**3. Current trend in hydrogel based targeted drug delivery**

#### **3.1 Supramolecular hydrogels**

Supramolecular hydrogels generated by the spontaneous self-assembly of peptides, proteins, and other biomolecules have recently gathered attraction as

#### *Hydrogels: Smart Materials in Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.104804*

next-generation drug delivery substitutes to synthetic polymers. Due to the comparatively expensive synthetic peptide hydrogels compared to synthetic polymer gels, self-assembling peptides are a promising class of supramolecular gelators for in vivo drug delivery that has been sluggish to catch on despite benefits in biocompatibility. Supramolecular hydrogels' superior biocompatibility and simplicity of formulation in comparison with polymer hydrogels have sparked study into the self-assembly events that lead to gelation and how to engineer the emergent features of supramolecular gels to generate excellent drug delivery materials. The development of stimuli-responsive hydrogels for medication administration has gained the attention of researchers. Changes in pH, temperature, ionic strength, and also exposure to light, electric, and magnetic fields, are all examples of external stimuli that might cause drug release. pH-sensitive smart hydrogels have been widely used as self-regulating drug delivery systems.

The supramolecular hydrogel framework comprises non-covalent intermolecular interactions that collectively hold two or more molecular units. The non-covalent cross-linking of these hydrogels is a particularly appealing feature since it avoids the challenges of restricted drug loading capability and drug integration for use solely as implantable, which is the only option with a covalently cross-linked system. These hydrogels achieve drug loading and gelation concurrently in aqueous conditions without the need for covalent cross-linking, in addition to providing the necessary physical stability for the hydrogels. Supramolecular hydrogels based on self-assembled inclusion complexes between cyclodextrins and biodegradable block copolymers have recently made headway in providing sustained and regulated release of macromolecular medicines [8].

In recent times, supramolecular hydrogels that are responsive to biological stimuli have gained a significant amount of interest for their potential as smart materials. A macroscopic sensor could, for instance, be a stimulus-responsive gel-to-sol phase transition. In response to the stimulus-responsive gel-to-sol phase transition, a drugencapsulated supramolecular hydrogel could deliver the drug. However, supramolecular hydrogels with a gel-to-sol phase change in response to biological stimuli must be developed under physiological settings to exploit the uses.

Supramolecular hydrogels are generally synthesized by heating followed by cooling a mixture of an LMWHG (low molecular weight hydrogelator) and an aq. solvent whereas external stimuli-triggered gelation enables the spontaneous synthesis of supramolecular hydrogels. Supramolecular hydrogels with high biocompatibility are desirable materials for medical and pharmaceutical applications. Nevertheless, the challenging preparation procedures for LMWHGs and the unavailability of very resistant supramolecular hydrogels restrict the potential possibilities of these materials. Several studies have shown that various LMWHGs can be prepared within a few steps from commercially available chemicals.

The structural tailoring of LMWHGs allows for the development of a more strong supramolecular hydrogel. Small quantities of a dimer with a similar structure to LMWHG can be added to a supramolecular hydrogel to enhance its physical characteristics. Supramolecular hydrogels with stimuli-responsive characteristics will be more beneficial. The formation of biological-stimuli-induced supramolecular hydrogels can be considered as a novel therapeutic technique based on the biological activity of self-assemblies. It is important to produce more specific and precise stimuli-responsive materials for the effective use of biological-stimuli-responsive supramolecular hydrogels [11]. The presence of competitive binders in the physiological surroundings, such as proteins or ions, is another factor to consider when designing supramolecular drug

delivery vehicles. Competing interactions can impact the supramolecular hydrogel's mechanical characteristics and/or change the release profile of loaded medicines [12].

#### **3.2 Multicomponent hydrogels**

Hydrogels that were multi-functional and carriers of anti-cancer drugs are a typical example of the versatility of these delivery vehicles and their amenability to chemical modifications to enhance their therapeutic effects. The cytocompatibility and excellent biocompatibility of the materials make them promising materials in biological applications including drug delivery, wound healing, and tissue engineering. However, during the material selection process, the potential toxicity of the breakdown products may be neglected. For instance, amazingly (polyacrylamide) is a popular breast implant that is nontoxic and has a low rate of rejection. On the other hand, the breakdown product acrylamide has medium toxicity for the neurological system and kidneys and has been classified by the World Health Organization (WHO) as one of the suspect carcinogens.

