BioNanoScience

https://doi.org/10.1007/s12668-024-01376-2

REVIEW

Harnessing Nanotechnology for Idarubicin Delivery in Cancer Therapy:

Current Approaches and Future Perspectives
Fatemeh Safari1 · Yeganeh Jalalian1 · Hamidreza Abdouss1 · Mehrab Pourmadadi2 · Payam Zahedi1 ·
Majid Abdouss3 · Abbas Rahdar4 · Sonia Fathi‑karkan5,6 · Sadanand Pandey7,8

Accepted: 25 March 2024

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024

Abstract
The global burden of cancer, which constitutes approximately one-sixth of all worldwide mortalities, poses a significant
challenge for scientific researchers in their pursuit of effective therapeutic interventions. This discourse delves into the
potential of idarubicin (IDA), an anthracycline antibiotic with pronounced lipophilicity, known for its accelerated nuclear
sequestration, enhanced cellular permeability, and potent cytotoxicity. Despite IDA’s demonstrated effectiveness in com-
bating a spectrum of cancers, its therapeutic utility is significantly hampered by the onset of deleterious side effects such
as cardiotoxicity and myelosuppression. The manuscript provides an exhaustive analysis of novel methodologies that have
been developed to circumvent the impediments associated with IDA delivery, encompassing lipid-based nanoparticles (NPs),
polymeric nanocarriers, carbonaceous nanostructures, and inorganic NPs. It examines key parameters such as drug release,
encapsulation efficacy, loading proficiency, zeta potential, along with in vivo and in vitro characterizations, offering a com-
prehensive assessment of the advancements in disparate delivery systems for IDA. Furthermore, the manuscript probes into
co-delivery formulations of IDA in conjunction with other anti-cancer agents, underscoring their promising implications for
future oncological therapy. The discourse also highlights the paucity of empirical research in this domain. The revelations
gleaned from this review are anticipated to make a substantial contribution to the genesis of innovative strategies for future
oncological treatment.

Keywords Idarubicin · Anthracycline antibiotics · Nanoparticles · Drug delivery systems · Co-delivery ·

Nanoformulations · Cancer therapeutics

Abbreviations AF9 5-[2,4-Bis(azanyl)pyrimidin-5-yl]oxy-

4-DMDR 4-Demethoxydaunorubicin 2-methoxy-4-propan-2-yl-benzenesulfon-
A549 Lung carcinoma epithelial cells amide
AML Acute myeloid leukemia

4
* Mehrab Pourmadadi Department of Physics, Faculty of Sciences, University
mehrabpourmadadi@gmail.com of Zabol, Zabol 538‑98615, Iran
5
* Abbas Rahdar Natural Products and Medicinal Plants Research Center,
a.rahdar@uoz.ac.ir North Khorasan University of Medical Sciences,
Bojnurd 94531‑55166, Iran
* Sonia Fathi‑karkan
6
Soniafathi92@gmail.com Department of Advanced Sciences and Technologies
in Medicine, School of Medicine, North Khorasan University
* Sadanand Pandey
of Medical Sciences, Bojnurd 9414974877, Iran
sadanand.au@gmail.com; spandey@shooliniuniversity.com
7
School of Bioengineering and Food Technology, Faculty
1
Department of Polymer, School of Chemical Engineering, of Applied Sciences and Biotechnology, Shoolini University,
College of Engineering, University of Tehran, Tehran, Iran Solan 173229, Himachal Pradesh, India
2 8
Protein Research Center, Shahid Beheshti University, Department of Chemistry, College of Natural Science,
Tehran 1983963113, GC, Iran Yeungnam University, 280 Daehak‑Ro, Gyeongsan,
3 Gyeongbuk 38541, Republic of Korea
Department of Chemistry, Amirkabir University
of Technology, Tehran, Iran

Vol.:(0123456789)

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 BioNanoScience

AuMPn Gold shell-coated magnetic polyester MPE Maleate-polyester

nanoparticles mTHPP 5,10,15,20-Tetrakis(meso-hydroxyphe-
BILM Biodegradable idarubicin-loaded nyl)porphyrin
microsphere MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphe-
BuCy Busulphan and cyclophosphamide nyltetrazolium bromide
combination NCI-H460 Human non-small cell lung carcinoma
C57BL/6 C57 black 6 NP Nanoparticle
Caco-2 Cancer coli-2 NLCs Nanostructured lipid carriers
CD β-Cyclodextrin NHL Non-Hodgkin’s lymphoma
CD8 Cluster of differentiation 8 NT Normothermia
CR Complete remission PBS Phosphate buffered saline
CNT Carbon nanotube PD1 Programmed cell death protein 1
DDC Dual drug conjugate PEG Polyethylene glycol
DLS Dynamic light scattering PGA Poly(glycolic acid)
DNA Deoxyribonucleic acid PSS Poly(styrene sulfonate)
DNR Daunorubicin POPC Glycerolphospholipid 1-palmitoyl-2-ole-
DSPC Distearoylphosphatidylcholine oyl-sn-glycero-3-phosphocholine
DPPC 1,2-Dipalmitoyl-sn-glycero-3-phospho- ptPVA Pteroic acid enhanced polyvinyl alcohol
choline PDT Photodynamic therapy
DPV Differential pulse voltammetry PTT Photothermal therapy
DXR Doxorubicin PGA Poly (α) L-glutamic acid
D-pen D-penicillamine SCARA5 Scavenger receptor class A member 5
DFT Density functional theory SDDS Smart drug delivery system
DL Drug loading SLNs Solid-lipid NPs
EDTA Ethylenediaminetetraacetic acid TACE Transarterial chemoembolization
EE Encapsulation efficiency TAM Tamoxifen
eNOS Endothelial nitric oxide synthase TfR1 Transferrin receptor protein 1
FA Folic acid TGI Tumor growth inhibition
GDY Graphydine tBA Tert-butyl acrylate
GDYO Graphydine oxide TEM Transmission electron microscopy
GFP Green fluorescent protein UV Ultraviolet
h Hour vdW Van der Waals
HBR Hyperbranched resin
HCC Hepatocellular carcinoma
HER Human epidermal growth factor receptor 1 Introduction
HPLC High-performance liquid
chromatography Cancer, stemming from genetic mutations within cells that
HT Hyperthermia control proliferation, differentiation, and apoptosis [1], has,
HsAFr Horse spleen apoferritin by statistical evidence, emerged as a significant cause of
IC50 Half maximal inhibitory concentration mortality in the USA, ranking second only to cardiovascular
IDA Idarubicin disease [2]. Despite substantial strides in cancer therapies
IgG4 Immunoglobulin G4 over the past five decades, it remains a persistent global
M Molar health conundrum, thereby necessitating the ongoing quest
MCF-7 Michigan Cancer Foundation-7 for innovative treatment methods [3]. Epidemiological
MD Molecular dynamics research underscores the efficacy of cancer cell reduction
MDR Multi-drug resistance by avoiding exposure to smoke, increasing consumption of
MLL Mixed lineage leukemia fruits and vegetables, minimizing sun exposure, enhancing
MMA Methyl methacrylate physical activity, and reducing alcohol and red meat intake
MNP Magnetic nanoparticle [4].
m-PEG-PLGA Methoxy poly(ethylene Current therapeutic interventions for cancer encompass
glycol)-b-poly(L-lactide-co-glycolide) radiotherapy, surgery, immunotherapy, targeted therapy, and
MPBH 4-(4-N-maleimidophenyl)butyric acid chemotherapy [5], all aimed at inhibiting cancer cell growth.
hydrazide However, these modalities often fall short in facilitating

