematics and Natural Sciences, College of Sciences and Human Studies,
Prince Mohammad Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia;
*
Corresponding Authors:
abhishekt1983@hmail.com; varshat1983@gmail.com; bimalbanik10@gmail.com
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150 Chemical and Clinical Applications of Tempol
UTILIZING TP-OXIDIZED
NANO-CELLULOSE FOR SILVER
NANOPARTICLE FORMULATIONS
Pawcenis etal. 2022, revealed the effectiveness of TOCNs and its fractions in
designing of AgNPs. Aqueous suspension of AgNO
3
containing TOCN was
heated to design AgNPs. The researchers developed three distinct nanocom‑
posite materials, each utilizing a different TOCN fraction, which were then
reduced in situ by TOCN‑synthesized AgNPs. Water‑soluble fractions give
rise to AgNPs, whereas insoluble fractions leads to NPs with non‑uniform
si ze [1].
FIGURE12.1 Development of nano-formulations since1989–2018
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12 • Nano-formulations of Tempol 151
MICRO- AND NANO-FORMULATIONS OF
CMC, DIALDEHYDE, AND TP
-OXIDIZED
CELLULOSE (TPOC) FOR ANTIMICROBIAL
AND WOUND TREATMENT
Alavi et al., discussed the challenges associated with treating persistent
infected wounds namely DFU, in immune compromised patients. As the
emergence of ABR bacteria and fungi, traditional medications may be inef‑
fective in future microbial infections at numerous sites. Therefore, biomateri‑
als, CMC, dialdehyde and TPOC may show promising effect in combating
this challenge against microorganisms [2].
TPOBC WITH AGNPS FOR
WOUND HEALING
Wu etal. explored the potential of utilizing bio‑compatible BCP in wound dress‑
ings. Despite its biocompatibility, it lacks inherent antibacterial activity, required
for further modication for biomedical applications. They reported the develop‑
ment of TOBCP with C
6
‑RCOO
‑
groups through TP‑mediated oxidation leads
to the development of AgNP and nanobers. These showed excellent biocom‑
patibility and antibacterial potential for Escherichia coli and Staphylococcus
aureus, may be an potential choice of drug against microorganisms [3].
SURFACE AMENDMENT OF TP
Elżbieta et al. revealed surface modication techniques employing stable
radicals, specically TP and fractions. This chapter delineates two pri‑
mary approaches. Firstly, they immobilize TP groups onto surface of silicon
wafers, nanomaterials, organic polymers, etc. Secondly, they explored the
utilization of nitroxide mediated radical polymerization (NMRP) to graft
multiple chains of polymer, designs polymer brushes on nanostructured sur‑
faces. They also investigate the effect of polymer modications on numerous
physicochemical parameters [4].
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152 Chemical and Clinical Applications of Tempol
FIGURE12.2 A, The immobilization of TP on silica surface TP trapping through sol-gel technique; B, The SBA-15 silica linked with
TP; C, The designing of silica improved with TP through silane
-coupling procedure; D, Organically linked TP through sol-gel method
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12 • Nano-formulations of Tempol 153
Silica associated Tempol
Tsubokawa etal. [5], very rst reported the TP immobilization on silica par‑
ticles, treated with TSPA converts surface OH group into RC(=O)OC(=O)R
group. The immobilization of TP radicals was achieved through the reaction
of TP with surface groups in the presence of N,N′‑dicyclohexyl carbodiimide
(DCCI) (Figure12.2).
Brunel etal. [6] designed mesoporous silica to immobilize TP. This silica
material is possess hexagonal network with particle size of 15–100 Å. These
silica supports immobilized TP due to superior pore size, internal surface and
silanol groups [7].
Brinker describes the Stöber method in the transformation of colloidal
solutions from precursors lead to gelation removal of liquids results in porous
monolithic substances using silica based tempol derivatives (3) [8]. This
method includes the use of liquid alkoxysilanes like Si(OR)
4
as precursors that
can be readily hydrolyzed into Si(OH)
4
, which on polycondensation, results in
three‑dimensional network. Water and alcohol remain entrapped within the
network removed subsequently. Through drying and aging processes [9].
