1. INTRODUCTION:

The word ‘nano’ has today become so popular that it has spread its wings across to solve most of the untackled problems that were existing from centuries together. The predictions of R Feynman regarding nano world has today become a reality¹. The mega world is shrinking to miniature. The medical field is not an exception to it^2,3. Successful treatment can be possible by selecting an appropriate formulation. An ideal formulation should be capable of fulfilling the needs of the therapy with no or minimum toxicity and must have the potential of being targeted at the required site with programmable release and possess maximum bioavailability. Such an ideal formulation is likely to find broader application in diagnosis, monitoring, and treatment^4,5

Nanoformulations being one among it are found to be better than conventional ones^6,7. Nanoformulations include Solid nanoparticles⁸, Nanostructured Lipid Carriers⁸^,9, Nanoemulsions¹⁰, Nanogels¹¹, Polymeric Nanoparticles and Nanosponges (NSs)¹². This review is focused on NSs and their pharmaceutical applications. NSs are tiny mesh-like structure having a spongy appearance that has created a lot of interest inthe pharmaceutical field as it is successfully providing new life to many formulations^13–15. NSs, when used as a drug delivery tool, is likely to enhance patient compliance to a great extent due to its uniqueness, the detailed explanation of which is illustrated in the review. Besides their potential use in the pharmaceutical sector, it also has wider applications in non-pharmaceutical world which include agrochemistry, biomedicine, bioremediation processes, catalysis, cosmetics^16–23.

1.1. What are NSs?:

NSs are tiny virus shaped sponges with diameter below 1μm, which can trap the drug inside their three dimensional (3D) sponge-like structure and at target site, it releases the drug in predictable and controlled manner¹². NSs is a type of nanoformulation that is said to be produced by the interaction of polymers and crosslinkers at a specified temperature. NSsposses hydrophobic cavity with tunable polarity and hydrophilic branching making them capable of encapsulating both hydrophobic and hydrophilic moieties^24–28.

Based on the process employed, the obtained NSs can either be in para-crystalline/crystalline nature. Among the two, the crystalline structure is of vital importance as it is involved in complexation, and the drug loading capacity predominantly depends on the degree and rate of crystallization. NSs exhibit remarkable benefits in comparison with other nanoparticles as their 3D structurespromote capturing, transportation, and targeted delivery of a variety of medicaments to the desired site^12,29. A schematic representation of NSs is shown inFig. 1.

Fig. 1. Schematic representation of NSs

Based on polymers used different types of NSs available includingtitanium-basedNSs, hyper cross-linked polystyrene NSs, cyclodextrin-based NSs, and peptide NSs. Titanium-based NSscan be obtained by coating polystyrene spheres with clear cut layer of amorphous titanium dioxide³⁰. Hyper cross-linked polystyrene NSscan be obtained by heating chloromethyl polystyrene with Tin(IV) chloride (SnCl₄) in a dilute solution of ethylene dichloride³¹.Cyclodextrins being biodegradable, Cyclodextrin-based NSs are widely used to achieve effective drug delivery at the target site and also to increase the solubility of poorly soluble agents³². Peptide NSs are spontaneously obtained from the aqueous buffer with trigonal supramolecular building blocks^31,33.

1.2. Advantages and disadvantages of NSs^{12,25,34–36}:

Advantages: Nanosponge formulations helps attain improved stability and elegance of the final product. The most important advantage of these is ‘tunability’, meaning it is possible to alter the structure, nature, and size of the pore by just altering the polymers employed. These nano formulations are considerably stable within a pH of 1 to 11 and temperature of up to 130^°C. They are said to be highly compatible with most of the vehicles. They are self-sterilized particles due to their pore size of around 0.25μm (through which bacteria cannot pass) implying these can be cost-effective formulations. Drug release can be modified, i.e. it is possible to achieve controlled, continuous release for more than 12 h. Increased solubility of poorly soluble drugs can be easily achieved as they can carry both hydrophilic and lipophilic molecules effectively. In some cases they play a vital part in manipulating the pharmacokinetic parameters of the drug itself. NSs are non-toxic, non-irritating, non-allergenic and non-mutagenic. They can be easily labeled with site specified linkers to target cells of interest. This can enhance the efficacy of therapy and reduce side effect. Dose and dosing frequency can be reduced if the above is achieved. This in turn can increase the patient compliance. The most important drawback of NS is its capability to form complexes with only tiny particles. Dose dumping and retarded release are other drawbacks of these formulations.

1.3. Composition and chemistry of NSs:

NSs are a novel class of nano-sized colloidal carriers whose size resembles a virus. They possess a backbone of long length polyesters/polymers that are naturally degradable, which implies that they break up in the body thus promoting the release of the drug. Polymer, copolymers, and cross-linking agents are the major components of NSs besides the drug. Type and nature of polymers employed can considerably influence the generation as well as the performance of these encapsulated nanoparticles. Maximum complexation takes place when the size of the cavity of these NSs is appropriate to accommodate the molecule of interest used. Among various polymers used for the NSs preparation, methyl β- cyclodextrin, hyper cross-linked polystyrenes, 2-hydroxy propyl β-cyclodextrins, alkyloxy carbonyl cyclodextrins, ethyl cellulose, eudragit are to name a few. Polyvinyl alcohol, ethylcellulose, poly (valerolactone allylvalerolactone) and poly (valerolactone-allylvalerolactoneoxepanedione) are a few examples of copolymers that are widely used.

