INTRODUCTION:

Today the term 'nano' has become so interesting that it addresses every health issue we experience. In the 1980s, the proposition of miniaturized robotic products in medicinal applications offered an impetus to research on developing new medicinal products, new methods of delivery, and therapeutics utilizing molecular and conjugate nanometre properties¹. An investigation into the progression of the release of the medication targeting the specified predetermined location is a significant factor to consider. Due to the ability to advance existing products and to develop new products in a variety of applications, the nanotechnology industry is considered an evolving technology.

Nanotechnology then consists of the designing, handling, creating, development, and use of architectures by regulating form and scale, properties, and compatibility². In the 1990s the name of the nanosponge emerged first, since it has a sponge-style porous design, to resolve the disadvantages of the conventional cyclodextrins as an encapsulating agent. The inner cavities, holes, or spaces when within a nanometre range, nanosponges are considered porous materials³. These nanosponges have at least a 1-100nm structure dimension⁴. The long polymer strands are blended with small "cross-link" molecules, which are identical to polymer pieces. Some parts of the polymer are cross-linked into a small spherical form, where the drug can be encapsulated. The polymer employed is biodegradable and biocompatible and can easily be encapsulated by a huge diversity of medications. This small formulation will circulate within the body until the goal is established, and then the surface gets adhered to that area and the drug is released in a sustained and predictable way. By adjusting the pharmacokinetic parameters, their use may overcome the inconveniences associated with low water solubility, drug release and bioavailability. The key objectives of this delivery system are to enhance the distribution of different dosage forms of drugs, proteins, and peptides⁵.

Figure 1: Basic structure of a Loaded Nanosponge

The Distinctive Feature of Nanosponges⁶^,⁷^,⁴^,⁸

· The dimension of nanosponges falls under the range of one μm or even lesser than that with an adjustable void’s polarity.

· Demonstrate both crystallines as well as the Para crystalline type of behaviour, depending upon the type of the processing condition.

· The degree of crystallization affects drug encapsulation ability. Para crystalline forms show higher encapsulation efficiency.

· They are biodegradable, non-toxic, porous material, insoluble in organic solvents, and are stable at a temperature of even above three hundred

· Steady at the pH range of 1 – 11.

· They can conjugate with the different functional groups on the target site, therefore targeted drug delivery is easily achievable.

· The complexes formed by these nanoparticles are either inclusion or non-inclusion types.

· They offer personalized delivery of drugs that have a “low solubility and high permeability” and also the ones which have both “low solubility and permeability” i.e., BCS class II and IV.

· They can carry both lipophilic and hydrophilic drug molecules.

· The 3D network like structure aids in the selective release of a wide variety of substances.

Composition and Architecture of Nanosponges:

Apart from the drug, polymer, co-polymer, and cross-linking agents are the principal components of a single nanosponge. The polymer along with the copolymer forms the backbone of the nanosponge architect, the cross-linking agent forms the in-between bridges eventually forming a spherical structure with voids or cavities like pockets in between the structure, this kind of architecture gives 3D form to the nanosponge structure. The cavities formed have a tunable polarity which aids in encapsulating a wide variety of drugs. Table 1 shows the different materials used for the synthesis.⁹^-¹²

Table 1: Components of Nanosponge.

Polymer

Alpha-cyclodextrin, Beta-cyclodextrin and their derivatives like Methyl-beta cyclodextrins, Alkyloxy carbonyl cyclodextrin, 2-hydroxy propyl beta-cyclodextrin, Eudragit RS 100

Co-polymer

Poly-allylvalerolactone, Polyvalerolactone, Poly-oxepanedione, Poly-methyl methacrylate, Hydroxypropyl methylcellulose, Poly-vinyl alcohol, Ethylcellulose

Cross-linking agent

Diphenyl carbonate, “2,2-bis-acrylamido acetic acid, Diaryl carbonate, pyromellitic anhydride (PMDA), Hexamethylene diisocyanate, Epichlorohydrin, “Carboxylic acid” dianhydride, carbonyl diimidazole (CDI), Toluene-2,4- “diisocyanates,”

Dichloromethane, Polyamidoamine.