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BioNanoScience
complete cellular recovery [6]. However, it is important to
note that while targeting cancerous cells, these treatments
may inadvertently cause damage to healthy tissues [7]. Sur-
gical interventions come with an assortment of risks includ-
ing pain, strength reduction, cognitive issues, and psychoso-
cial implications such as depression [8]. Chemotherapy, on
the other hand, is associated with a litany of side effects like
hair loss, fatigue, and occasionally, cognitive impairment
[9]. The emergence of resistance to current chemotherapeu-
tic agents underscores the urgent need for novel, improved
treatment approaches [10]. Current modalities plagued by
numerous of drawbacks including side effects, drug resist-
ance, and inadequate drug delivery to tumor sites, which
underscores the pressing need for innovative functional
methods to circumvent these challenges [11].
The utility of nanoparticles (NPs) has been explored
extensively in recent times, specifically for drug delivery
purposes, owing to their idealistic size that permits seam-
less interaction with cellular and subcellular biomolecules
[12]. Since most of the drug molecules are at or near the cell
membrane surface, the uniform characteristics of these par-
ticles guarantee a large surface area, which is advantageous
for drug delivery. Hence, NPs with larger surface area facili-
tate rapid drug release, while larger particles encapsulate
additional drugs for slower distribution [13]. Nanotechnol-
ogy provides plausible solutions for drug delivery, especially
harnessing NPs [14]. Nanotechnology-assisted devices typi-
cally meet the criteria of having a coverage ranging from 1
to 100 nm at the minimum scale [15]. This technology has
found applications across diverse fields, including cancer
diagnosis and treatment [16].
In the near future, “targeted drug delivery” systems using
NPs to carry drugs to cancer cells are expected to gain prom-
inence. These modern cancer cures and innovations bear the
potential to be less invasive and more patient-friendly com-
pared to conventional chemotherapy. Their controlled drug
release process can enhance specificity while diminishing
side effects in patients [17, 18]. Furthermore, enhanced drug
solubility and stability can be achieved via nanotechnology
with benefits including optimal drug concentration at spe-
cific sites, mitigation of off-target effects, and enhancement
of drug plasma half-life [19]. NPs provide protective capa-
bilities against degradation caused by physical and chemi-
cal elements, enabling extended delivery and reduction of
toxicity [20]. Additionally, they offer multiple administra-
tion approaches and facilitate drug delivery across critical
and specific barriers [21]. However, NPs do present with
some disadvantages, primarily linked to the poor biocom-
patibility of the nanomaterials employed in their formation
[22]. Various nanocarriers, such as polymers (nanoemul-
sions, micelles), lipids (liposomes), and gold and metallic
NPs, are used for drug administration to cancerous sites [23,
24]. Significant advancements in nanotechnology have led
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to numerous anticancer drugs based on NPs progressing to
the experimental phase since 2001 [25].
At the moment, anthracycline antibiotics, such doxoru-
bicin (DXR), epirubicin, daunorubicin (DNR), and IDA, are
some of the most often used anticancer medications. They
are used to treat a variety of solid and medical tumors [26].
However, their usage is significantly limited due to severe
side effects such as cardiotoxicity and myelosuppression.
Notably, cumulative dose is the cause of cardiotoxicity, a
common adverse effect of these medications. Anthracyclines
exert their cytotoxic effects primarily by traversing the cellu-
lar membrane and forming covalent bonds with DNA pairs,
thereby enhancing their cytotoxic potency [27]. This work,
as delineated in Fig. 1, primarily underscores the exploration
of IDA and its varied delivery routes as feasible alternatives
to conventional anthracycline treatment. The core objective
of this study is to unravel methods that mitigate the detri-
mental side effects associated with IDA use while potentiat-
ing its cytotoxic effect on cancerous cells. Given the limited
empirical research in this area, our aim with this study is to
offer a substantial impetus for the development of innovative
strategies in future oncological therapy.
2 Idarubicin as a Chemotherapeutic Agent
IDA is an antitumor drug primarily used to treat leukemia
and other hematological cancers [28]. As an anthracycline
combined with cytarabine, IDA was discovered by Arca-
mone et al. in 1976 [29] and was first used to treat cancer
in the late 1980s. Since then, IDA has played a significant
role in the treatment of acute myeloid leukemia (AML) and
is presently the subject of extensive clinical study for the
treatment of various types of solid cancer lesions, includ-
ing carcinoma of the breast, plasmacytomas, and lympho-
mas [30]. Moreover, IDA has exhibited a remarkably higher
antileukemic efficacy compared to other drug combinations,
such as busulphan and cyclophosphamide (BuCy) [31].
IDA, also referred to as 4-demethoxydaunorubicin
(4-DMDR), is derived synthetically from DNR in which a
hydrogen atom is substituted for the C-4 methoxyl group
[32]. Having greater lipophilicity that results in more rapid
accumulation in the nuclei [33], higher cell-permeability,
and cytotoxicity compared to similar anthracyclines, includ-
ing DNR and DXR [34], are among the most potent charac-
teristics of this chemotherapeutic agent. Furthermore, IDA
has demonstrated greater effectiveness in treating cancer cell
lines that exhibit resistance to DXR, DNR, and aclarubicin
[35]. Additionally, IDA possesses lower relative cardiotoxic-
ity than those of epirubicin and DXR [36].
IDA has also undergone considerable evaluation for
AML induction treatment and has been discovered to be
more beneficial than other anthracyclines in improving

Fig. 1  A schematic overview of IDA and its main methods of delivery to cancer cell lines
overall survival [37]. For instance, nivolumab, a human
IgG4 anti-PD-1 antibody, was added to IDA and cytarabine-
based induction therapy for AML in a study conducted by
Ravandi et al. [38]. The results indicated that the IDA-based
formulation could extend the length of remission, eliminate
remaining malignancy, and increase the activity of cyto-
toxic T cells. Furthermore, additional reductions of severe
graft-versus-host-disease could be more feasible with an
induction therapy based on IDA. Moreover, using IDA has
shown higher rates of complete remission (CR) in compari-
son with DNR [39].
However, as an essential treatment for cancer therapy,
the clinical utilization of IDA has detrimental effects, with
cardiotoxicity being the most prominent among them.
Therefore, its dosage is constrained and can put cancer
survivors at higher risk of cardiovascular morbidity and
mortality [33]. Additionally, topoisomerase II may be
inhibited by IDA’s non-covalent interactions with DNA,
which prevent DNA unwinding and nucleic acid synthesis
[40]. Planar organic compounds, such as IDA, often bind
to DNA by intercalation due to their condensed aromatic
rings [41].
In order to determine IDA and its metabolites, a few
methods have been documented in the literature by using
capillary electrophoresis alongside high-performance liquid
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BioNanoScience
chromatography (HPLC) in plasma, urine, saliva, and aque-
ous solutions with mass spectrometry [42] detectors, amper-
ometric [43], fluorescence [44], and UV [45]. Kurbanoglu et
al. [46] utilized a voltammetric method for examining the
electrochemical properties of IDA by employing pyrolytic
graphite electrodes and a multi-walled glassy carbon elec-
trode modified by carbon nanotube (CNT). The objective
was to develop the modified electrodes for the adsorptive
stripping DPV test to determine IDA in the pharmaceutical
dosage form.
The current paper provides a comprehensive review of the
characteristics, pharmacology, and recent developments in
the use of IDA in the delivery of drugs for cancer therapy.
Moreover, medical uses, side effects, synthesis, and mech-
anisms to overcome IDA drug resistance are reviewed. A
classification of this therapeutic agent is developed based on
lipid-based and polymeric structures, as well as their stimuli-
responsive and non-responsive formulations. Furthermore,
inorganic and carbon-based platforms, alongside co-delivery
formulations for encapsulating and delivering IDA to malig-
nant cells, are discussed to comparatively show their advan-
tages and disadvantages. This study provides an overview of
the most recent improvements in IDA, confirming it as one
of the most promising anthracyclines for treating different
cancers, including AML.
BioNanoScience
3 IDA Delivery Systems
Nanotechnology has the potential to enable the delivery
of IDA in significantly higher doses to cancer cells, pav-
ing the way for a more powerful cancer treatment. This
strategy aims to enhance the therapeutic efficacy of the
medication while minimizing any associated unwanted
effects by optimizing its delivery [47]. One strategy is to
use lipid-based NPs as IDA carriers, composed of bio-
compatible lipids that regulate drug-release properties and
enhance the medication’s pharmacokinetic characteristics
[48]. An alternate methodology involves the use of poly-
meric nanocarriers, which are NPs composed of various
biodegradable and biocompatible polymers. The use of
these nanocarriers allows for the encapsulation of IDA,
enabling precise and sustained release, hence ensuring
specific drug delivery while minimizing adverse effects
on the whole system [49].
The other approach entails employing carbon-based
nanostructures as carriers for the pharmaceutical agent.
The aforementioned structures, such as carbon nanotubes
and fullerenes, exhibit notable characteristics in the realm
of drug delivery. These features include a substantial drug-
loading capacity, the ability to overcome cellular barriers,
and the possibility for functionalization to regulate drug
release [50]. Inorganic NPs, such those composed of iron
oxide or gold, may be used as vehicles for specific intracel-
lular drug delivery. NPs’ surfaces may be altered to allow
for targeted delivery, and their properties can be used for
concurrent imaging or diagnostic applications in connec-
tion with cancer treatments [51]. Co-delivery platforms
are an alternative approach that involves the simultaneous
administration of IDA and other anti-cancer medications
via a singular nanocarrier. The principal purpose of these
systems is to optimize the therapeutic efficacy by promot-
ing medication synergy, mitigating multidrug resistance,
and offering complete therapy for intricate and diverse
cancer types [52].
The primary objective of these nanosystems is to
enhance the cytotoxicity of IDA towards cancer cells
while mitigating its adverse effects, therefore augmenting
the overall efficacy of cancer therapy. A more thorough
examination of each drug delivery technique, including
its benefits, underlying mechanisms, and potential applica-
tions in the treatment of cancer, is provided in the sections
that follow.
3.1 Lipid‑Based Nanoparticles
Lipid-based NPs fall into many groups according on
their properties; they include liposomes, niosomes,
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transfersomes, solid-lipid NPs (SLNs), and nanostructured
lipid carriers (NLCs). Each of these groups possesses its
own set of benefits and drawbacks when used for drug
encapsulation. For instance, liposomes have the ability to
reduce the toxicity of chemotherapeutic agents and improve
bioavailability but are unstable and difficult to synthesize
[53]. SLNs play a crucial role in regulating drug release by
enhancing drug payload and stability, mitigating toxicity
[54], and enabling the incorporation of significant quantities
of both lipophilic and hydrophilic drugs. The advantages
of NLCs are comparable to those of SLNs, but they can
also overcome some shortcomings including high moisture
concentration, drug leakage, and poor loading capacity [55].
Conventional drug carriers cannot deliver hydrophobic
drugs. In that case, lipid-based NPs can be used instead,
due to their lipophilic nature [56]. IDA is a hydrophobic
drug [49], and both stimuli-responsive and non-responsive
lipid-based NPs are deployed for the encapsulation and
application of IDA in cancer therapy. Figure 2 depicts a clas-
sification of lipid-based NPs, frequently employed in drug
delivery approaches.
3.1.1 Non‑responsive Nanoparticles Derived from Lipids
Few investigations on non-sensitive lipid-based NPs for IDA
delivery have been conducted. Cancerous cells possess the
capability to develop resistance against chemotherapy agents
and hinder drug absorption, thereby leading to treatment
failure of the tumor. This phenomenon is called multi-drug
resistance (MDR) [57], and ways to overcome this problem
for cancer treatment must be sought. Ping Ma and cowork-
ers [58] developed an SLN formulation for IDA and DXR
encapsulation to overcome MDR in leukemia. The NPs
exhibited a diameter below 100 nm, accompanied by an
entrapment effectiveness over 80%. Furthermore, the meas-
ured zeta potential ranged from around − 5 to − 15 mV. In
most cell lines tested, the I­ C50 rates of IDA nanocarriers
were comparable to those of free IDA, as demonstrated by
in vitro studies. In the P388 animal model studied in vivo,
IDA NPs was comparable to free IDA, but different in the
HCT-15 animal model.
Gian Paolo Zara [59] invented an SLN-based IDA formu-
lation to treat cancerous cells in rats. The objective of this
study was to enhance the bioavailability of the pharmaceuti-
cal compound. The size of the drug particles ranged from
around 70 to 90 nm, while the zeta potential was approxi-
mately 39.5 mV. Moreover, the release rate of the medica-
tion was found to be less than 1% after a duration of 2 h. The
experiments indicated that administering IDA-SLN duode-
nally resulted in improved tissue distribution and a decrease
in the release rate of IDA.

