1. Introduction
Targeted drug delivery to specific body parts has become one of the important ventures of the today’s world as conventional dosage forms are generally associated with difficulties in approaching the target site at the specified dose after or during a proper time period. As a result, the search for novel drug delivery systems and a new mechanism of action has become very active. Novel drug delivery systems comprise of lipidic, proteic and polymeric technologies that provide a controlled and sustained drug delivery with better pharmacokinetics, stability towards the harsh external environment and avoid rapid clearance of drugs. Many of these advances have reached the market therefore as new drug carriers [
1]. Many drawbacks are associated with conventional drug delivery system, e.g., poor patient compliance, which leads to missing the frequent doses of drugs with a shorter half-life. A typical sawtooth pattern of plasma concentration-time profile is observed which makes attainment of steady-state concentration very difficult. There is also unavoidable fluctuations in the drug concentration that may cause under or overdose activity of drugs as the steady state concentration value fall or rise beyond the therapeutic range. Recent research in advanced pharmaceutical preparations thus aims to provide stable and cost-effective drug delivery systems. The main focus is on hydrogels to reduce not only the shortcomings of old conventional dosage forms but also those of novel drug delivery systems to provide a more convenient, compatible and stable drug delivery system for small drug molecules like NSAIDs (Non-steroidal anti-inflammatory drugs) or large molecules as proteins and peptides [
2,
3]. Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery [
4]. Hydrogels have been defined in many different ways by researchers over the past years. One of them, the most common defines hydrogel as a polymeric material that possesses the capability of swelling and retains a certain high amount of water within its structure and does not dissolve in water medium itself [
5,
6,
7].
Initially, poly (2-hydroxyethyl methacrylate) (poly HEMA) was mentioned as a hard, brittle and glassy polymer and it certainly it was not considered of much importance. The intrinsic ability of hydrogels to absorb water is due to several functional groups (such as –NH
2, COOH, –OH, –CONH
2, –CONH–, and –SO
3H) which are hydrophilic and attached to the polymeric chain. Hydrogels are resistant to dissolution and this property arises from cross-links between polymeric chains [
8]. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility which meet fulfill material and biological requirements to treat targeted tissues and organs or replace it or interact with the biological systems [
9,
10,
11]. The important characteristics of these hydrogels are its ability to swell when interacting with water [
12].
Hydrogels can be classified as natural, synthetic or semisynthetic, according to the nature of crosslinking polymers. Hydrogels constitute chemical or physical crosslinking of polymers. The hydrogel matrix allows physical incorporation of proteins and its mechanism of release is usually controlled diffusion, swelling, erosion/degradation, or a combination of these. Hydrogels provide fine-tuning of the protein and peptide drugs release by redefining their cross-linking through changes in the polymer structure, its concentration, molecular weight, or chemistry. Other methods to tailor drug release from hydrogel matrix are also known that involve reversible protein−polymer interaction or protein encapsulation in a secondary delivery system as micro/nanoparticles dispersed in the hydrogel matrix [
13,
14]. Hydrogels have enormous uses in clinical medicine and experimental settings for a wide range of applications, including tissue engineering and regenerative medicine [
15], diagnostics [
16], cellular immobilization [
17], separation of biomolecules or cells [
18], and barrier materials to regulate biological adhesions [
19].
Although hydrogels have many advantageous properties, several limitations are also associated with these materials. They have a poor tensile strength which could limit their use in drug loading applications and can result in the premature dissolution or flow away of the hydrogel from targeted tissues and organs. This drawback is of much importance in many typical topical and subcutaneous drug delivery technologies. The amount and homogeneity of hydrophobic drugs are also minimized in hydrogels. Another disadvantage is the presence of high quantity of water and large pore sizes in most hydrogels which often result in relatively rapid drug release, in few hours. The application of hydrogel can also be problematic sometimes; though some hydrogels are ultra-deformable to be injected, many are not, thus need surgical insertion. Each of these issues critically limits the practical use of hydrogel drug delivery systems in the clinical applications [
20]. Hydrogel innovation is also linked to problems such as solubility, high crystallinity, non-biodegradability, unfavorable mechanical and thermal properties, unreacted monomers and the use of toxic crosslinkers. Therefore, the improvement of these properties can be possible with the use of a combination of natural and synthetic polymers with enhanced properties [
21].