Alpha-, beta- and gamma-cyclodextrin are the common and natural agents for the formulation of nanosponges in a complex form with cross-linking. Among these, beta-CD is the most widely used for pharmaceutical purposes. As it has suitable and specific cavities of required dimensions for encapsulating a wide range of drugs and gives high production rates, is readily available and accepted by the USFDA. These are regarded as safe and non-toxic, but it also has some drawbacks like low aqueous solubility for the parenteral route and chances of nephrotoxicity, which is not seen in the case of alpha- and gamma-CD. However, the cavity for forming inclusion complexes is inadequate, and in comparison to the two other, gamma-CDs is too expensive. ¹³.

Categorization of Nanosponges:

Depending upon the types of association:

Nanosponges are nanoparticles that retain the drug molecule into its porous matrix. So, depending upon the kind of association between the drug and the nanomaterial, nanosponges are of the following types- ¹¹^,¹⁴^,¹⁵

· Encapsulating nanosponges: Among these, the drug moiety gets entrapped within the sponge-like cavity of the carrier particle.

· Complexing nanosponges: This type of association involves electrostatic charges.

· Conjugating nanosponges: in this type, the association between the drug and the nanoparticle is by the formation of a sturdy covalent bond.

· Magnetic nanosponges: The magnetic character of those types of nanoparticles are accompanied by magnetic compounds surrounding them.

· Metal nanosponges: These types of nanoparticles are incorporated with metal, such as titanium.

· Silicon nanosponges: These nanomaterials are incorporated using “silicon” as a core material to style a hybrid system such as hybrid photovoltaics silicon nanosponges and solar cells.

Depending upon the type of crosslinker used for the synthesis: The crosslinker is one of the major components in nanosponge architecture and for the formulation and development of nanosponges. Table 2 depicts the various types of nanosponges categorized based upon the type of cross-linker used: ^6,7,11,¹⁶

Engineering Methods For Nanosponges¹⁷^,¹⁸^,¹²^,¹⁹^,²⁰

The following techniques are employed for the engineering of the blank unloaded nanosponges:

Melt/Fusion technique:

In this technique for the synthesis of blank unloaded nanosponges, the polymer i.e., the cyclodextrin along with the proper crosslinker were melted together and the ingredients were properly blended by subjecting them to a temperature of 100°C at least for 5 hours with consistent stirring. Then the obtained product was cooled at room temperature and was washed using an appropriate solvent. Washing is necessary to remove any untreated starting material, any by-products, and to break the melted mass into the form of a nanosponge. These nanosponges are then subjected to drug loading.

Solvent dependent technique:

In this technique, the suitable crosslinker and the polymer is solubilized in a hydrophilic dipolar aprotic solvent such as DMF and DMSO separately. The polymer solution is added to the crosslinker solution in an excess amount, usually in a ratio of 4-16 (cross-linker/polymer). The mixture is subjected, over 1-48 hours, to a temperature within the range of up to 10°C and the optimal temperature for reflux should be specific to that of the fluid selected. This technique is preferred for the type of nanosponges that involves carbonyls as the part for cross-linker. Once the reaction is conducted the solution is cooled at an ordinary temperature. To this, an excess quantity of double-distilled water has been added to this solution mixture which is then subjected to filtration under vacuum and simultaneous purification via Soxhlet extraction using ethanol, water, or acetone. To obtain the final product the purified solution was dried under vacuum and sized using a mechanical milling procedure to obtain a dry powder of nanosponge.

Solvent diffusion method:

Again, under this there are two techniques, namely emulsion, and quasi-emulsion solvent diffusion technique: Both above-mentioned techniques involve the same steps i.e., the formation of a dispersed phase and the dispersing medium. The dispersed phase includes both the polymer and the drug in a suitable solvent, the polymer used is ethyl cellulose in the case of the emulsion solvent diffusion technique while eudragit RS100 is the other technique. This dispersed phase or the inner phase is then slowly added to the continuous aqueous medium i.e., polyvinyl alcohol and stirred for 2 or more hours. The mixture is then filtered, washed, and air-dried at ambient temperature or in a vacuum at 40°C for 12-24 hours to obtain the nanosponge.

Solvent independent/ultrasound-assisted technique: This method is usually employed to get nanosponges of more defined characteristics, homogenous size, which is less than 5 microns, and when diphenyl carbonates or PMDA are being used as cross-linker. In this technique, the anhydrous form of cyclodextrin is made to react with the crosslinker at 90°C for 5 hours in an ultrasound Sonicator. This is then allowed to cool, broken down, washed with water, and purified using ethanol in a Soxhlet extractor for a sufficient time. The final product is vacuum dried and stored at 25°C.