It is necessary to examine the biocompatibility of hydrogels and their degradation products for medical applications. The invention of new cost-effective biomimetic materials or natural products from high throughput processing, such as hyaluronic acid, chitosan, gelatin, collagen, and so on, could improve material safety. Stimuli-responsive hydrogels, as a kind of smart materials, offer promise for tailored drug delivery. The hydrogel structures can be triggered automictically in response to diseased microenvironments and deliver cargos with better spatial/temporal resolution thanks to an elaborate design. Nevertheless, uneven circulatory networks raised interstitial fluid pressure, and diffusion of target stimuli around the tumor microenvironment could result in unintended medication leaks and possibly off-target effects during transportation.

Furthermore, improper drug deposition in solid tumors can lead to drug resistance and a significant reduction in therapeutic benefit. This field could be advanced by drug-loaded hydrogel capsules that react to target biomarkers. Hydrogel capsules with high specificity and permeability provide a new outlook for cancer therapy250, thanks to the modification of aptamers that target certain cells. Multi-triggered hydrogels with programmable functions are also a promising technique for overcoming the challenges stated above and improving therapeutic effects. The off-target scenario might be considerably decreased if the medicine could be released in a planned logic operation in response to multiple disease/therapy-related parameters. A programmable ON/OFF switch is required for improving drug dose in various therapeutic circumstances. Incorporating cell regulators (such as peptides, proteins, and nucleic acids) into hydrogel frameworks to attract cancer cells inside and execute in situ contact-killing is another potential strategy that should be explored [13].

#### **3.3 DNA-hydrogels**

Active body regeneration scaffolds are obtained from the nucleic acid molecule of living organisms, sometimes these are known to be DNA nanostructures. Hydrogels that are made out of DNA have a uniqueness in the following characteristics; degradability, non-immunogenicity, high sensitivity, and drug delivery. The self-assembling of biomaterials works on the principle Watson–Crick base pairing and this is how the DNA hydrogels are formed. The unique mechanical and biochemical properties of DNA, along with its biocompatibility, make it a suitable material for the assembly of hydrogels with controllable mechanical properties and composition that could be used in several biomedical applications, including the design of novel multifunctional

#### *Hydrogels: Smart Materials in Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.104804*

biomaterials [14]. Recent studies reported that DNA hydrogels are responsive to stimuli such as; light, biomolecules, and temperature. This stimuli-responsive helps in improving the therapeutic field as well as may decrease the side effects. **Table 1** below shows the two types of triggers; nonbiological and biological [15].

When a drug carrier holds features like upkeeping of intact bioactivity of drugs and inhibiting chemical and enzymatic degradation and improved retention effect it means a successful drug carrier. The benefited properties such as biocompatibility, available binding for cargos, easily triggered stimuli responsiveness, and effective active targeting ability uplifted DNA hydrogel. In a small loading efficiency, drug molecules and inorganic nanoparticles can be incorporated into the porous structured network [16]. Another highlight is to capture high performance in the deliveries of chemotherapy, immunotherapy, and gene by allowing the co-delivery agent with various physicochemical properties [17]. To inhibit the permeation of enzymes a highly crosslinked cage or network is used to deliver nucleic acid drugs and this way will protect the biological activity of the proteins. The trending research on inorganic materials delivery has inspired. Cutting down edge research has put down the obstacles and made the hydrogel drug delivery system a great progression stage over the past 2 years. To fabricate DNA hydrogel in a low-cost method with a high yield end product is a challenge in application. To overcome this challenge, it is necessary to check on the synthetic approach and it is very crucial to find a way in low-cost production for the same. Toward this end, a highly parallel gene synthesis method based on DNA microchips and specific oligonucleotide pool amplification was demonstrated. It led to a remarkable cost reduction for scale-up DNA production [18].

