Hydrogels have become a hot topic in recent years, with about 5000

papers published in 2010, which is nearly five times the amount of

papers published in 2010 linked to ‘nanotechnology’, also lately become
a most focused area in the scientific community (Lee et al., 2013).
Hydrogels prevalence is due to four characteristics: biocompatibility,
biodegradability, loading capacity of drug entity, and controlled release
profile. Biocompatibility suggests that the hydrogels are not associated
with significant cellular or systemic toxicity in the body upon its
implantation, and are not included in stimulating the immune system.
Moreover, many of the polymers used to make hydrogels for cancer
therapy are biodegradable, including natural polymers and synthetic
polymers (e.g. chitosan (CTS) (Jamal et al., 2018), hyaluronic acid (HA)
(Cho et al., 2015), alginate (ALG) (Shih et al., 2018), polyesters (Shen
et al., 2017), and polyphosphazene (PPZ) (Society, 2018)) which are
rapidly depleted by cells and remodeled in the body after administration
(Yamaguchi et al., 2007).
Hydrogels are large polymeric networks that are highly magnified,
hydrophilic, and capable of retaining a large amount of water within
their pores (Martin & Youssef, 2018; Wang, 2018). Due to their enhanced
biocompatibility, these bioactive resources are commonly used in tissue
engineering (Vermonden & Klumperman, 2015). Hydrogels have a
porous structure and soft surface and behave similarly to natural living
tissues. Owing to various stimuli-responsive potential to temperature,
pH, pressure, electric and magnetic fields, these hydrogels are
undoubtedly referred to as smart materials. Even at a slight pH change in
the swelling medium, these materials have a high potential for proton
release and uptake (Liu et al., 2015). The above mention characteristic of
hydrogels makes them able to be served as an effective drug delivery
vehicle. Literature has demonstrated the remarkable contributions of
multi-responsive hydrogels such as polyvinyl alcohol crosslinked
polyacrylamide and poly(N-isopropylacrylamide) (PNIPAM)/CTS as
smart sensors, effectors, and targeted delivery to tumor cells (Liu
et al., 2017; Manga & Jha, 2017)
 Hydrogel-based drug delivery systems: Hydrogels are a 3-dimensional, hydrophilic, cross-
linked polymeric network that has the ability to swell or de-swell and still retain a significant
fraction of water within their structure [8]. They will never dissolve in water, and they have the
potential for development in drug delivery systems. The most important properties of hydrogels
are that they swell in the presence of water and shrink in the absence of water. Hydrogels are
intelligent systems because they can respond to environmental stimuli like temperature and pH
changes thereby effect changes in their physical or chemical behavior, resulting in the release
of entrapped drugs in a controlled and sustained manner [7-9]. There are two kinds of
hydrogels, they include synthetic and natural. Natural and synthetic polymers are known to be
effective drug delivery polymers to target tissues [11-13]. To reach the targeted tumor tissue,
polymeric nanoparticles stay in the bloodstream for a sustainable amount of time without being
eliminated. They must exhibit nontoxicity, biocompatibility, and biodegradability [14].
Natural polymers such as starch, chitosan, alginate, hyaluronic acid, silk, gelatin, collagen,
fibrin, and glycosaminoglycans attracted researchers’ interest because of their unique
advantages like abundance, nontoxicity, biocompatibility, and biodegradability [14,15]. Cellulose
is one of the abundant natural polysaccharides usually used as a hydrogel because of its
excellent biocompatibility, and biodegradability [16].

Multifunctional stimuli-responsive hybrid

nanogels for cancer therapy: Current status
and challenges
Author links open overlay panelAmaal Abdulraqeb Ali , Amani Al- a

Othman , Mohammad H. Al-Sayah

b c

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Abstract
With cancer research shifting focus to achieving multifunctionality in
cancer treatment strategies, hybrid nanogels are making a rapid rise
to the spotlight as novel, multifunctional, stimuli-responsive, and
biocompatible cancer therapeutic strategies. They can possess cancer
cell-specific cytotoxic effects themselves, carry drugs or enzymes that
can produce cytotoxic effects, improve imaging modalities, and target
tumor cells over normal cells. Hybrid nanogels bring together a wide
 range of desirable properties for cancer treatment such as stimuli-
responsiveness, efficient loading and protection of molecules such as
drugs or enzymes, and effective crossing of cellular barriers among
other properties. Despite their promising abilities, hybrid nanogels are
still far from being used in the clinic, and their available data remains
relatively limited. However, many studies can be done to facilitate this
clinical transition. This review is critically summarizing and analyzing
the recent information and progress on the use of hybrid nanogels
particularly inorganic nanoparticle-based and organic nanoparticle-
based hybrid nanogels in the field of oncology and future directions to
aid in transferring those results to the clinic. This work concludes that
the future of hybrid nanogels is greatly impacted by therapeutic and
non-therapeutic factors. Therapeutic factors include the lack of
hemocompatibility studies, acute and chronic toxicological studies,
and information on agglomeration capability and extent, tumor
heterogeneity, interaction with proteins in physiological fluids,
endocytosis-exocytosis, and toxicity of the nanogels' breakdown
products. Non-therapeutic factors include the lack of clear regulatory
guidelines and standardized assays, limitations of animal models, and
difficulties associated with good manufacture practices (GMP).