Microwave irradiation technique:

This technique was conducted in a specialized microwave system called cata’s and the fabric optic probe attached to this system is used for temperature monitoring purposes. It involves the use of a crosslinker, diphenyl carbonate, and a solvent, diphenyl formamide. The mixture of the cyclodextrin and the crosslinker in a suitable solvent is subjected to radiation by this system for a specific duration of time, after that, the solvent was removed completely, the residue was treated with water and was subjected to Soxhlet extraction for the purification purpose using ethanol as the solvent, at last, the fine powder is obtained which is oven-dried at 60°C.

Mechanochemical technique:

Rubin Pedrazzo et al. produced a new technique that is based upon the principles of mechanochemistry and assures to be a more safe, efficient, and greener technique as it is conducted in absence of solvent and consumes lesser energy, hence also called green synthesis. Rubin Pedrazzo et al. employed this method for the synthesis of carbamate nanosponge, wherein the required amount of cyclodextrin and the crosslinker mixture in a suitable solvent is subjected to mechanical stress using a ball mill for 3 hours, the speed was maintained at 600rpm along with the change in the direction of rotation for every 15 mins with an external temperature of about at 90°C. The obtained fine powder is then washed with deionized water and acetone multiple times. An extra unwanted solvent is then removed to get the purified product of the nanosponge using pressurized solvent extraction (PSE). The nanosponge obtained using this method has a mean diameter of around 200nm.

Charging of Drugs in the Nanosponge:

The NSs are firstly pre-treated to cross below 500nm in the target size range and then it is suspended in distilled water which is then subjected to sonication and is centrifuged to deform the clumps and to get a fractional suspension, the supernatant is separated and “freeze-dried” to obtain the dry samples. An aqueous suspension of this dried sample is prepared, and an extra amount of drug is added onto it while constantly stirring the suspension for the required period allowing the nanosponge to form a complex with the drug. After completion of this process, the processed suspension is again centrifuged to separate the unloaded nanosponge and the uncomplexed drug from the suspension. Again, after this procedure like freeze-drying and solvent evaporation to obtain solid crystals of nanosponge loaded with the drug. Charging of drugs in nanosponge is usually done in the aqueous state²¹. Usually, all drugs form an inclusion complex as the result of the complexation process, but the drugs which exhibit poor crystalline behaviour forms a complex by mechanically mixing them. It is also seen that Para crystalline nanosponges show a different drug loading behaviour when compared with that of the crystalline nanosponges¹³.

Release Kinetics from the Charged Nanoparticle^7,²²

As mentioned, the nanosponge has an open and porous architecture which forms voids and drug molecule gets encapsulated, this sort of free and open arrangement (as there is no continuous membrane in the boundary), eases the free movement of the drug molecule form and to the particle and as well as into the vehicle unless it reaches equilibrium. In the case of the topical application, the actives from the carrier nanosponge vehicle get penetrated onto the target area or tissue, when the final formulation is applied. This causes a gradual decrease in the vehicle leading to an unsaturated state, consequently fluctuating the equilibrium state. This will initiate the active flow of the particles from the sponge into the vehicle and then into the target tissue until either dry or consumed by the body. And even after the particulate sponge stays on tissue surfaces will continue to provide extended release of the active into it for a prolonged time. In the case of tablet oral tablet dosage form, the lansoprazole loaded nanosponge showed a non-fickian release which indicates that for the release of the drug molecule, the formulation undergoes swelling and erosion which is associated with diffusion and dissolution mechanisms²³.

Characterization of Nanosponges²⁴^,²⁵^,²⁶^,¹⁸

The evaluation of the composition and complete characterization of nanosponges is not just a small task, requiring the use of various sophisticated methods to examine their characteristics. Systemic application of various methodological methods eases a superior understanding of the interaction between the nanoparticle and the drug. Besides, aids in the proper collection of suitable polymer structures for the required guest representing the active pharmaceutical unit. The functional or thermodynamic characteristics of the active unit encapsulated in the nanosponge can be analysed by various analytical methods. Besides, these methods allow for a more detailed and reliable classification of experimental differences in nanosponges. Frequently used tools for the analysis discussed in the literature shall include, UV-Visible spectroscopy, microscopy techniques to detect the microscopic aspect of the drug-loaded nanosponge, thermal analysis like DSC and DTA studies for detection of any thermal degradation, X-Ray diffractometry studies to know about the inclusion complex formed within, zeta potential to analyse the particle size, FTIR studies to study about the interaction between the polymer, crosslinker and the drug molecule, chromatography methods like TLC which assists in the detection of the complex formation, nuclear magnetic resonance, solubility studies, and loading efficiency by HPLC or UV methods.