Ciriminna et al., very rst reported the silica modied TP synthesis
through sol‑gel technique, which has been further proved efcient as catalyst in
oxidation of sugars into urinates (4) [10]. They utilized a TP precursor through
amination between oxo‑TP and trimethoxy silane. Afterward, TP‑derived alk‑
oxysilane was merged into silica surface through sol‑gel technique using H+/
OH− followed by co‑polycondensation with Si(OCH
3
)
4
as depicted in (5) [11].
Adsorbed TP on metal and its oxide NPs
These MNP’S imparts numerous benets, i.e., stability, functionality, solubil‑
ity, self‑assemble, etc. Moreover, these also show promising potential support
for functional foods especially catalyst, in view of large surface area and
synergistic effects [12].
Karimi et al. [13] revealed an EASA method [14] to design coating of
mesoporous silica MCM‑41 onto electrodes functionalized with TP. Firstly,
thin lm of APS has been deposited on the surface of graphite electrode
by condensation among functionalized/non‑functionalized precursors
triethoxysilane and TEOS in the presence of CTAB as structure‑ modifying
agent. Figure12.2 depicts the reductive amination of APS in the presence of
NaBH
3
CN in presence of silica‑substituted electrodes (Figure12.3).
Swiech et al., designed N‑AuNPs on gold electrode surface using a
1,9‑nonanedithiol linker. This electrode has been used in electrocatalytic
oxidation of C
6
H
5
CH
2
OH to aldehyde. The catalytic effectiveness of the
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154 Chemical and Clinical Applications of Tempol
N‑AuNPs has been compared with that of nitroxides monolayer formed
through direct chemisorption on Au surface (Figure12.3) [15].
Carbon nanomaterials grafted with TEMPO
Zhao etal. [16], rst reported the surface modication of carbon nanotubes
(CNTs) with TP derivatives. They oxidized MWNT by treating with mix‑
ture of HNO
3
/H
2
SO
4
. These COOH group were further transformed into
COCl
2
taking SOCl
2
. This reaction has been applied to TP as depicted in
Figure12.4, Figure8 [16, 17].
FIGURE 12.3 A, The pathway of electrode modification with a thin layer of
TP-functionalized ordered mesoporous silica (TGSE); B, The diagram depicts an
electrode modified with N-AuNPs acquired using as a stabilizing agent, and an
electrode modified with a monolayer obtained via the direct chemisorption of on
a flat gold surface
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12 • Nano-formulations of Tempol 155
Yang et al. [18], designed 4‑step technique for developing TP‑
functionalized MWNTs. The researchers includes sequential stages namely
carbon nanotubes subjected to oxidation taking. Their procedure involved
several sequential stages: initially, the carbon nanotubes underwent oxida‑
tion using C
5
H
6
O
4
followed by subsequent COOH attachment on the surface
of MWNTs via coupling with C
3
H
7
BrO in the presence of DCC. The bromo
atom transferred to azo group. This leads to azide/alkyne copper(I) formation
through “click” reaction as depicted in Figure12.4, Figure9.
Graphene (G) and graphene oxide (GO)
Bosch‑Navarro etal. [19], designed graphene‑linked TP through Bingel‑Hirsch
reaction taking graphene as starting material. Graphene was designed by
directly shedding graphite in oDCB/C
6
H
5
CH
2
NH
2
with the aid of ultrasonic
radiation (Figure12.5).
FIGURE12.4 A, The scheme of multi-walled carbon nanotubes (MWNTs) modi-
fication with TP; B, Route to synthesis of TP
-functionalized MWNTs
FIGURE12.5 The procedure for the synthesis of graphene grafted with TP
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156 Chemical and Clinical Applications of Tempol
SILVER NPS SYNTHESIS ON
TP
-SUBSTITUTED BACTERIAL CELLULOSE
Elayaraja etal. [20] investigate the TP oxidation to activate COOH group,
lead to BC oxidation in AgNO
3
results in AgNP with BC in order to trig‑
ger vibriocidal potential. It further leads to evaluation through SEM, EDS,
and XRD. They have also assessed the vibriocidal potential against V. p ara ‑
haemolyticus and V. h arve yi revealed AgNP revealed greater effectiveness
against above pathogens, therefore may be the promising therapy in manage‑
ment of shrimp pathogens [4].