Graphical abstract

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Introduction
Of the many polymeric biomaterials exploited for biomedical
applications, nanogels are receiving significant attention, especially for
drug delivery [1,2]. Nanogels are hydrogels with sizes typically less
than a 100 nm [3,4]. Hydrogels, the first biomaterials designed for
human use [5], are 3D networks of hydrophilic, crosslinked polymeric
chains that are capable of absorbing water and swelling [[4], [5], [6]].
Nanogels provide the advantages that come with being nano-sized
such as the ability to cross biological barriers, enter the cell and
deliver contents intracellularly [3] through non-specific endocytosis [7]
with the advantages offered by a hydrogel which include
biocompatibility due to high water content [5,6,8], porous nature which
enables them to host materials such as drugs, biodegradability,
softness, and high surface area [6,9]. The development of the first
synthetic hydrogels in 1953 opened doors for the tuning of hydrogel
properties thereby allowing the tailoring of the gel's porosity,
mechanical strength, degradability, as well as other properties for a
specific purpose [6]. Unlike macro-sized hydrogels, nanogels are
considered “smart” biomaterials as they have the ability to respond
rapidly to changes in their local environment [3,4].
Nanogels' rapid responsivity to triggers stems from their nano-scale
size. It allows them to quickly react to stimuli, while their macro-scale
size counterparts respond more slowly to the same stimuli because of
their larger size [10]. Smart nanogels can respond to a range of
triggers that cause a reversible change in the nanogel's structure. The
most common stimuli-induced change in the nanogel's framework
involves their conversion from a swollen state to a collapsed state
upon exposure to the right trigger. This structural change in turn
results in the expulsion of encapsulated cargo (e.g. drugs) thereby
achieving a stimuli-controlled cargo release [10]. The stimuli that
nanogels react to can be grouped into 1) internal/intrinsic/endogenous
stimuli which include changes in pH, redox conditions, reactive oxygen
species, and enzymatic activity, and 2) external/applied stimuli which
include applied magnetic field, temperature, ultrasound, and
electromagnetic irradiation. Stimuli-sensitivity is especially important in
drug delivery as it ensures no premature release of the encapsulated
drugs thereby, overcoming one of the most common hurdles in drug
delivery systems [[11], [12], [13]]. Therefore, stimuli-responsive
nanogels have been widely investigated for drug delivery purposes
[[14], [15], [16], [17], [18]]. In addition to the delivery of drugs,
nanogels have also been utilized for the delivery of proteins and
nucleotides and their biomedical applications were further extended to
diagnosis and imaging [19]. Furthermore, nano-sized vehicles can
generally deliver multiple drugs while also improving their circulation
time [20].
Nanogels can be further modified to earn additional advantageous
features such as targeting specific cells, having a prolonged
circulation time [21], earning responsivity to a particular stimulus [[22],
[23], [24]], or even combining several of those properties and
becoming ‘multifunctional’ [21]. Nanogel multifunctionality is another
especially important property in disease treatment generally, and in
cancer therapy, specifically. Multifunctionality involves the combination
of desirable properties such as prolonged blood circulation time,
targeting, stimuli responsiveness, and intracellular localization within a
single structure. Such multifunctionality can be achieved by modifying
the nanocarrier via surface functionalization (e.g. for targeting or
prolonging circulation time) or by incorporating another nanomaterial
into the nanocarrier (e.g. for imaging or stimuli responsiveness)
[25,26]. In the case of cancer, the production of composites capable of
diagnosis, image-guided drug delivery, and controlled drug release is
a highly advantageous and desired [27]. The review by Torchilin et al.
[25] very well elaborates on the multifunctionality of nanocarriers for
drug delivery. One such modification of nanogels to achieve
multifunctionality that is currently emerging with great potential in
nanomedicine involves hybridizing the nanogel with other
nanoparticles. This allows the utilization of the properties of both the
nanoparticle and the nanogel [1,[28], [29], [30]]. Such hybridized
nanogels, called hybrid nanogels, can carry out multiple functions
such as imaging, diagnosis, and cancer therapy (magnetic
hyperthermia [29], photothermal therapy [31,32], photodynamic
therapy [33], drug delivery [29], enzyme-based therapy [28]),
simultaneously [34]. It is important to note that the drug resistance and
side effects typical of conventional cancer therapeutics can be
overcome using a multifunctional, tumor-specific approach [35]. Hybrid
nanogels could provide the needed multifunctionality and tumor-
specificity (via targeting and stimuli-responsivity) to overcome the
resistance and side effects of conventional cancer therapy.
Although very promising, hybrid nanogels' application for cancer
therapy is considered pretty much recent and still far from being used
at the clinical stage. Therefore, up until this point, there are no
comprehensive reviews discussing the current status of the use of
hybrid nanogels in the field of oncology. This review fills this gap in the
literature by discussing the recent information and progress on the use
of hybrid nanogels, specifically, nanogels hybridized with inorganic
nanoparticles (magnetic nanoparticles, gold nanoparticles, gadolinium,
manganese oxide, silica nanoparticles, metal-organic frameworks, and
silver nanoparticles) and organic nanoparticles (carbon-based, and
lipid-based nanoparticles) for cancer therapy. Throughout the
manuscript, specific focus is given to the stimuli-responsivity and
multifunctionality of the hybrid nanogels for cancer theranostics. Fig. 1
shows the different hybrid nanogels, the stimuli to which they respond,
and the multiple functions they are capable of performing. This review
also highlights the milestones achieved with the use of hybrid
nanogels, some of the challenges standing between their transference
to the clinic, as well as future directions on what could be done to
facilitate their clinical transition. From here on, the review proceeds by
discussing the properties of hybrid nanogels, the urgent need for a
tumor-specific multifunctional cancer treatment, the different stimuli
capable of inducing release from the polymeric nanogel for stimuli-
responsive therapy, then critically analyzing studies exploring
nanoparticle-nanogel hybrids for stimuli-responsive, multifunctional
cancer therapy. The paper concludes by discussing the issues that
challenge the use of hybrid nanogels in the clinic and predicting the
clinical fate of hybrid nanogels for cancer therapy.