Fig. 2  Different subtypes of lipid-based NPs commonly used for drug encapsulation
In another work, Pakawadee Sermsappasuk [60] con-
ducted a synthesis of a liposomal formulation for the pur-
pose of encapsulating IDA. This was achieved by using
cholesterol, 1,2-distearoylsn-glicero-phosphocholine, and
1,2-distearoyl-sn-glicerophosphoethanolamine-N- [poly
(ethylene glycol)2000. The objective of this study was
to assess the use and limitations of liposomal IDA. The
liposomes containing drugs exhibited a mean diameter of
around 100 nm, accompanied by an entrapped efficiency of
approximately 90%. Additionally, the absorption of the free
IDA decreased to 20%, and the new formulation exhibited a
decrease in coronary vasoconstriction.
The human epidermal growth factor receptor (HER) is a
significant approach used in the field of cancer therapy and
detection. This receptor plays a crucial role in regulating
cellular development and viability. The family unit com-
prises four main individuals identified as HER-1, HER-2,
HER-3, and HER-4 [61]. Mansour Amin and coworkers [62]
designed two formulations, namely immunoliposomes and
liposomes, for the targeted delivery of IDA to breast can-
cer cells expressing the HER2 receptor. The dimensions of
the immunoliposomes and liposomes were measured to be
156.5 ± 2.7 nm and 169.5 ± 3.3 nm, respectively. The average
zeta potential of the immunoliposomes and liposomes was
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found to be − 19.31 mV and − 50.33 mV, respectively. Con-
sequently, there was a substantial increase in cellular absorp-
tion and medication efficacy. The observed phenomenon
is likely attributed to trastuzumab-conjugated liposomes,
which demonstrate a greater ability to target malignant cells
compared to free IDA, as seen in Fig. 3. Table 1 provides a
comprehensive overview of formulations based on lipids that
exhibit limited reactivity and are employed for the delivery
of IDA in the domain of cancer treatments. The application
of these formulations holds significant promise in enhanc-
ing the efficacy of IDA by improving its targeted delivery,
thereby enhancing therapeutic outcomes while mitigating
non-specific effects.
3.1.2 Stimuli‑Responsive Nanoparticles Derived
from Lipids
The performance of stimuli-responsive lipid-based NPs
may be adjusted by altering certain parameters, such as
temperature and pH. This section primarily focuses on cur-
rent research concerning stimuli-responsive lipid-based
nanoparticles utilized for the transportation of IDA [64]. Tao
Lu and colleagues [65] developed a novel IDA formulation
that was a combination of thermosensitive liposomes and
BioNanoScience
Fig. 3  This schematic representation depicts the methodical deliv-
ery of IDA through liposomes coupled with trastuzumab to breast
tumor cells that excessively express the HER2 receptor. To ascertain
the impact of various IDA formulations, the viability of the MCF-7
and SK-BR-3 cell lines was assessed. In a series of three consecutive
tests, the cells were subjected to treatment with conventional IDA,
liposomal IDA, and immunoliposomal IDA, respectively. The dura-
hyperthermia (HT) with the goal of enhancing IDA retention
and drug release in different temperatures. The size of the
synthesized liposomes was around 85 to 130 nm. Moreover,
the drug entrapment efficiency was around 100%, and the
zeta potential was between − 5 and − 9 mV. In vitro studies
showed low leakage at 37 °C for 1 h, whereas at 42 °C, the
experiments indicated an ultra-fast and total induced release
of the drug. In addition, IDA-TSL was as cytotoxic as the
free drug to tumor cells at 42 °C. However, the cytotoxic-
ity was found to be less at 37 °C. In vivo studies indicated
high drug absorption by tumor cells, and studies using mice
models revealed that the combination of mild HT and IDA-
TSL inhibited tumor growth and caused more cell survival
compared to free HT and IDA.
To increase the effectiveness of delivering IDA and DXR
into tumors, Yongzhong Wang [66] developed a method to
deliver the drug by using PazPC, an oxidized phospholipid.
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tion of each treatment was 4 h, and it was followed by a 72-h period
of incubation during which the assessment of cell viability was con-
ducted. Significant alterations in cellular viability were seen in all
instances, as compared to both the control groups that were not sub-
jected to any treatment and the MCF-7 cell line. Reprinted from ref.
[62] with permission from Elsevier, copyright 2018
These formulations had a molar ratio of about 5 to 1 (lipid
to drug) at pH 7, and the size of these particles was around
10 nm, with the drug entrapment efficiency of 87%. The
observed nanoformulation demonstrated pH-responsive
characteristics, leading to an accelerated drug release rate
under acidic conditions (pH > 7). Moreover, experiments
showed that these formulations caused better uptake of drugs
and indicated more cytotoxicity in leukemia cells compared
to free drugs.
Nancy Dos Santos and coworkers [67] synthesized pH-
responsive liposome formulations to improve antitumor
activities. The objective of this research was to elevate the
plasma levels of IDA and encapsulate the drug in liposomes
to prolong its circulation time. The novel compositions were
prepared using a molar ratio of about 5 to 1 (lipid to drug)
in an extracellular environment at pH 7.4 and an intracellu-
lar environment at pH 4. Furthermore, the drug entrapment
 BioNanoScience

Table 1  Non-responsive lipid-based formulations for IDA-loaded cancer therapeutics

Formulation Particle size Zeta potential EE (%) DL (%) Release Characterization Case study Reference
(nm) (mV)

