Vol 4, Issue 1, 2022 (189-198)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : husni@unpad.ac.id (P. Husni)
https://doi.org/10.24198/idjp.v4i1.40691
© 2022 P. husni et al
Utilization of 1-(3-aminopropyl)-imidazole in development of pH-sensitive nanocarrier
for anticancer drug delivery
Patihul Husni1,2, Norisca Aliza Putriana1
1Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy,
Universitas Padjadjaran, Jatinangor 45363, Indonesia
2Department of Global Innovative Drugs, College of Pharmacy, Chung-Ang University, 221
Heukseok dong, Dongjak-gu, Seoul 06974, Korea
Submitted : 13/07/ 2022, Revised : 27/07/ 2022,, Accepted : 02/08/ 2022, Published : 09/08/2022
Abstract
pH-sensitive nanocarriers have demonstrated as successful drug carriers due to the
higher drug accumulation at the tumor site by pH-dependent release at acidic tumor
microenvironment. Imidazole can be utilized to obtain pH-sensitive nanocarriers.
One of the imidazole-based compounds used by researchers in development of pH-
responsive carriers is 1-(3-Aminopropyl)-imidazole. This review is focused on
utilization of 1-(3-aminopropyl)-imidazole to develop pH-sensitive nanocarrier
especially for delivery of anticancer drug. In addition, this review also shows
research performed by researchers to develop pH-sensitive nanocarrier for
anticancer drug delivery using 1-(3-aminopropyl)-imidazole to prepare imidazole-
based pH-sensitive nanocarriers. The data were collected from published journals
with 15 and 20 journals as primary and supporting literatures, respectively.
Properties of imidazole groups to deprotonate at pH 7.4 and protonate at pH ≤ 6.5
implies that the drug release was pH-dependent, leading to a limited release of drug
from carriers under physiological pH conditions and diminishing the drug’s effect
in blood circulation before reaching the tumor site, resulting in more effective
anticancer activity.
Keywords: pH-sensitive, imidazole, poly (β-Benzyl-L-Aspartate), polymer,
nanocarrier
1. Introduction
Delivery systems of drug using
pH-sensitive carrier have shown improved
anticancer activity in comparison with pH-
insensitive carrier (1, 2). pH-sensitive
nanocarriers have shown great interest
because of their advanced functionality (3-
6). Different characteristics were shown by
the pH-responsive nanocarriers under an
acidic, basic, or neutral environment (7, 8).
In the case of anticancer drug delivery, pH-
sensitive carriers have been reported as
competent drug carrier as pH-dependent
release of anticancer agents triggered by
tumor microenvironments (tumor
extracellular pH (pHex = ~ 6.5 to 7.2) or
endosomal pH (pHen ≤ 6.5) (3-6).
Imidazole is a typical pH-sensitive
compound, which was used to obtain the
pH-sensitive and sustained drug release
ability of nanoparticles (9). 1-(3-
aminopropyl)-imidazole has been used in
development of pH-sensitive nanocarrier.
Imidazole can protonate resulted in a
P. Husni et al / Indo J Pharm 4 (2022) 189-198
190
positive charge under acidic pH condition
(10). Deprotonation at physiological pH
(pH 7.4) and protonation at pH ≤ 6.5 of
imidazole groups provided pH triggered
drug release and tumor pH targeted drug
delivery. Some methods can be used to
synthesize pH-sensitive nanocarrier using
1-(3-aminopropyl)-imidazole either by
grafting or by directly
substitution/modulation of functional side
groups of a polymer (11, 12).
This review is aimed to depict
utilization of 1-(3-aminopropyl)-imidazole
in development of pH-sensitive nanocarrier
including properties of imidazole group as
pH-sensitive moiety and synthesis methods
to prepare pH-sensitive nanocarrier using 1-
(3-aminopropyl)-imidazole. In addition,
this review also shows several studies
performed by researchers that use 1-(3-
aminopropyl)-imidazole in development of
pH-responsive nanocarrier to deliver
anticancer drug. Urgency of this review
paper is to introduce the use 1-(3-
aminopropyl)-imidazole in preparation of
pH-sensitivity carrier using easy and simple
method.
2. Methodology
By using specific keywords
“imidazole, 1-(3-aminopropyl)-imidazole
pH-sensitive nanocarrier for cancer”, this
review was prepared. Inclusions criteria
(related to specific keywords) and
exclusions criteria (opinions and unrelated
topics) were also determined. Finally, 15
and 20 journals published in 2011-2022
were collected as primary and supporting
literatures, respectively. Figure 1 depicts
the flowchart of the methodology.
Figure 1. Flowchart of methodology
2.1 Properties of imidazole group as
pH-sensitive moiety
Acidic microenvironment is
abnormality of tumor tissue (10).