Section snippets
Stimuli-responsiveness and properties of hybrid
nanogels for cancer therapy
In terms of stimuli responsiveness, hybrid nanogels were reported to
respond to external [29,31] and internal triggers [29,30,36].
Nanomaterials that have been incorporated into nanogels to produce
multifunctional, stimuli-responsive hybrid nanogels include inorganic
nanomaterials (such as magnetic [29,30] and noble metal
nanoparticles [31,37]) and organic nanomaterials (such as carbon-
based nanomaterials [38,39]). Unlike bare nanoparticles, hybrid
nanogels possess nanogel-associated softness

The urgent need for a multifunctional stimuli-

responsive cancer treatment
Despite all the advances in cancer therapy, cancer continues to be a
major burden faced by the world. In 112 of 183 countries, cancer
remained the first or second cause of death in individuals aged below
70 years as reported by the World Health Organization in the year
2019 [58]. On a global scale, about 19.3 million new cancer cases and
10.0 million deaths were reported in 2020 [58,59]. The number of
cancer cases and deaths is expected to increase even further to 27.5
million and 16.3 million,

External and internal stimuli and stimuli-responsive

polymers
Stimuli-responsive drug delivery systems have been developed and
studied since the 1978 [61]. Despite the effectiveness of some drugs
as anti-tumor agents, their use is greatly limited, as previously
discussed, by their adverse side effects. To overcome this limitation,
drug delivery systems have been developed to trap drugs, carry them
to the tumor site, and release them particularly when signaled to by
specific stimuli [62]. Utilizing such stimuli-responsivity ensures the
availability of the

Multifunctional stimuli-responsive inorganic

nanoparticle hybrid nanogels for cancer therapy
Several inorganic nanoparticles hold interesting properties for
biomedical applications. For instance, noble metal nanoparticles such
as gold and silver nanoparticles possess the ability to absorb light and
convert it to heat. This heat can then be used for hyperthermic tumor
eradication [83], or heat-triggered release of a drug from a nanocarrier
[31]. Such heating is also achieved with the inorganic iron oxide
nanoparticles upon exposure to a magnetic field [69]. Therefore, due
to their

Challenges of translating hybrid nanogels for cancer

therapy to the clinic
Regardless of how promising a biomaterial is, if it cannot be translated
to the clinic, it is technically of no use. Translating laboratory results to
a clinical setting is faced with several obstacles that can render the
most promising drugs unsuitable for human use such as lack of
efficacy or safety when inside the human body [224]. Many hydrogels
have made it to the stage of clinical trials as found on
the ClinicalTrials.gov database, however, none of the nanogels or
hybrid nanogels have

Conclusion and future perspectives

In conclusion, multifunctional stimuli-responsive hybrid nanogels as
cancer theragnostic strategies seem to hold massive potential in the
field of oncology due to their ability to encompass and combine a wide
variety of characteristics that have long been desirable for cancer
therapy specifically, and drug delivery generally, in one single
complex. The most important of those features provided by hybrid
nanogels are their stimuli-responsiveness to internal tumor-specific
stimuli and externally

Declaration of Competing Interest

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper. The author Amaal
 Abdulraqeb Ali dedicates this work to her parents: "To my parents, my
role models, whose love, support and encouragement has always
been my source of strength in everything I do."

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