SLN-IDA 100 − 5 to − 15 > 80 10 100% in 6 h In vivo and Leukemia P388 [63]

in vitro and HCT-15
mouse model
SLN-IDA 80 ± 10 39.5 5 98 < 1% at pH 7.4 In vitro Rats [59]
in 2 h
Liposome-IDA 100 N/A 90 N/A N/A In vivo Rat heart [60]
Liposome-IDA 169.5 ± 3.3 − 50.33 N/A N/A N/A In vivo and HER2-positive [62]
in vitro breast cancer-
ous cell line
(SK-BR-3 and
MCF-7)
Immunolipo- 156.5 ± 2.7 − 19.31 N/A N/A N/A In vivo and HER2-positive [62]
some-IDA in vitro breast cancer-
ous cell line
(SK-BR-3 and
MCF-7)

efficiency of these formulations exceeded 95%. Experi-
ments indicated the best formulation was achieved when
the levels of polyethylene glycol (PEG)-lipid incorporation
increased under iso-osmotic conditions which caused more
IDA release. In vivo, research conducted on some mice indi-
cated that compared to free IDA, the liposome formulation
increased the lifespan. It was observed that the new formula-
tion improved the circulation longevity and antitumor activi-
ties in the drug but was ineffective in multidrug resistance.
Jerzy Gubernator [68] developed a pH-sensitive liposome
formulation by utilizing a novel approach that dissolves the
medicine in EDTA salt solutions. The present formulation
demonstrated an extended retention period and was specifi-
cally designed to inhibit the release of the medication from
the PEGylated liposomes, which also contained cholesterol.
The primary objective of the study was to develop a novel
and stable liposomal formulation with the aim of decreasing
the dissolution rate of IDA in an in vivo setting. The size of
these liposomes was between 95 and 120 nm, and they had a
zeta potential ranging from 2 to 4.5 mV. Moreover, the drug
entrapment efficiency of these formulations was around 98%
with a 0.2 molar ratio of drug to lipid. This method indicated
higher stability and plasma level compared to other encap-
sulation methods for IDA.
In another study, Nancy Dos Santos [69] developed a
new cholesterol-free liposomal formulation to encapsulate
IDA. The formulation consisted of distearoylphosphati-
dylcholine (DSPC): distearoylphosphatidylethanolamine
(DSPE)-PEG2000 liposomes. The liposomes that were pre-
pared exhibited an average size of around 110 nm, and a
significant proportion of the encapsulated medication was
released during a 15-min period at a temperature of 37 °C,
exceeding 95% in quantity. Experiments revealed that the
existence of PEG was an important factor in cholesterol-free
liposomes, and it caused improvement in circulation lon-
gevity. Additionally, this formulation exhibited an improved
medication retention rate in comparison to liposomes con-
taining cholesterol. The release of entrapped IDA (present
in both unbound and precipitated forms) from the aqueous
core of a liposome into the surrounding medium is depend-
ent on the drug’s partitioning properties, as seen in Fig. 4.
Table 2 presents a complete summary of several lipid-based
NPs that exhibit responsiveness to stimuli and are used for
the purpose of delivering IDA to cancer cells. The NPs in
question have been purposefully created and programmed to
respond to certain triggers or events, hence increasing their
capacity to efficiently transport IDA to cancer cells that have
been carefully targeted.
3.2 Idarubicin Polymeric Delivery Systems
Due to anthracyclines’ ability to permeate across cell mem-
branes, target topoisomerase II, and intercalate between
DNA base pairs, cytotoxicity is an inevitable barrier inhib-
iting wider clinical use of idarubicin as an anticancer drug
[76]. Because of its much greater lipophilicity—which
results from the aglycone’s D ring missing a methoxy group
at position 4—IDA shows higher cytotoxicity in comparison
with DXR and DNR [63]. IDA’s proper encapsulation is a
crucial aspect of an effective application of this therapeutic
agent in cancer treatment. The most relevant polymeric car-
riers for achieving this purpose are included in this section.
Utilizing polymeric NPs as drug carriers is a suitable
approach since they possess certain beneficial features
such as biodegradability, stability, and the state of not
being able to inflame. Another prominent characteristic of

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Fig. 4  It is possible to control the drug partitioning process within
liposome membranes by using pH gradients and crystalline precipita-
tion development. The protonated (BH +) and unprotonated (B) forms
of IDA enter a steady state of equilibrium as they move from the
encapsulating precipitate inside the liposome’s aqueous core, over the
bilayer interface, and finally through the bilayer itself. IDA’s availa-
these NPs is the crucial quality of nontoxicity [70], which
makes the use of these agents less hazardous for the body
than that of other particles. These particles range in size
from 20 to 250 nm, with their surface consisting of non-
fouling water-soluble polymers, namely dextran and PEG
[71]. Polymeric NPs can be deployed in two different ways
to deliver drugs to the tumor site or inside the infected
cells. Either the anticancer drug is joined to the NP’s sur-
face or is enclosed and preserved in the polymeric bed.
Various physiochemical structures of these particles con-
tribute to a diversity of morphologies and compositions in
the polymeric core and periphery, as illustrated in Fig. 5. A
variety of biological barriers can be surmounted by poly-
meric NPs, which release the ideal dosage of the intended
therapeutic payload. The functionalization of these medi-
cations helps to target the surface antigens of tissues and
cells with a ligand (such as an aptamer, peptide, antibody-
antibody fragment, or small molecule) to reduce the agent’s
nonspecific dispersion and increase the duration of blood
residence time [72, 73].
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
bility is dependent on how the drug partitions; this behavior may vary
depending on a number of parameters, including pH, membrane sur-
face charge, and the particular characteristics of the lipid acyl chains.
Reprinted from ref. [62] with permission from Elsevier, copyright
2002
3.2.1 Non‑responsive Nanoparticles Derived
from Polymers
Insensitive polymer-derived NPs are a promising vehicle
for the delivery of anticancer drugs. In light of this, Liang
et al.’s study [49] examined the antileukemic effects and cell
absorption of polymeric NPs loaded with IDA. In this work,
an amphiphilic diblock copolymer (m-PEG-PLGA) was
developed from methoxy poly(ethylene glycol)-b-poly(L-
lactide-co-glycolide). The MLL-AF9-induced antileukemic
activity was put to the test using IDA-loaded mPEG-PLGA
NPs in mice. The study discovered that IDA/mPEG-PLGA
NPs displayed exceptional encapsulation efficiency (EE)
and drug loading (DL) values. It was suggested that PLGA’s
hydrophobic segments, which provide sufficient hydropho-
bic force to encase a substantial IDA payload in the mPEG-
PLGA NPs’ cores, were responsible for the high EE and DL
values. Results also revealed that IDA/mPEG-PLGA dis-
played lower I­ C50 in leukemia blasts than pure IDA. Addi-
tionally, the cell viability of IDA/mPEG-PLGA was found
 BioNanoScience

Table 2  Stimuli-responsive lipid-based formulations for IDA-loaded cancer therapeutics

Formulation Particle size Zeta potential EE (%) DL (%) Release Characteriza- Case study Reference
(nm) (mV) tion

Thermosensi- 85–130 − 5 to − 9 100 30 ~ 90% at pH In vivo and Hyperthermia [70]

tive liposome 5.5 and 42 °C in vitro (HT)
loaded with in 1 h
IDA (IDA- ~ 20% at pH
TSL) 5.5 and 37 °C
in 1 h
PazPC-IDA 10 − 24.3 ± 3.7 87 14.8 ~ 62.5% at pH In vitro Leukemia P388 [71]
6.5 in 10 h and P388/ADR
Cholesterol-free N/A N/A > 95 N/A N/A In vivo and Mice P388/ [72]
liposomes in vitro ADR and
loaded with MDA435LCC6/
IDA MDR1
PEGylated 95–120 2–4.5 98 N/A ~ 98% at pH 4 In vivo and Mice BALB/c [73]
cholesterol- and 37 °C in in vitro
containing 24 h
liposomes
loaded with
IDA
DSPC 110 ± 30 N/A N/A > 95 > 95 at 37 °C in In vivo Balb/c mice [74]
PEGylated 15 min
cholesterol-
free liposomes
loaded with
IDA
IDA-SDDS N/A N/A 13.0 ± 3.6 N/A 100% at 42 °C In vitro eNOS-Tag-GFP [75]
in 1 h mice

Fig. 5  A classification of polymer-based nanoformulations for drug delivery according to their physiochemical structures