Intracellular pH (pHi) of normal cells in
healthy tissues is 7.2 and a slightly higher
extracellular pH (pHex) of 7.4. However, a
pHi of 7.2 and pHen of 6.2–7.0 are found in
tumor cells (13-16). The lower pHen in the
tumor interstitium is caused by lactate
accumulation. Elevated anaerobic
metabolism by the cancer cells produces an
acidic by-product called lactate in the
hypoxic tumor microenvironment (17-19).
Therefore, pH in tumor microenvironment
or inside cancer cells is one of the internal
stimuli for cancer targeting (7, 14). pH-
responsive nanocarriers containing weakly
acidic or basic ionizable groups (pKa
values 3 - 10) can either donate or accept
protons in response to changes in
environmental pH, resulting in change in
P. Husni et al / Indo J Pharm 4 (2022) 189-198
191
structural and other properties (surface
activity, solubility, chain conformation,
etc.) (7, 8, 20). Thus, pH activation of
nanoparticle by tumor microenvironment
can be used to release of drug (Figure 2)
(21-25).
Figure 2. Schematic illustration of pH activation of nanoparticle by tumor
microenvironment (21)
One of the imidazole-based
compounds used by researchers in
development of pH-responsive carriers is 1-
(3-Aminopropyl)imidazole (Figure 3)
which is used in the synthesis of pH-
responsive polyaspartamide derivatives and
the preparation of pH-sensitive amphiphilic
polymers (26). Imidazole exhibits a
prominent pH-sensitive functional group in
pharmaceutical sciences. pKa value of
imidazole is 5.0–6.5, leading to protonate
under acidic pH, resulting in a positive
charge (Figure 4) (10-12, 27).
Figure 3. Chemical structure of 1-(3-
Aminopropyl)imidazole (26)
If the imidazole groups are grafted to a
polymer or substituted /modulated of
functional side groups of a polymer for a
drug carrier, the disintegration of carrier is
induced by pH change (11, 12). At pH 7.4,
the imidazole groups are deprotonated.
However, at pH ≤ 6.5, imidazole groups
protonate, leading to change in structure of
carrier, resulting in release drug from its
destabilized cores of the carrier (Figure 4)
(11, 12, 28).
N
N
N
N
H
pH 7.4 pH 6.0
Figure 4. Illustration of protonation of
imidazole groups under different pH
conditions (pH 7.4 and 6.0)
2.2 Synthesis methods to prepare pH-
sensitive nanocarrier using 1-(3-
aminopropyl)-imidazole
Either by grafting or direct
substitution/modulation of functional side
groups method can be used for synthesis
pH-sensitive nanocarrier using 1-(3-
aminopropyl)-imidazole (11, 12, 29-31).
For the grafting method, Kim et al. develop
a pH-sensitive polymer by grafting the
P. Husni et al / Indo J Pharm 4 (2022) 189-198
192
imidazole groups to poly(aspartic acid)-
block-poly(ethylene glycol) (P(Asp)-PEG),
resulting in P(Asp-g-Im)-PEG to target
acidic pH (Figure 5) Briefly, poly(ethylene
glycol)-poly(β-benzyl-L-aspartate) (PEG-
PBLA) was prepared by coupling PBLA
with monocarboxylated PEG. Next, the
benzyl groups were removed from PBLA
by dissolving the PBLA-PEG in a solution
of dimethylformamide/methanol
(DMF/MeOH) mix and Pd/C catalyst. To
graft the imidazole groups, the preactivated
of deprotected P(Asp)-PEG was dissolved
in DMF in the presence of 1-(3-
aminopropyl)-imidazole and stirred for 24
h at 30 °C (11). Other researchers, Cheng et
al. also developed pH-sensitive
carboxymethyl chitosan nanoparticles by
grafting N-(3-Aminopropyl)-imidazole
onto carboxymethyl chitosan and showed
pH-triggered drug release at acidic
environment (29). In addition, Han et al.
synthesized a pH-responsive nanocarrier
using hyaluronic acid (HA)-graft-
imidazole-dodecylamine (HID) for
anticancer drugs delivery (32).
Figure 5. Synthetic route of grafting the imidazole group to P(Asp)-PEG (11)
For substitution/modulation of functional
side groups method, Chu et al. prepared pH
and reduction micelles using methyloxy-
poly(ethylene glycol)-b-poly[(benzyl-L-
aspartate)-co-(N-(3-aminopropyl)
imidazole-L-aspartamide)] (mPEG-SS-
P(BLA-co-APILA). These researchers
introduced imidazole groups in the side
chain of the block copolymer for pH
sensitivity moiety by substitution reaction
from mPEG-SS-PBLA, resulting in mPEG-
SS-P(BLA-co-APILA (Figure 6). The
block copolymer and 1-(3-aminopropyl)-
imidazole was mixed in DMF under stirring
at 40 °C for 5 h (33).