## **3.4 Stimuli-responsive hydrogels**

For example, malignant tissue (pH 6.8) and endosomes/lysosomes (pH 5.5) are more acidic than normal tissue (pH 7.4), necessitating hydrogels that can deliver payload medications in response to a pH change. Several polymers have been intensively explored for the construction of intelligent hydrogels throughout the last few decades. Because of their intrinsic biocompatibility, renewability, and availability, natural-resourced polysaccharide-constructed hydrogels have gotten a lot of attention, fueling the urge to use them as drug carriers. Many polysaccharide-based hydrogels, on the other hand, lack mechanical strength rigidity and are susceptible to rapid erosion, making them unstable. This makes it difficult to use polysaccharide hydrogels for medication administration. Physical diffusions, on the other hand, are commonly used to release medicines from gel matrices, which might result in premature burst release. It's difficult to tailor drug delivery in a predictable and on-demand manner [19].


**Table 1.** *Different types of triggers [15].*

Transitional changes occur in stimulus-responsive hydrogels in reaction to environmental factors. The concentration of certain biomolecules such as enzymes can cause them to expand, shrink, degrade, or undergo a sol-gel phase transition if there is a change shown in the temperature, pressure, ionic strength, and insolvent. This type of hydrogels is particularly valuable for therapeutic delivery because of their unique ability to perform specialized activities, such as the release of drug and in situ gel formation, in response to tiny changes in ambient circumstances.

Stimuli-responsive hydrogels that change structural or mechanical properties in reaction to environmental cues/triggers are categorized as vital subgroups in hydrogels. These hydrogels are very beneficial in robotics and biological fields. Several stimuli including light, temperature, magnetic fields, electric field, pH, and chemical and biological triggers could be used to stimulate phase transition or stiffness change of these materials implying a wide range of applications in separation, drug delivery, sensing, bionic devices, regenerative medicine, and more.

Two types of bio-stimuli called endogenous stimuli that exist naturally within the bio-environment and exogenous biocompatible stimuli that activate smart functionalities of the hydrogel system have been garnering attention for the building of bio-functional materials. pH value, metal ions, enzymes, redox environment, antigen, and other endogenous stimuli are examples of endogenous stimuli. In wounds or bacterial infections, for instance, reactive oxygen species are produced, resulting in an oxidative environment; the exocellular pH of tumor tissues is lower than normal tissues caused by abnormal metabolism, particularly glycolysis overactivity; and lung cancer cells have a particular protein that could be recognized by antibody-functionalized microgels. The application with the various stimuli is illustrated in **Figure 4**.

Hydrogels ingrained with efficient cross-linkers or chemical modifications will recognize abnormal signals in pathological or wounded tissues and accomplish endogenous initiation, resulting in automated and focused behaviors such as drug delivery, cell capture, or warning signal output, with proper designing. Light, temperature, magnetic fields, electric fields, ultrasonic waves, and other exogenous stimuli are examples. Exogenous stimuli-responsive hydrogels, in contrast to endogenous stimuli-responsive hydrogels outlined above, are developed to function remotely and non-invasively [20].

It has been found that Magnetic nano-participles embedded in DNA hydrogels provide the networks with shape-adaptive and locomotion-controllable features. Light-guided fibroblast migration and angiogenesis were achieved using hydrogels treated with photo-caged RGD. The sensible integration of endogenous and exogenous stimuli-responsive units into a single hydrogel system could provide a comprehensive "toolbox" for customizing intelligent materials. The addition of programmable, multi-stimulus responsiveness enables the integration of multiple functionalities into a single hydrogel system, such as searching, recognizing, and curing. The gelator-gelator and gelator-solvent interactions are implicated in the stimuli-response pathway, which includes volume change, phase transition, and structural change.

#### **3.5 Nanogels**

The nanostructures comprising drug molecules with innovative structures represent the new frontier in the biological and medical fields. The application of nanogel in various biological fields is shown in **Figure 5**. The crosslinked polymer network with a three-dimensional structure and having a nanoscale size range are known to be nanogels. These nanogels can hold a large volume of water but they

*Hydrogels: Smart Materials in Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.104804*

**Figure 4.** *Stimuli-responsive hydrogels and their applications [13].*

**Figure 5.**

*Schematic representation of nanogels in the various biological applications (adapted from [21]).*

will not dissolve in an aqueous medium [16]. They are common in spherical shape but they can vary in the synthetic strategies [22].