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

BioNanoScience
to be higher than that of pure IDA, showing higher efficacy
both in vivo and in vitro. The research demonstrates excel-
lent release properties of mPEG-PLGA for encapsulation of
IDA chemotherapeutic agent to treat AML.
In one study, Jain, Ratnesh, et al. [74] modified the outer-
most layer of propyl starch NPs laden with IDA in an attempt
to increase the anti-cancer agent’s intracellular absorption.
The pteroic acid-enhanced polyvinyl alcohol (ptPVA) was
synthesized and afterwards used in the NP formulation as
a stabilizing agent. The NPs treated with ptPVA exhibited
enhanced protein adsorption, resulting in heightened cel-
lular internalization. The results of protein binding assays
demonstrated a greater degree of adhesion of the model pro-
teins onto NPs formed with ptPVA in comparison with those
prepared with PVA. The cellular uptake tests provided con-
firmation of the enhanced cellular uptake of NPs stabilized
by ptPVA (Fig. 6).
The study conducted by Güç, Gündüz, and Gündüz [75]
focused on the use of nano-scale dendrimer/hyperbranched
polymer for drug delivery purposes. A novel hyperbranched
resin (HBR) based on fatty acids was developed with the
particular purpose of facilitating the transfer of Tamoxifen
(TAM) and IDA. The HBR is constructed using dipentae-
rythritol as the core component, dimethylolpropionic acid
Fig. 6  A Propyl starch NPs were investigated for their ability to
bind proteins, with bovine serum albumin serving as a representa-
tive protein in the studies. PVA (identified as PVA 1–3) and ptPVA
(also referred to as ptPVA 1–3) were used to create three distinct
batch of propyl starch NPs. B The given data illustrates the release
pattern of indocyanine green (IDA)-loaded propyl starch NPs modi-
fied with ptPVA in an in vitro setting. The graph shown illustrates the
pattern of release during a 24-h period. The present study illustrates
the investigation of the cellular absorption of propyl starch NPs that
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for branching, and ricinoleic acid for termination. In contrast
to IDA, which had a chemical bond with the resin, TAM had
a physical one, according to the study results. The release
velocity in the phosphate buffer was found to be boosted by
triggering factors like Pseudomonas sp. lipase and sodium
dodecyl sulfate. Conversely, an increase in loading concen-
trations was shown to lead to a reduction in release veloc-
ity. Comparing the administration of pure medications with
drug-loaded NPs showed significantly higher cell death rates
in the cytotoxicity assays performed on MCF-7 breast cancer
cells. Particles devoid of medicinal materials, on the other
hand, showed no discernible toxicity. Table 3 provides an
overview of non-responsive polymeric systems used in can-
cer therapy.
3.2.2 Stimuli‑Responsive Nanoparticles Derived
from Polymers
The term “stimuli-responsive” generally refers to environ-
ment-sensitive nanocarriers that undergo swelling, disinte-
gration, or collapse in response to either an external pro-
vocative agent (such as temperature, light, magnetic field,
or ultrasound) or an internal stimulant (such as lysosomal
digestive enzymes, glucose, and redox potential). Recently,
have been treated with ptPVA in HT-29 cells. The red fluorescence
highlights the cell membranes, which have been stained with RRCA,
while the blue fluorescence depicts the cell nuclei, which have been
stained with DAPI. After a period of 2 h (C), the NPs start the pro-
cess of binding to the cell membrane, and this binding activity inten-
sifies after 4 h (D) with an increase in uptake. Conversely, there was
no absorption of the propyl starch NPs made using unmodified PVA
(E). Reprinted from ref. [74] with permission from Elsevier, copy-
right 2011
 BioNanoScience

Table 3  Non-responsive polymer nanoformulations for IDA encapsulation

Formulation Particle size Zeta potential EE (%) DL (%) Release Characteriza- Case Study Reference
(nm) (mV) tion

IDA/mPEG- 81.2 ± 3.4 − 34 ± 3.6 93.95 ± 3.2 8.59 ± 0.96 80.2 wt% at In vivo and MLL-AF9- [49]
PLGA 37 °C in in vitro induced
40 days, PBS murine
as the release leukemia
medium
IDA-loaded 218.5 ± 6.12 − 5.54 ± 0.88 84.2 ± 3.23 82 ± 4 46.7 ± 3.2%. In vitro HT-29 [74]
propyl starch at 37 °C in
NPs modified 7 days
with ptPVA
HBR-IDA 217.1 ± 5.6 − 41.4 ± 1.6 74 59.6 ± 4.3 < 0.7% at pH In vitro MCF-7 [75]
7.4, 37 °C in
67 days

these groups of NPs have garnered considerable interest
because of their enhanced capacity to promote drug release
at the malignant spot (spatial control) or at the appropri-
ate moment (temporal control) [77]. Recent research has
revealed a groundbreaking group of polymeric nanomedi-
cines that are bio-sensitive and adept at delivering drugs to
specific sites with remarkable efficiency. These nanocarriers
maintain stability in extracellular environments and circula-
tion, effectively addressing the challenge of balancing sta-
bility and drug release within polymer-based carriers [78].
According to research conducted by Wadhwa et al., the
group used pH-responsive hydrazone bonds and disulfide
to covalently bind IDA and D-penicillamine (D-pen) to the
peripheral chain of poly (α) L-glutamic acid (PGA). When
compared to unconjugated IDA, it was found that the dual
drug conjugate (DDC) considerably increased drug exposure
by a factor of seven and extended the half-time of plasma
circulation. Additionally, significant growth in tumor accu-
mulation was seen, which resulted in 89% tumor growth
inhibition (TGI) as opposed to 60% with unconjugated IDA.
This resulted in a 17% enhancement in NCI-H460 tumor
viability in mice models (Fig. 7) [79].
Blaudszun et al. investigated cell-mediated drug deliv-
ery that utilizes living cells to transport and dispense
the medication, with the aim of minimizing premature
cell death. To this end, the biocompatible poly(lactic-
co-glycolic-acid) (PLGA) and maleate-polyester (MPE)
NPs were encapsulated with IDA and the effects of the

Fig. 7  A An illustration demonstrating the steps involved in forming
an IDA-MPBH. B Examination of the PGA and DDC circular dichro-
ism spectra. Prior to coupling, the spectral observations are compared
with the DDCs at room temperature (25 °C) and around 50 M PGA
level. The figure shown is the average of two separate investigations.
C The observation of HL-60 cells using confocal microscopy during
DDC administration, displaying clear interference contrast and fluo-
rescence images, correspondingly, after 4 h (upper) and 12 h (lower)
of treatment. D Evaluation of potential anticancer effectiveness using
the NCI-H460 tumor model. A tumor development trajectory in
athymic nu/nu mice fed a bi-daily, three-dose regimen of NCI-H460
xenografts (50–100 mm.3). Reprinted from ref. [79] with permission
from Elsevier, copyright 2012