TNFC FOR CONTROLLED RELEASE
AGAINST ANTIMICROBIAL CU
Cu NPs were designed from using CuSO
4
(0%, 30%, 50%, and 70%) with
respect to cellulose‑Cu material mass. This mixture was then treated with
FIGURE 12.6 Different formulations of TP include silica particles, magnetic
nanoparticles, metallic nanoparticles, carbon nanotubes, graphene, polymer
brushes, nanohybrids, fullerenes, inorganic flat surfaces, and polymers
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12 • Nano-formulations of Tempol 157
PVA to form thin lm, this lm was subjected to antibacterial potential of
against E. coli. They revealed that by enhancing the cellulose content Cu
amount can be regulated, it depicts that it follows the power law as when the
concentration is 30% or low exponential release of Cu has been observed
whereas when it has been raised to 70%, the conc. of Cu has been decreased.
Figure12.6 depicts the various compositions of the cellulose‑Cu hybrid mate‑
rial [21].
BRAIN-TARGETED DELIVERY OF
TP-LOADED NANOPARTICLES FOR
NEUROLOGICAL DISORDERS
Nanoprecipitation of TP on PLGA to target brain disorders, na mely Parkinson’s
and Alzheimer’s have been designed. These conditions may be specied an
increase in ROS and these TP NPs may act as protective effect in manage‑
ment of the above disorders. They have loaded NPs with TP and transfer‑
rin antibodies, covalently with PLGA NPs using NHS‑PEG3500‑Maleimide
crosslinker in order to make the sustained release formulation.
Anticancer potential of these NPs have been evaluated through
MTT assays which further lessen cell death in RG2cells and compared
with that of conjugated and unconjugated TPL. The results revealed that
TP‑conjugated NPs showed potential for the management of neurodegen‑
erative disorders [22].
NES FOR HAIR LOSS
A novel NEG targeting mechanisms of inammation and apoptosis. It includes
the formulation development of NE’s for hair loss. The NEG has been for‑
mulated for topical use by taking TP and cyclosporin‑A. Pharmacological
analysis revealed that this formulation delivered the drug efciently, inside
the dermis. In‑vivo study was further performed which promotes the hair
growth, color intensity further conrmed by histological analysis. On the
basis of this study, CsA‑Tempol was found to possess signicant therapeutic
platform for the management of alopecia [23]. This is another novel use of
tempol‑derived NES in maintain the hair growth.
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158 Chemical and Clinical Applications of Tempol
NF’S AGAINST MDRC
Multidrug resistance is becoming an alarming factor in chemotherapy over
90% of patients. This resistance is associated with reactive oxygen species
(ROS)‑regulated drug efux proteins, specically P‑glycoprotein (P‑gp) and
multidrug resistance‑associated protein 1 (MRP1). The multidrug resistance
by utilizing nanoparticles containing ROS‑scavenging nitroxide radicals,
termed RNPN (pH‑sensitive) and RNPO (pH‑insensitive), in combination
with the conventional chemotherapy drug doxorubicin (Dox), in drug‑
resistant
epidermoid cancer cell lines KB‑C2 (P‑gp expressing) and KB/MRP (MRP1
expressing) have been reported.
Moreover, RNP treatment effectively disrupted crucial ROS signaling
pathways, downregulates ROS‑regulated drug efux protein expression (P‑gp
and MRP1), thus sensitizing resistant cells to Dox. These results underscore
the potential of ROS‑scavenging RNPs as promising therapeutic candidates
for overcoming drug resistance in multidrug‑resistant cancers. Figure 12.7
depicts the design of TP‑loaded NPs in cancer, illustrating the suppression of
resistance and the promotion of sensitivity [24].
NANOPLATFORM TARGETING
NUMEROUS ROS WITHIN THE BRAIN
Zhang etal., developed a nanomedicine possessing properties to SOD and
catalase by merging H
2
O
2
‑neutralizing substance, Oxb CD, with TP, referred
FIGURE12.7 Tempol-loaded nanoparticles in treatment of epidermoid cancer
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