Facets of Nanosponge Toxicity²⁷^,²⁸

Toxicity evaluation is an important parameter to evaluate drug safety thresholds and the optimizing of the right amount of dose in animals and humans. The purpose of this type of research is to figure out the toxicity of various NS formulations synthesizing with various crosslinking agents and preparation techniques in laboratory animals.

Acute toxicity analysis:

It shows that, in all the treated types, animals displayed no lethal effects or mortality during the test period after the oral administration of nanosponge samples at 300 and 2000mg/kg doses. The overall appearance of the animals was not altered, and the morphological features remained unchanged. No shaking, convulsion, salivation, diarrhoea, lethargy, or unusual behaviour was present, in comparison to the control group.

Analysis of repeated-dose toxicity:

Test nanosponge formulations was not adversely affected by toxicity or mortality for 28 days. There is no statistical significance between any biochemical and haematological parameters in the relation between the control and the treated group.

Application and Significance:

Boosting bioavailability and solubility enhancement: The nanoporous layer of nanosponge will disperse drug molecules and will only release these dispersed molecules on the target site to prevent degradation and increase the overall drug solubility.²⁹ Biopharmaceutical classification scheme Class II and IV drugs are a problem for formulators, as their limited bioavailability is due to reduced water solubility resulting in low drug absorption. Rao et al. (2018) synthesized Rilpivirine (RPV) nanosponge using beta-cyclodextrin crosslinked to carbonyl diimidazole (CDI) and pyromellitic dianhydride (PMDA). Saturation solubility tests of RPV in various complexes have proved improved solubility in the presence of multiple carriers. Dissolution experiments in phosphate buffer pH 6.8 complexes have been performed. The rate of combined drug release increased 3-foldings for ternary complexes and around 2-folds for binary complexes compared to RPV. An increase in dissolution can be correlated with an enhancement in saturation solubility. The entrapment of RPV molecules into the beta-cyclodextrin hydrophobic cavity of the nanosponge structure and increased wettability can lead to increased dissolution. The relative bioavailability of RPV was increased by 2–3-fold. Increased solubility and dissolution rates can explain increased bioavailability³⁰. Nifedipine serves as a blocking agent for the calcium receptor and is used in treating angina pectoris and hypertension. The oral route of nifedipine is widely recognized but is associated with contraindicative issues, such as gastrointestinal damage, with reduced oral bioavailability owing to its short biological half-life. Shringirishi et al. (2017) worked to boost the oral solubility of nifedipine by integrating beta-cyclodextrin and diphenyl carbonate into nanosponges. In vitro drug release from drug-loaded nanosponges resulted in a rapid onset of release for the fourth hour followed by a controlled release sequence in the next twenty-four hours.³¹These nanostructures are also employed to enhance the solubility of herbal drugs like curcumin.³²

As the system of drug delivery:

Nanosponge is solid and can be formulated as different drug delivery dosage forms³³^,³⁴. The porous structure of nanosponges further helps in the trapping of flavour and odours by adsorption, which masks the undesirable taste and smell of those kinds of products, as well as providing the medium for processing liquids into the solid powders. The primary benefits for using nanosponge in the form of nanocarrier across for drug delivery applications are dependent on its facility to associate with weakly soluble drugs within its 3-dimensional framework, as a result of this the bioavailability and aqueous solubility of water-soluble molecules is increased, also protecting the degradable compounds within its structural network, as well as restricting the rate of release of drugs corresponding to BCS class II and IV³⁵.