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BioNanoScience
stimuli-responsive and active medication were examined
on human T cells. To further assess the uptake, T cells
were treated with the poly(styrene sulfonate) (PSS)-com-
plex of 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin
(mTHPP). The results revealed that MPE-IDA NPs were
more effective at preventing IDA toxicity than PLGA-IDA
NPs in T lymphocytes, and PSS/mTHPP loaded lympho-
cytes could survive for 4 days minimum unless they are cul-
tivated in the light [80].
Another study by Nafee et al. [81] proposed that employ-
ing pH-triggered polymeric NPs, star polymer deployment,
might help with chemotherapy. β-cyclodextrin (CD) formed
the hydrophilic center of the amphiphilic star polymer
known as MMA-tBA CD. The hydrophobic arms, moreo-
ver, were made using tert-butyl acrylate (tBA) and methyl
methacrylate (MMA). The resulting polymer exhibited a
slightly negative zeta potential and varied in size from 130
to 200 nm. When loaded with CD-NPs, the polymers were
observed to release their payload over a period of 48 h, with
an initial burst of 40%. Additionally, polymeric magnetic
NPs (MNPs) have recently drawn attention in cancer therapy
due to their favorable properties, including reduced agglom-
eration, improved biocompatibility, and cellular uptake. The
exterior section of these NPs consists of polymers, while
a magnetic core serves as the inner section. As a poten-
tially effective delivery approach for the treatment of breast
cancer, Gunduz et al. [82] reported encapsulating IDA in
PEG-coated, folic acid (FA) linked MNPs in MCF-7 cells.
Researchers found that compared to pure IDA, there would
be an increase in cytotoxicity when using IDA-loaded FA-
PEG-MNPs. Exposure of IDA-loaded magnetically sensitive
NPs to magnetic fields resulted in a successful uptake by
MCF-7 cells.
To conquer the rapid elimination of the therapeutic agent
into the cardiovascular system using transarterial chem-
oembolization (TACE) locoregional therapy, Zheng et al.
[28] employed gelatin and carrageenan to prepare biode-
gradable microspheres capable of being loaded with IDA
(BILMs), resulting in IDA-MS to treat hepatocellular car-
cinoma (HCC). TACE with IDA-MS significantly reduced
tumor growth while posing no additional significant adverse
effects beyond those seen in the IDA group, according to
research conducted on an HCC model in mice and rabbits.
Furthermore, by promoting CD8 + T cell expression and
boosting the effectiveness of anti-PD1 immunotherapy,
TACE with IDA-MS improved the HCC tumor immuno-
logical environment (Fig. 8). Additionally, Ronak Rafipour
and her colleagues have utilized protein-based nanocarriers
for carrying IDA with the goal of mitigating toxicity and
enhancing the drug’s anticancer properties. This procedure
entailed demounting and remounting horse spleen apofer-
ritin (HsAFr) in the presence of IDA, without modifying the
tertiary structure of the protein. The group achieved a drug
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
loading efficiency of 7.15% and an entrapment efficiency of
84.7%. The MTT viability test was used to assess the anti-
cancer effects of free and HsAFr-IDA on MCF-7 cancer cells
in humans [83]. An overview of the many stimuli-responsive
polymeric formulations used to administer IDA therapies is
given in Table 4.
3.3 Carbon‑Based and Inorganic Delivery Systems
The potential of carbon-oriented delivery systems to effi-
ciently carry medications for the purpose of cancer treatment
is attracting wide attention. These structures, renowned for
their unique attributes, such as a vast surface area, thermal
conductivity, and potent penetrative abilities, are an excel-
lent candidate for focused drug delivery, especially the con-
veyance of IDA [84]. Researchers have been successfully
encapsulating IDA with the carbon-derived nanocarriers
with an aim to lower the drug’s toxicity and enhance its anti-
cancer properties [85]. The encapsulation process typically
involves a strategic disassembly and reassembly approach
that maintains the tertiary structure of the carrier protein,
thereby preserving its ideal function [86]. Groundbreaking
research in this realm has yielded commendable results.
For instance, investigations indicate that deploying these
carbon-focused nanocarriers for IDA delivery attains high
loading and entrapment efficiencies [87]. Furthermore, vari-
ous studies deployed molecular dynamics (MD) modeling
to ascertain the graphydine oxide nanosheet’s ability to load
the IDA medication. The lowering van der Waals (vdW)
interaction energy of IDA and graphydine oxide nanosheet
explains their strong attraction, suggesting that the latter is a
suitable carrier for IDA delivery. The simulation also looks
at how the loaded IDA-graphydine oxide nanosheet combi-
nation penetrates the biomembrane, and it shows that IDA
adsorbed molecules continue to be conjugated with graphy-
dine oxide [88].
In order to encapsulate IDA, Lu et al. [89] created a smart
drug delivery system (SDDS) that used 1,2-distearoyl-sn-
glycero-3-phosphocholine (DSPC) and phospholipid-based
heat-triggered 1,2-dipalmitoyl-sn-glycero-3-phosphocho-
line (DPPC). In both in vivo and in vitro settings, the drug
release, biodistribution, and cell uptake of IDA-loaded
delivery systems were evaluated and compared with those
of DXR. The findings demonstrated that as opposed to
DXR-SDDS, IDA-SDDS exhibited quicker release and 10
times higher cellular uptake evaluated in vitro. Furthermore,
IDA appeared to have reduced drug redistribution and four
times more absorption of entire tumor drugs than DXR
in vivo, collectively leading to improved therapeutic effi-
cacy. According to the research, DXR-SDDS exhibits greater
tumor absorption and content release efficiency in vivo when
heated at high temperatures (Fig. 9).
 BioNanoScience

Fig. 8  IDA-MS reduced tumor

development and improved anti-
PD1 efficacy in the H22 carci-
noma model. A The plan of the
carried-out research. B Tumor
images taken from the IDA,
IDA-MS, IDA + PD1, and IDA-
MS + PD1 cohorts. Size (C)
and assessment of each group’s
subcutaneous lesions’ mass (D).
E PET scans demonstrating the
tumor-ridden animals in each
group. F Differences in the
maximum ID%/g. From Ref.
[28], used under Creative Com-
mons CC-BY license

Via deploying MD simulation, graphydine oxide
(GDYO) nanosheets were found to be useful for loading
IDA [88]. As a membrane model, Shahabi and Raissi exam-
ined the use of graphydine (GDY) to transport IDA in an
environment of glycerolphospholipid 1-palmitoyl-2-ole-
oyl-sn-glycero-3-phosphocholine (POPC). The primary
reason for decent IDA adsorption on GDYO nanosheets
was associated with van der Walls interaction energy, as it
was negatively changed during the first 12 ns of simulation
run time. Results also showed that the stable IDA-GDYO
complex proceeded towards the POPC membrane sponta-
neously at the early stages of simulation, demonstrating
GDYO nanosheets as highly potential carriers for IDA at the
near cell membrane. Shahabi and Raissi carried out similar
research on assessing the transfer efficacy of graphydine
nanosheets loaded with IDA, using MD simulation and den-
sity functional theory (DFT) [90]. The IDA molecules and
the nanosheet interacted weakly, with an adsorbed strength
value of 81.305 kJ/mol, according to the Non-covalent
Interaction technique of DFT calculation. The results imply
that applying electric fields in the xy and z directions may
enhance the contact between the adsorbed medication and
the porous framework of the nanosheet by raising the vdW
interaction energy. The findings support those of the earlier
research and demonstrate that the hydrophobic characteris-
tics of the graphene nanosheet lead to a higher vdW interac-
tion’s energy value. Table 5 summarizes the aforementioned
carbon-based formulations and their major characteristics.

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BioNanoScience

Table 4  Stimuli-responsive polymeric formulations for IDA-loaded cancer therapeutics

Formulation Particle size Zeta potential EE (%) DL (%) Release Characterization Case study Reference
(nm) (mV)

DDCs from IDA N/A N/A N/A N/A 90% at pH 5.2, In vivo and NCI-H460 [79]
and D-pen 10 mM glu- in vitro
conjugated to tathione, and
PGA in 14–16 h
< 10% at pH 7.4
in 16 h
PLGA-IDA 215.8–9.6 − 20.57 ± 0.76 92.6–0.2 2.26 50% at pH 7.4 in Ex vivo Human T lym- [80]
48 h phocytes
MPE-IDA 226.8–7.1 − 1.88 ± 0.28 81.4–1.34 1.97 15% at pH 7.4 in Ex vivo Human T lym- [80]
24 h phocytes
MMA-tBA CD 130–200 0 to − 2 ~ 40 N/A 80% at pH 7.4 in In vitro Caco-2 and [81]
star copoly- 48 h A549
mers
FA–PEG–MNP 10–40 N/A 36.1 ± 3.4 N/A ~ 80% at pH 5.4 In vitro MCF-7 [82]
in 12 h
~ 60% at pH 7.0
in 12 h
IDA-MS from 1.5–2.9 e + 5 N/A 99.12 N/A 38.4% in 0.9% In vivo and VX2 rabbit and [28]
gelatin and NaCl solution in vitro C57BL/6 mice
carrageenan- in 12 h HCC
synthesized
BILMs
HsAFr-IDA 6–8 N/A 84.75 7.15 Through interac- In vitro MCF-7 [83]
tion with the
SCARA5 and
TfR1 receptors