Self-assembly is also used in the generation of hydrogels with significantly improved properties. Molecular self-assembly comprises many non-covalent interactions with which basic molecular building blocks organize spontaneously and reversibly into a novel, supramolecular and functional nano-scale manner. Peptides and proteins are useful building blocks for supramolecular hydrogels and can combine structural and functional activity [
22].
Self-assembling peptides serves as attractive candidate for the development of hydrogels with well-controlled biological, mechanical and material properties. Peptide-based hydrogels offer numerous advantages such as their easy synthesis, characterization and decoration, biodegradability and most importantly their very high biocompatibility [
23]. Current findings shows that relatively short peptides (di-, tri- and tetra-peptides) can freely self-assemble into ordered nanostructures including hydrogels, that have made this area of research very dynamic and exciting [
24]. The spontaneous self-assembly of a dipeptide, Leucine-α,βdehydrophenylalanine, containing a non-protein amino acid, α,β-dehydrophenylalanine (ΔPhe) at its C-terminal, into a highly stable hydrogel under physiological conditions. ΔPhe is an analogue of phenylalanine, with a double bond between Cα and Cβ atoms, whose incorporation in peptide sequences introduces conformational restriction in the peptide backbone and provides increased resistance to enzymatic degradation [
25,
26]. The hydrogel designed by LeuΔPhe was transparent, self-supportive, fractaline in nature, of high mechanical strength, non-toxic, injectable, proteolytically stable and responsive to external stimuli, such as ionic strength, pH and temperature. Fibrilar network of the dipeptide gel could encapsulate and release numerous hydrophobic and hydrophilic drug molecules in a controlled manner. The gel restored its original strength after disturbance of its structure, showing its thixotropic behaviour. Administration of the antineoplastic drug, mitoxantrone, entrapped in LeuΔPhe hydrogel in tumor bearing mice, significantly controlled growth of tumors and improved the antitumor activity of the drug. These distinctive characteristics of this low molecular weight dipeptide hydrogel make it an exciting candidate for further improvement as a drug delivery platform. Several other supramolecular self-assemblies of small molecules proteins are also reported to have supportive interaction. Several other self-assembling peptide have been reported, including those based on
d- and
l-amino acids, which have several advantages [
27,
28]. Hydrophobic drugs, such as NSAIDs, can be delivered in a prolong manner with these systems if they participate to the self-assembly process and are thus bond non-covalently to the supra molecular structure [
29]. Examples of enzyme in-structure self-assembly include phosphatase and thermolysin-based self-assembly of small molecules. These enzymes catalyse hydrolysis to trigger self-assembly. Similarly for small molecule bounded proteins the supramolecular material is attached with photoreactive motif that drive the self-assembly. This in turn transform into transparent hydrogel that can retain several proteins, such as tubulin, actins and several others [
22].
Peptides and proteins are known for years as complex structures. Naturally, there are twenty different amino acids join together peptide bonds and build chains known as peptides and proteins. Several processes as fermentation, purification and recombination technology led to the production of potential proteinaceous drugs in an economical way which isused in wide range of diseases. They can be administered through various routes like oral, transdermal, nasal, pulmonary, ocular, buccal, and rectal. By making the availability of these pharmaceutical proteins and peptides possible these drugs can prove to safe and effective therapeutics. Due to its large applications in pharmaceutical fields, they will probably take the important place of organic-based pharmaceuticals. In recent years, therapeutic peptides and proteins have reached a successful level. Several diseases can be treated with this type of therapeutics include auto-immune diseases, cancer, mental disorder, hypertension, and certain cardiovascular and metabolic diseases. Recombinant technology has made possible the production of potential proteins and peptide drug it possible in a cost-effective way. This allows the treatment of severe, chronic and life-threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis in an easy manner. Currently, over 160 protein drugs are available on the world market, and several hundred are on way in clinical trials. The total market for protein and peptide drug market has crossed 30 billion and expected to increase at 10% per year at least. The therapeutical peptide and proteins are have gained a place of important therapeutic agents rapidly. The peptides and protein-based drugs will be produced on a large scale by biotechnology processes and available on market for therapeutic use soon. The benefits of having favorable time to market and high level of success in clinical applications in comparison with conventional pharmaceuticals, therapeutical peptides and proteins will play the main role in the treatment of various ailments [
30,
31].