Smart fibres:

Biofunctional textiles are a new class of advanced materials that combine traditional textiles with innovative delivery of drugs for the development of fabrics that can release active drug principles through the skin. Researchers produced a porous 3D structure, cyclodextrin based carbonate nanosponge (CDI-NS) encapsulated with melatonin, to verify the feasibility of the finishing process, cotton fabrics were treated with plain CDI-NS by physical adsorption followed with melatonin complex. Results concluded that the in-vitro release tests of functionalized tissues showed zero-order kinetics, which is characteristic of a reservoir diffusion regulated system.³⁶

Controlled and sustained release:

The nanosponge can indeed be crafted to be one of a unique size range and deliver the number of drugs throughout the period and not in just the 'flash' mode which is traditional to all the other modes of delivery. Conventional structures are associated with many drawbacks, e.g., stability problems, dose dumping toxicity, gastric irritation, acid pH instability, massive cost, and lower dose change. To counter these issues, various types of nanosponge based dosage forms have been designed and produced for continuous and controlled release of synthetic as well as herbal API’s.³²^,10,³⁷ Shoaib et al. (2018) synthesized nanosponge formulations of naproxen and ibuprofen using the emulsion solvent diffusion process. This study concluded that the formulations offer a sustained release pattern based on the Higuchi model, the drug release mechanism was Fickian, possibly due to the porosity of the nanosponge³⁸.“Gabapentin (GBP)”, which is a “BCS class III” drug and employed as a primary drug candidate for the therapy-based treatment or management for partial seizures in patients 12 years and older. In the market, the available dosage types include tablets, capsules and as a sustained-release matrix. In paediatric patients, it is difficult to adhere to these prescription formulations because of difficulties with swallowing. Another potential concern with the drug is the bitter taste. Nanosponges crosslinked with an appropriate cross-linker was employed as a sustained release carrier for the drug and which also helped in masking the bitter taste.³⁹ A precursor to dopamine, L-DOPA is a dopamine amino acid commonly used for the treatment of Parkinson's disease. However, L-DOPA can degrade and impair its therapeutic properties if exposed to light or added to aqueous solutions. For the extended, controlled release of L-DOPA, a new form of pharmaceutical cyclodextrin-based nanosponge obtained with molecular imprint has been identified.⁴⁰

Anticancer therapy:⁴¹

The release of anti-cancer medicines is highly controlled by cyclodextrin-based nanosponge (CD-NS). Lipophilic and hydrophilic medicines may be transported through nanosponge to be targeted and the solubility and bioavailability of the medication can ultimately be enhanced to avoid environmental influences.³⁵

Gas delivery:

Nanosponges of cyclodextrin type i.e., formed by bridging of the cyclodextrin to carbonildiimidazole are kind nanomaterial solids with strong crosslinking ability towards distinct types of gaseous molecules. Because the gases have such a low molecular mass and are therefore small and compact, alpha-cyclodextrin has been the cyclodextrin preferred for such use. The encapsulation of CO2 with CDs was patented earlier in Japan anticipates its use in cosmetics and the goods of personal care.⁴² The ability of all forms of nanosponges has been proved to encapsulate and store oxygen. The oxygen-filled nanosponge can be used to supply oxygen to the hypoxic tissues⁴³, or as a bio-inspired mechanism for the recovery by free scavenging and control of the oxygen ischemic stroke.⁴⁴

Decoy for SARS-CoV-2 virus:

The pandemic has resulted in a massive global public health crisis. An effective therapeutic agent to suppress SARS-CoV-2 infection, as well as its possible mutated organisms, will be a big notable change in the fight against this public health crisis. Considering the broad range of applications of traditional nanosponges, the scientist designed a biomimetic nanosponge to inhibit host cell infections. The nanosponge core consists of biodegradable polymer PLGA with DiR iodide draped with human lungs and immune cell membranes. The virus is deceived into infecting nanosponges that are then unable to replicate, reducing the infection rate and therefore the chance to spread the infection. Researchers concluded that the findings were quite positive and that nanosponges were shown to be quite successful in in-vitro cell studies, reducing the virus's infectivity by up to 90%. The main approach of this study was, as far as the virus can still enter the cells that we imitate, the nanosponge approach should still work. ⁴⁵

Miscellaneous:

Nanosponges spongy nature and the myriad cavities throughout cyclodextrin, alongside swelling and molecular encapsulation activity, allow nanosponges to entrap a variety of molecules and can play a key role in the areas of biology, cosmetics, and pharmaceuticals. The ability of them to deliver both hydrophilic and lipophilic molecules also assists in the delivery of protein, peptides as well as oligonucleotides.⁴⁶ The targeted behaviour of the nanosponges assists in the magnetic imaging⁴⁷ and as a chemical sensor ⁴⁸ for cancer and other such threatful diseases. The architecture of these nanoparticles also allows reducing the volatility of the many essential oils which are largely employed in antimicrobial in food packaging and also in cosmetics, for example, cinnamon ⁴⁹ and coriander ⁵⁰ volatile oil. Along with this the structure also acts as an adsorbent ⁵¹ for the pore-forming toxins and helps in detoxification ⁵². Blood filtration has been achieved with dialysis therapy for a long time. In one of the experiments, therefore, better techniques for blood purification were tried. Researchers have prepared and tested the size of selective nanoporous polymer adsorbents, with an extra dose of mesopores for such purpose.⁵³ For ultra-filtering protein, a variety of nanoporous carbon membrane inorganic ultrafiltration with support from stainless steel has also been produced.⁵⁴ These nanostructures are also employed in the removal of organic impurities from the wastewater and in waste-water treatment systems⁵⁵. Nanosponges have many challenging benefits in the arena of drugs and nano therapy and to resolve the few constraints associated with nano-dispensation systems including traditional formulation, as well as the above-mentioned approaches ^56-60.

CONCLUSION AND FUTURE ASPECTS:

As in the context of these kinds of observations, it could be conferred that cyclodextrin-based nanosponges are indeed a new category of polymeric biocompatible nanoparticles. Nanosponge based drug delivery be a useful drug system because it resolves hydrophilic and lipophilic moieties, limits dose and dosage rates, and eases drug personalization, thereby fulfilling most features of an ideal drug delivery system. Our market has seen tremendous opportunity towards the nanosponge-based formulation related innovation and its flexibility, with the increasing need for advanced and accessible pharmaceutical, biomedical, and cosmetic products. Nanosponges can be formulated into a wide variety of doses, due to their compact size and spherical shape. It should also be acknowledged that this technology is costly, and thus calls for it to be cost-effective in enhancing the quality of life for the healthcare and medical sectors.

ACKNOWLEDGEMENT:

The authors are thankful to “Manipal College of Pharmaceutical Sciences” and “Manipal Academy of Higher Education”, Manipal, Karnataka.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 09.03.2021 Modified on 08.10.2021

Research J. Pharm. and Tech 2022; 15(9):4253-4260.

DOI: 10.52711/0974-360X.2022.00715

Generation	Types	Cross-linker	Uses
First-generation	Cyclodextrin based urethane/carbamate nanosponges	Hexamethylene and Toluene-2,4-diisocyanate	Water treatment, removing organic contaminants and volatile materials from effluent, Enhancing the pharmacokinetic parameters of bilirubin and amino acids.
	Cyclodextrin based carbonate nanosponges	Carbonyl compounds, triphosgene, 1,1′-carbonyldiimidazole and diphenyl carbonate	Gas storage, immobilization of the enzyme, Smart materials, tools for drug delivery
	Cyclodextrin based ester nanosponges	Dianhydrides, di/polycarboxylic acids such as pyromellitic dianhydride, EDTA dianhydride and citric acid	For drug delivery like, topical, oral and as tablets excipients, the absorptive base for pharmaceutical residues, dyes, and metals
	Cyclodextrin based ether nanosponges	Epoxide like bisphenol-A diglycidyl ether, diglycidyl ether, epichlorohydrin and ethylene glycol	Drug delivery, disintegrant in tablets, taste masking, prevent enzymatic browning of fruit juices, chemical catalysis, in the form of stationary phase for chromatography, peptide drug delivery, absorbent for pharmaceuticals
Second generation or Functionalized Nanosponges	Fluorescent-labelled nanosponges	Fluorescent colourants like rhodamine and fluorescein with attaching ligand such as azido	In vivo/ex vivo, in vitro tracking of drug delivery
Second generation or Functionalized Nanosponges	Charged side chains nanosponges	Charged enabled cross-linkers such as dianhydrides or polyfunctional carboxylic acids	Modified drug delivery
Third generation	Stimuli-Sensitive Nanosponges (Glutathione responsive, Amino cyclodextrin, Pyromellitic, and PEG block nanosponges)	Aliphatic polyamine linkers, pyromellitic dianhydride (PMDA) (functionalized by anti-IgG antibody), Nano assemblies of hydrophilic copolymers	Stimuli-responsive drug release, anti-tumour therapy, drug depot, and enhancing signals to the tumour cells
Fourth generation	Molecularly Imprinted Polymeric nanosponges	1,1'-Carbonyldiimidazole	Sustained drug release material for biosensing, selective drug release, catalysts, quantitative assay, and cell imaging