3.4 Inorganic Formulations interactions with cell membranes, and drug delivery.

Researchers have formulated IDA into inorganic medica-
tions or formulations to enhance its therapeutic potential
and delivery. These formulations, such as IDA-loaded NPs,
utilize the advantages of inorganic materials, including
enhanced stability, controlled release, and targeted deliv-
ery, in addition to possessing a high surface-to-volume ratio.
By improving the drug’s solubility and cellular absorption,
this approach may boost therapeutic effectiveness. Further-
more, by carefully controlling the NPs’ size and form, one
may significantly influence their distribution and clearance
levels, which will increase the medication’s effectiveness
even more [91]. Due to their biocompatibility and ease of
surface functionalization for targeted delivery, IDA has been
incorporated into silica or mesoporous silica NPs in certain
instances [92]. The design of multifunctional inorganic for-
mulations containing IDA, in which NPs are not only drug
carriers but also possess therapeutic properties, is gaining
popularity. For example, IDA-carrying MNPs may be tar-
geted to the tumor location using an external magnetic field,
and their magnetic features can also be used to enhance the
overall therapeutic impact.
Among inorganic structures, apoferritin was found to
have suitable properties, such as self-assembly, decent
Rafipour et al. [83] used HsAFr as nanocages for IDA and
examined their efficacy on human breast cancer tumors
(MCF-7). Encapsulation efficiency (EE), as a parameter to
evaluate drug-loading capacity, was found to be 84.75%,
showing high compatibility between IDA and the protein.
Additionally, it was determined that IDA and HsAFr-IDA
had ­IC50 values of 5.57 and 1.6 ng/mL, correspondingly,
which led to increased toxicity in MCF-7 cells. To opti-
mize antileukemic synergy and minimize cardiotoxicity in
patients with acute promyelocytic leukemia (APML4), a
combination of IDA, arsenic trioxide (ATO), and all-trans-
retinoic acid (ATRA) was created [93]. ATO was put on an
IDA and ATRA backbone for two cycles of consolidation
after introduction. Consequently, APML4 patients exhibited
a remarkable rise in freedom from relapse and failure-free
survival compared with previously studied ATRA/IDA-
based protocol (APML3) [94].
In another study, the drug-eluting embolic (DEE) agent
ONCOZENE (CeloNova BioSciences) appeared to be a
viable platform for loading IDA which could be used to
treat patients with HCC [95]. To form the exterior shell,
DEE agents were coated with poly[bis(trifluroexthoxy)
phosphazene], an inorganic polymer consisting of negatively
charged sodium polymethacrylate as the hydrogel core.

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 BioNanoScience

Fig. 9  When combined with

hyperthermia, the IDA-SDDS
exhibits a greater effectiveness
of release and greater assimila-
tion by tumors in living bodies
compared to the DXR-SDDS. A
A depiction of the hyperthermia
(HT) therapy method and the
blood sample collection process
for rodents is provided. B, C
Three tumor-bearing BFS-1
mice are administered with a
low or high dosage of SDDS
(A for low dose and B for high
dose) in order to assess the lev-
els of medicines in the plasma
before and after 1-h HT (42 °C)
or normothermia (NT) (37 °C)
treatment. There is a complete
release when IDA-SDDS and
HT are used in tandem. D Com-
pared to DXR, tumors in an HT
environment absorb the released
IDA more effectively, sustaining
greater drug levels 48 h after
treatment. A nonparametric
Mann–Whitney test on a mini-
mum of three rats per cohort
yielded a *p < 0.03 result. E It
has been shown that during the
first 48 h of therapy, the ratio of
IDA to DXR concentration in
the tumor, which is generated
from D, steadily increases. This
suggests that IDA is kept in
cells after absorption for a con-
siderable amount of time. From
Ref. [89], used under Creative
Commons CC-BY license

Table 5  Carbon-based formulations for IDA loading

Formulation Particle size Zeta potential EE (%) DL (%) Release Characterization Case study/plat- Reference
(nm) (mV) form

IDA-SDDS N/A N/A 13.0 ± 3.6 N/A 100% at 42 °C In vivo and eNOS-Tag-GFP [89]
composed of in vitro mice
DPPC and
DSPC
IDA-GDYO 6 (via simula- N/A N/A N/A 150 ns (produc- MD simulation POPC bilayer [88]
tion) tion run-time)
IDA-GDY 7 (via simula- N/A N/A N/A ~ 10 ns (produc- DFT and MD Liquid water [90]
complex tion) tion run-time) simulation
IDA-loaded 218.5 ± 6.12 − 5.54 ± 0.88 84.2 ± 3.23 82 ± 4 46.7 ± 3.2%. at In vitro HT-29 [74]
propyl starch 37 °C in 7 days
NPs stabilized
with ptPVA

Results indicated that 10 mg of IDA could be loaded onto since IDA exhibits strong cytotoxicity against HCC cancer
the ONCOZENE DEE agents within 10 min, proving a rapid cells even at low doses. Rui Meng’s [96] research led to in
loading process. Conversely, the slow release of IDA from the development of AuMPn, an innovative, multipurpose NP
the ONCOZENE DEE agents was seen as advantageous encased in a gold nanoshell. The production of AuMPn was

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BioNanoScience

achieved by combining the processes of emulsion solvent of the spheroid-shaped AuMPn particles that were produced
evaporation and hydroxylamine reduction. The researchers was 235.71 ± 34 nm, with an encapsulation efficiency of
employed IDA to assess the drug loading and release capa- 72.08% and drug loading efficiency of 1.73%. The gold
bilities of the NPs through dialysis. The average dimension exterior of the AuMPn emitted a spectrum resembling a

Fig. 10  Discoveries concerning

apoptosis in controlling the cells
and IDA. The combination of
MNP-GA-IDA indicates that
the majority of control cells are
still viable. Upon application of
MNP-GA-IDA, cells begin to
accumulate in areas related to
apoptosis, yet they do not pro-
gress to necrosis. These results
show that the MNP-GA-IDA
combination does not induce
necrosis-mediated cell demise.
Instead, it induces cell death by
activating the apoptotic path-
way. From Ref. [97], used under
Creative Commons CC-BY
license

Table 6  Inorganic structures developed for IDA delivery

Formulation Particle size (nm) Zeta EE (%) DL (%) Release Characterization Case study Reference
potential
(mV)

HsAFr-IDA 6–8 N/A 84.75 7.15 Through interaction In vitro MCF-7 [83]
with the SCARA5
and TfR1 receptors
IDA-loaded ATRA N/A N/A N/A N/A N/A AMPL4 Protocol APML4 [93]
and ATO complex
IDA-loaded ATRA​ N/A N/A N/A N/A N/A AMPL3 Protocol APML4 [94]
IDA with ONCOZ- 106 ± 11 N/A ≥ 99.5 N/A 75.9 ± 2.3% In vivo and in vitro HCC carcinoma [95]
ENE DEE agents
AuMPn 235.71 ± 34 N/A 72.08% 1.73% N/A In vitro N/A [96]
MNP-GA-IDA 21 ± 2.5 N/A N/A N/A N/A In vitro HL-60 [97]