P. Husni et al / Indo J Pharm 4 (2022) 189-198
193
Figure 6. Substitution reaction of mPEG-SS-PBLA to prepare mPEG-SS-P(BLA-co-APILA)
(33)
Recent study by Sim et al. also developed a
pH-sensitive polymer prepared by partly
modulation of benzyl groups of the
hydrophobic PBLA block of PBLA-PEG.
Dissolving PBLA-PEG in DCM containing
1-(3-aminopropyl)-imidazole and
triethylamine (TEA) at 35 °C under stirring
for 24 h would result in poly[(benzyl-L-
aspartate)-co-(N-(3-aminopropyl)
imidazole-L-aspartamide)]-poly(ethylene
glycol) (PABI-PEG) (Figure 7) (12).
Figure 7. Modulation of functional side groups of PEG-PBLA to form PEG-PABI (12)
2.3 Utilization of 1-(3-aminopropyl)-
imidazole in development of pH-sensitive
nanocarrier for anticancer drug delivery
A number of studies have used 1-(3-
aminopropyl)-imidazole to develop pH-
responsive nanocarrier for delivery of an
anticancer drug (28-31, 33-35). For
example, Chu et al. prepared dual sensitive
(pH and reduction) micelles. Doxorubicin
(DOX) was loaded into the micelles. DOX
release from micelles showed retarded
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194
release in pH 7.4 and fast release at acidic
or reductive environment. These
researchers reported DOX was found rapid
internalization and fast release inside cells.
The cytotoxicity study using HeLa cells
showed that the DOX-encapsulated
micelles could kill cancer cells (33). Cheng
et al. developed nanoparticles of surface-
fluorinated and pH-sensitive
carboxymethyl chitosan (CMCS). To
prepare pH-responsive nanoparticles, N-(3-
aminopropyl)-imidazole (API) was grafted
to CMCS. At acidic condition, the swelling
of nanoparticles containing imidazole was
obtained, resulting in the accelerated
release of DOX (29).
Figure 8. Schematic diagram of irinotecan-loaded pH-sensitive nanogels. Reproduced with
permission of Sim T, Lim C, Cho YH, Lee ES, Youn YS, Oh KT., Development of pH-
Sensitive Nanogels for Cancer Treatment using Crosslinked Poly(Aspartic Acid-graft-
Imidazole)-block-Poly(Ethylene Glycol); published by John Wiley and Sons, 2018.
Oh’s group developed pH-responsive
nanogels using crosslinked P(Asp-g-Im)-
PEG for cancer treatment (Figure 8).
Irinotecan (IRI), an anticancer drug, was
used as a model drug that was loaded into
nanogels (ILNs). Study results indicated
that IRI release was higher under pH 6.5
than pH 7.4 condition. Further, the effect of
ILNs on cell viability was also tested
against colorectal cancer. Cytotoxic effect
of the ILNs was higher at pH 6.5 than at pH
7.4 (34).
P. Husni et al / Indo J Pharm 4 (2022) 189-198
195
Figure 9. Illustration of pH-sensitive nanocluster (NC) system using a pH-sensitive polymer,
P(Asp-g-Im)-PEG, for encapsulation of gold nanorods and DOX for cancer treatment (28).
In other studies, Oh’s group prepared pH-
responsive nanocluster (NC) using a pH-
responsive polymer. Gold nanorods and
DOX were encapsulated by P(Asp-g-Im)-
PEG for cancer treatment (Figure 9). These
researchers reported not only a stable and
structured but also low systemic toxicity at
pH 7.4 of NC systems resulted. In contrast,
aggregated structures of the NC systems
were occurred at pH 6.5, leading to high
drug release. Furthermore, the NC systems
also resulted an increased accumulation and
high DOX release at the tumor site at pHex
and pHen with application of near-infrared
light locally, leading to increase antitumor
efficacy (Figure 10) (28).
Figure 10. (a) DOX release at different pH conditions (pH 7.4 and pH 6.5). (b) whole body
imaging after i.v. injection. (c) EX vivo optical and fluorescent imaging of tumor and organs
obtained 24 h post-injection. (d) relative biodistribution by quantitative fluorescence intensity
(FI) of tumors and main organs. Modified from (28).
P. Husni et al / Indo J Pharm 4 (2022) 189-198
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3. Conclusion
1-(3-aminopropyl)-imidazole has
been used in development of pH-sensitive
nanocarrier. pH activation of nanocarrier by
tumor microenvironment can be used for
anticancer drug delivery. Deprotonation at
physiological pH (pH 7.4) and protonation
at pH ≤ 6.5 of imidazole groups implies that
the drug release was pH-dependent, leading
to minimal drug effect in the bloodstream
before the drug-loaded carrier reach the
tumor site. The tumor pHex and pHen would
trigger release of drug from its carrier,
resulting in effective antitumor activity.
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