4. Conclusions and Future Perspectives
Significant progress has been made in the field of hydrogels as a functional biomaterial. Hydrogels form a promising material for controlled release of pharmaceutical proteins and peptides due to their capacity to incorporate therapeutical agents in the hydrophilic polymeric network. The soft nature, porous structure, and large water content make hydrogels suitable carriers to incorporate a lot of drugs and to provide sustained release for a specified period of time. Their characteristics enable them to be employed as essential tools in almost all fields such as biomedical, agricultural, industrial and environmental areas. These hydrogels are of high interest for the encapsulation and entrapment of bioactive substances. Many cross-linking methods have been devised for hydrogel synthesis. Protein loaded hydrogels are prepared by a wide number of methods with the aim to improve therapeutic efficacy and patient compliance. Most of the preparation methods applied for hydrogels preserver the native structure of proteins and peptides, thus ensuring their stability for long period of time. Stimuli-responsive and smart hydrogels form an attractive approach for non-invasive treatment. Hydrogels provide fine tuning of proteins and peptides delivery with significant results in clinical medicine. The unique features of smart and stimuli-responsive hydrogels can be utilized for the effective pharmacological impact of active therapeutic agents. The soluble polymers make these hydrogel biodegradable and biocompatible. A versatile combination of polymers makes these hydrogels responsive to different stimuli like temperature, pH, and various chemical stimuli. These stimuli-responsive hydrogels are reported to have diverse applications for chronic diseases. In short area of hydrogels is making efforts to bring protein delivery to the clinical application. Moreover, the characteristic properties of hydrogels can be controllable with significant impact on the stability of therapeutic agents.
We further expect an increased knowledge of the composition of hydrogel material will allow controlling the release of more sensitive drugs. The hydrogel can be fabricated from nano-sized particles termed as nanohydrogel, which is expected to provide improved stability to biopharmaceuticals such as peptides and proteins. Nano hydrogels can help to retain the three-dimensional structure of these agents and direct them specifically to the target site. Nano-sized hydrogel formulation can also be expected to minimize enzymatic degradation of peptides and proteins by protecting these agents in the polymeric network. Hydrogel formulation with tunable properties will provide patient-specific treatment that would be highly promising for chronic diseases. There is a need to produce hydrogels with enhanced durability, improved mechanical properties, and significant biocompatibility. Even though biocompatibility issues are resolved, there is still a need for the synthesis and evaluation of biodegradable and aqueous soluble polymers with the aim to improve the efficacy and safety of drug delivery hydrogels. The biosafety and cytotoxicity are other important features that must be evaluated by using specified tests to render these materials safe for drug delivery purposes. Nano hydrogels with smart polymers are considered to fulfill all these properties in near future. The concept ofnanogels with conjugated biomolecules, such as proteins, peptides, and antibodies, can be utilized to target cancerous cells and induce apoptosis thus improving normal cellular functions. Similarly, smart co-polymeric hydrogels can also be considered for the disease modification in diabetes, cardiovascular problems, and immune complications. Scientists are also working on another class of hydrogels with remotely controlled properties. These remote-controlled hydrogel nanocomposites are thought to be highly efficient for clinical applications. Further studies are required in this area to make the remotely controlled hydrogel nanocomposite responsive to external biochemical, physical and chemical stimuli. Protein engineering and chemical modification can also be useful for the modification of characteristics properties of protein loaded hydrogels.
Commercialization of drug delivery systems based on hydrogels and their nanocomposites is required for the efficient utilization in clinical areas and better Pharmaco-economics. This is a further demand for the involvement of industries and healthcare systems. The preparation and evaluation techniques for hydrogels face certain challenges, such as high cost, low durability, and complicated procedures. This extensive research is required is to reliable techniques and overcome the issues. All the variables in the process cycle must be critically evaluated and controlled for optimized results. Composite hydrogels systems can be prepared with less complexity to allow for the commercialization of the product. More attention is needed to meet the specific requirements of advanced drug delivery systems. Several challenges are still a part of advance hydrogel formulations, which have to be overcome for diverse clinical applications in coming years. Focusing on clinical requirements and reducing the complexity of hydrogels are considered to be the main goals form coming decades.