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fingerprint when exposed to near-infrared light. Additional
research indicated that the release of IDA from AuMPn
could be controlled using near-infrared irradiation.
Hasan Ulusal and colleagues examined the efficacy and
toxicity of IDA by stabilizing this therapeutic agent on
MNPs coated with glutaraldehyde (GA) based on their cost-
effectiveness and toxicity-free nature. The study found that
the ­IC50 value decreased by 5 to 7 due to MNP usage. Flow
cytometry and PCR analysis revealed that MNPs increased
apoptosis, while suppressing the production of MDR1 and
genes preventing apoptosis (Fig. 10) [97]. This suggests that
MNP mechanisms could help curb drug resistance by con-
trolling drug release and preventing drug exit from cells.
Table 6 demonstrates inorganic formulations developed for
IDA encapsulation.
4 Idarubicin Co‑delivery Platforms
Co-delivery nanosystems for cancer treatment represent a
rapidly evolving area of medical research. They are intended
to enhance the therapeutic efficacy of medications by facili-
tating the simultaneous delivery of various therapeutic
agents. These systems can deliver conventional chemother-
apy drugs, gene-based molecules, and plant-derived mate-
rials, achieving synergistic effects and leading to enhanced
desired responses compared to single drug strategies [98].
Co-delivery can enhance therapeutic effects, decrease side
effects, and to some extent, prevent multidrug resistance
(MDR) [99]. However, few studies have been presented on
the co-delivery of IDA with other drugs. This section dis-
cusses the studies and experiments conducted on the co-
loading of IDA with other medications.
Drug conjugation is a mechanism that enables several
drugs onto the same carrier by covalently preconjugating
through hydrolyzable linkers [100]. Saurabh Wadhwa and
coworkers [79] synthesized a DDC of PGA to co-deliver
IDA and D-penicillamine (D-pen). PGA was covalently
bound to the medications. According to the findings, the
DDC increased the exposure of IDA by sevenfold and
caused an extension in the circulation half-time of plasma.
Moreover, enhanced tumor accumulation was observed. The
increase in antitumor activity was attributed to 89% in tumor
growth inhibition (TGI), which was 60% in free drugs and
contributed to a notable improvement of 17% regarding the
survival of NCI-H460 tumors in mouse models.
In another study, Danfeng Wanga and colleagues [101]
used DNA nanostructures to co-load mithramycin-acridine
orange and IDA. This research aimed to explore the impact
of various types of binding in drugs on drug release and
cytotoxicity. The nanostructured DNA that was used in this
experiment was AS1411NTrs, which was a combination of
aptamer AS1411 (used to attack cancerous cells) and DNA
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
BioNanoScience
double strands (utilized to load the drugs). The results indi-
cated that when AS1411NTrs was employed for IDA deliv-
ery, a greater capacity of IDA was loaded compared to free
drug. Furthermore, the link between IDA and AO caused
an improved stability in AS1411NTrs. Additionally, in vitro
experiments using the MCF-7/ADR and MCF-7 lineages
showed that 37 °C enhanced the cytotoxicity and synergistic
effects of IDA/(MTR)2Zn2 + /AO. Furthermore, loading the
AS1411NTrs resulted in improved drug-induced apoptosis.
MCF-7/ADR demonstrated superior absorption of the com-
bination of drugs in the cell uptake assays.
The current body of research on novel interventions
for non-Hodgkin’s lymphoma (NHL) has predominantly
focused on the utilization of IR780. This dye operates in
the near-infrared spectrum and acts as a photosensitizer in
both photothermal therapy (PTT) and photodynamic therapy
(PDT). Researchers created a NP system that could transport
IR780 and IDA, a chemotherapeutic drug, to bridge PTT/
PDT and chemotherapy for a more comprehensive treat-
ment. The NPs, made of PEG-b-PTMC, were individually
loaded with IR780 and IDA, exhibiting potent PTT/PDT
efficiency when exposed to a near-infrared laser. Addition-
ally, they exhibited the process of endocytosis and displayed
heightened formation of reactive oxygen species. The cell
lines Raji and U937 exhibited decreased cell proliferation
upon exposure to the NPs. Furthermore, in vivo experiments
demonstrated a significant decrease in growth and enhanced
biological safety, as seen in Fig. 11 [102].
In a previous work, the synthesis of PEG-b-PTMC was
conducted, whereby the amphiphilic mPEG-b-PTMC169
was employed for the purpose of encapsulating ABT-
199, resulting in enhanced effectiveness and drug loading
[103]. The results obtained from dynamic light scattering
(DLS) and transmission electron microscopy (TEM) images
revealed that the size of the nanocarriers containing both
agents was approximately 138 nm and 210 nm, respectively.
This disparity is attributed to the contraction of PEG seg-
ments in dry conditions. Furthermore, the zeta potential of
NPs was improved showing a better encapsulation rate of
positively charged IR780. The loading efficiency of anthra-
cycline in nanocarriers was about 7.38 ± 0.46% and its EE
percentage was almost 78.73 ± 6.8%. Experiments showed
the release rate of IDA was about 39.3 ± 8.0% after 4 h in
PBS, as the release medium. Raji and U937 lymphoma cells
showed an excellent uptake of NPs which changed over time
in vitro. These NPs have also obtained better cytocompat-
ibility and biological safety in vivo. The findings indicate
that the simultaneous administration of all three therapeutic
approaches led to a notable eradication of lymphoma cells.
Despite the ongoing research, co-delivery mechanisms of
IDA with other therapeutic agents are still relatively obscure
and demand more comprehensive investigations. Current
studies have indicated the potential for improved therapeutic
BioNanoScience

Fig. 11  The study investigated

the in vivo tumor prevention
effects on U937 tumor-bearing
mice. A The development of
tumor volume after therapy
was seen in a sample size of
5. B The impact of various
therapies on the body weight of
mice afflicted with U937 tumor.
C Photographs depicting the
distinct tumor tissues in isola-
tion after to a 13-day period of
exposure to various treatment
modalities. D The histologi-
cal and immunohistochemical
examination of the tumor cells
after various treatment regimens
was conducted using hema-
toxylin and eosin staining. From
Ref. [102], used under Creative
Commons CC-BY license

efficiency and durability due to mechanisms like drug conju-
gation and DNA nanostructure utilization. These integrated
systems demonstrate increased drug exposure, enhanced
tumor accumulation, and improved in vitro cytotoxicity.
Similarly, the co-delivery of the photosensitizer IR780 with
IDA also exhibited promising outcomes in terms of inhibit-
ing cell proliferation and enhancing biosecurity in the con-
text of non-Hodgkin’s lymphoma. Nevertheless, in order
for these co-delivery systems to be widely used in the field
of cancer therapy, more research is necessary to enhance
the synthesis techniques and to verify their effectiveness,
safety, and stability in both laboratory settings (in vitro) and
living organisms (in vivo). Undoubtedly, the integration of
nanotechnology and drug delivery has significant potential
in enhancing the efficacy of cancer therapies, hence demand-
ing sustained research efforts to achieve further refinement.
5 Conclusion
The escalating need for effective intervention for malig-
nant cancers has motivated profound exploration of differ-
ent strategies to transform oncological treatment. Recently,
IDA, an anthracycline antibiotic, has shown much promise
with its potential in cancer therapy. This is due to its anti-
leukemic activity, increased lipophilicity, higher cell per-
meability, and improved cytotoxic effect compared to its
anthracycline counterparts. Despite these favorable qualities,
the full potential of IDA is currently hampered by significant
side effects, namely cardiotoxicity, myelosuppression, poor
absorption, rapid metabolism, and inadequate distribution.
Hence, with advancements in nanotechnology, novel meth-
odologies have been developed to overcome such delivery
impediments. Lipid-based NPs, polymeric nanocarriers,
carbonaceous nanostructures, and inorganic NPs have been
proven to revitalize IDA’s therapeutic potential. Among the
mentioned structures, lipid-based NPs, stimuli-responsive
or not, and polymeric nanocarriers appear to be particu-
larly promising in encapsulating IDA, exhibiting significant
encapsulation efficiency, drug loading values, and release
characteristics.
Although strides have been made, the non-responsive and
stimuli-responsive lipid-based and polymeric nanocarriers
systems still face multiple challenges. The issues included
in this context are to the assurance of therapeutic levels at
the designated treatment site, regulation of drug release, and
effective encapsulation of the medication. Additionally, it is
crucial to improve the manufacturing process of nanocarriers
to enhance their stability and extend their circulation time.
For example, in carriers that respond to stimuli, controlling
the triggers for drug release can be challenging in a clinical
setup, which requires more research and investigation.
Carbon-oriented delivery platforms have also demon-
strated potential as effective IDA delivery systems due

Content courtesy of Springer Nature, terms of use apply. Rights reserved.


to their vast surface area and penetrative properties. The
unique advantages of carbon-based NPs include low-
ered toxicity and enhanced anticancer characteristics of
the encapsulated IDA. Notwithstanding these promising
results, more empirical investigation is required to com-
prehend and enhance the potential of these NPs as a deliv-
ery mechanism for IDA.
In contrast, inorganic NPs have shown the capacity
for precise medication administration, improved durabil-
ity, and regulated release. The platform offered by these
entities is very commendable owing to their versatility in
terms of dimensions, configurations, and physiochemical
characteristics. Nevertheless, the assembly and modifica-
tion of the surfaces of these NPs continue to provide a
significant difficulty, necessitating more comprehensive
study to address these concerns.
Another promising field is the use of combination ther-
apy techniques with IDA along with additional chemo-
therapy drugs. The enhancement of medication therapeu-
tic effectiveness using co-delivery nanosystems and IDA
has shown encouraging outcomes. Some of the possibili-
ties that exist within the co-delivery nanosystems are the
SDDS that uses phospholipids and the co-delivery of pho-
tosensitizer IR780 with IDA. To verify these techniques’
effectiveness, security, and general stability, further inves-
tigation is necessary.
This multidisciplinary study may give rise to new para-
digms in cancer therapy in the years to come. The foundation
has been laid for lipid-based NPs, polymeric nanocarriers,
carbon-based NPs, and even inorganic NPs to potentially
revolutionize cancer therapeutics. However, further preclini-
cal studies and clinical trials are required to evaluate the effi-
cacy and safety of these intriguing nano-delivery technolo-
gies. It is essential that legislation and procedures pertaining
to medication development adapt to the unique problems
presented by these innovative treatments.
Author Contribution F.S., Y. J, H. A., M.P.: investigation, data cura-
tion. P.Z., M. A.: writing, review, and editing. A. R., S. F-k., S. P:
validation, writing, review, and editing. All authors reviewed the
manuscript.
Funding Abbas Rahdar thanks from University of Zabol for funding
(UOZ-GR-8906). The authors (Sadanand Pandey) express profound
gratitude to Shoolini University for their invaluable support, which
played a pivotal role in facilitating the completion of work.
Data Availability No datasets were generated or analyzed during the
current study.
Declarations
Ethical Approval Not applicable.
Competing Interests The authors declare no competing interests.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
BioNanoScience
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