Nanogels have been identified recently by researchers and it has been used as a promising tool in response to the critical issues of intracellular delivery: due to their peculiar properties, including swelling behavior, nanogels can cross the cellular membrane (clathrin-mediated endocytosis, caveolin-mediated endocytosis, phagocytosis,

**Figure 6.**

*The schematic of drug release from the nanogel network (adapted from [27]).*

and macropinocytosis) and release their cargo in the cytosol, avoiding the activation of immune responses. These can be fabricated using natural polymers, synthetic polymers, or a combination of both. The distinct characteristics of nanogels can be varied by their chemical composition [23].

The properties like swelling and encapsulation and the prior response in the specifically targeted sites put them in the frontline of drug delivery and gene delivery. The nanosized gel can be synthesized by two approaches; top-down and bottom-up. Generating nanoparticles from large clusters of particles by different methods (physical, chemical) is known to be a top-down approach. The imperfections in particle surfaces can be a limitation of this method. The designing and arranging of molecules by direct polymerization of monomers and assembling of polymer precursors bonding can be the bottom-up approach [24, 25]. In the biomedical application, nanogels size distribution with their stability is very important. The stability depends on the chemical composition of the polymer matrix and the crosslinking type of the polymer chains. In comparing the physical and chemical nanogels, physically crosslinked nanogels are weaker and have lesser stability, due to their stability and reproducibility the chemically crosslinked nanogels are much more attractive [26].

The schematic representation in **Figure 6** shows that under a specific environmental condition the hydrogel loaded with the drug will start swelling or start shrinking and it leads to the release of a drug. This completely depends on the interaction of hydrophobic, hydrogen links, complexation, and/or coordination of drug molecules with the polymer chain networks [28]. The thermoresponsive polymeric nanogels allow the interaction of water molecules with hydrophilic groups help in swelling by maintaining its native structure. This occurs in the lower critical solution temperature (LCST), the removal of water content occurs during the hydrophobic nature. This further decreases the size of nanogel and the drug is released by the triggered temperature stimuli [29, 30]. Nanogels can be used to incorporate small nanosized molecules such as drugs and fluorophores, proteins, peptides, nucleic acids. The nanogel can act as multi-drug carriers and nanostructured gels can encapsulate multi-agents too.

### **4. Translation to the clinic research**

The vast area of the potential application of hydrogel formulations has overcome barriers of in vitro/pre-clinical studies and finally found fit into the market. It is very *Hydrogels: Smart Materials in Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.104804*


#### **Table 2.**

*Lists of the widespread practical applications of the hydrogel concept that have been translated to the clinical level.*

important to have the uniqueness and the salient feature to cover the clinical-stage studies. There is a lot of research going on in the background and some of them are in the pre-clinical stage. The time to fabricate these carriers for the delivery was not at all wasted and it has all been the best and the most versatile drug delivery. Here, in **Table 2**, the list on the research on different hydrogel carriers for exploring the new era of therapeutic delivery is shown.

### **5. Conclusions**

Although myriad chemical moieties of the hydrogel are readily available for drug delivery. The specific problem related to hydrogel fabrication is the need to evaluate the polymer that can produce versatile hydrogels that is apt for a certain intervention that mandates the final goal of the delivery system and route of administration. Understanding the influencing elements that influence swelling behaviors, hydrophilicity, biodegradability, biocompatibility, and targetability of the selected polymer is necessary for the development of a successful hydrogel-based delivery system. Hydrogels as targeted drug delivery have several advantages, including biocompatibility, low toxicity, and good swelling behavior. There have been certain impediments in the processing of hydrogels depending on the chemical moieties of the gel-forming polymers and the route of administration, some limitations in the delivery of active pharmaceuticals, such as slow stimuli-sensitive hydrogel responsiveness, the possibility of rapid burst drug release, the possibility of drug reactivation, limited hydrophobic drug delivery, and low mechanical strength. Thus, the field of nanoscience is

contributing positively to the fundamental advances in intelligent hydrogel formulation that can mimic tissues by changing their swelling and non-swelling mechanisms that directly contribute to their property as intelligent carriers that can be made use in pharmaceutical sciences.