Cross-linkers are used to link polyester portions as they have an affinity for certain portions of polyesters and the link formed results in the formation of a spherical shaped structure having numerous pockets. These pockets make NSs encapsulating type of nanoparticles; they encapsulate the active drug molecules within their core and protect them from degradation. They can engulf, transfer, and deliver different kind of molecules selectively. These features of NSs are due to their 3D structure, containing enormous nanometric size cavities. These cavities exhibit tunable polarity. Selection of crosslinking agent or cross-linkers too depends on the structure of the polymer and the molecule to be formulated as NSs. Dichloromethane, carboxylic acid dianhydride, diaryl carbonates, diphenyl carbonate, carbonyl diimidazole, di-isocyanates, pyromellitic anhydride, epichloridine glutaraldehyde and 2,2- bis (acrylamido) acetic acid being some of them^9,37–39.

NSs are soluble in most of the organic solvents and chemically they do not breakup in water. NSs can either be para crystalline or crystalline in nature. The degree of crystallization decides the loading capacity. They can be regenerated using simple procedures like washing with an eco-compatible solvent, mild heating, changing ionic strength, stripping with moderately inert hot gases^10,40. Brief details on drugs formulated as nanosponges are listed in Table 1.

2. FORMULATION DEVELOPMENT OF NSs:

2.1. Preparation methods:

NSs can be prepared by using an either solvent dependent method or solvent independent method.

2.1.1. Solvent dependent method:

In the solvent dependent method, the polymer is to be mixed with a suitable solvent followed by mixing with the crosslinker. Crosslinker to polymer molar ratio is one of the important parameter to yield an ideal product. The time (ranges from 1 to 48 h.) and temperature (ranges from 10°C to the solvent reflux temperature) required for the completion of the reaction is also important considerations in the nanosponges preparation. Once the reaction is completed, the entire solution must be subjected to the cooling process at room temperature (RT). Then obtained product must be added to an excess of distilled water followed by filtration under vacuum for the recovery of the product. Prolonged Soxhlet extraction with ethanol or any other suitable solvent helps in obtaining a purified product. A homogenous product is obtained by drying the final product under vacuum and by subjecting it to grinding in a mechanical mill^51–56. Fluconazole⁵⁷, Voriconazole⁵⁸, Cephalexin⁵⁹, Lansoprazole⁶⁰, Econazole⁵³, Lemongrass⁶¹, Isoniazide⁶², Naproxen⁶³, Ibuprofen⁶³ and Rutin⁶⁴ nanosponges were prepared by this method and evaluated for various evaluation parameters.

2.1.2. Solvent independent method:

In solvent independent method, the polymers and crosslinkers are added to a flask in an appropriate molar ratio and reacted without solvent. The flask is to be heated to 90°C by placing it in a water-filled ultrasound bath followed by sonication for 5 h. This obtained mixture must then be allowed to cool. The cooled product is then broken and made free from the unreacted polymer by thoroughly washing with water. Prolonged Soxhlet extraction with ethanol helps in obtaining a purified product. The purified product so obtained must be dried, preferably in the vacuum and stored at around 25°C for future usage. This method helps to obtain NSs of spherical and uniform size^38,42,51,65.Paclitaxel⁶⁶, Curcumin⁶⁷ and Babchi oil⁶⁸l oaded NSs was prepared using this method and evaluated for different evaluation parameters.

2.2. Evaluation of NSs^{23, 49–51, 58,63,66}:

The NS formulations can be characterized and evaluated for various parameters such Particle size, PDI and zeta potential, FTIR, DSC and DTA, Porosity, Loading Content, Drug loading efficiency, SEM and TEM, Solubility studies and In vitro release.

2.3. Drug loading in NSs:

Drug can be loaded to nanosponge either during the process of obtaining nanosponge or can be added by separately obtaining the NSs^4,29. The diagramaic representation for drug loading in NSs is shown in Fig. 2.

Fig. 2. Drug loading technique in NSs

2.4. Challenges in formulation:

Though NSs can be obtained by either of the above methods, formulating it is very challenging. The drug type is one of the important factors that influences the NS formation and this includes the molecular weight, molecular structure, solubility, and melting point of the drug. The performance and formation of NSs are also greatly influenced by the type polymers employed aswell²⁷. For example, hydroxypropyl β-cyclodextrin possess a good affinity to form inclusion complex as compared to α, β, and γ-cyclodextrin. Temperature too affects the NSs formation. In general, as the temperature increases drug- NSs interaction forces like hydrophobic forces and Van-der Waal forces decrease, resulting in decreased stability of the complex formed. The method of preparation of NSs and loading of drug can greatly influences the complex stability¹². Few studies by researchers has revealed freeze-drying technique to be the more effective technique for achieving effective drug complexation. Stability also depends on the nature of drug and polymers used. The quantity, position and substituent type present on parent moiety even can enhance or decrease the effectiveness of the drug encapsulation in the NSs³⁶.

2.5. Drug release mechanism and factors affecting the release:

The open structure of the sponge enables the movement of active ingredients in and out of the particles and into the vehicle. This continues until an equilibrium state is attained. For example in case of topical delivery, once the ultimate product (the formed complex) is applied on the skin, the skin absorbs the drug molecule already present in the vehicle. The so depleted vehicle is now unsaturated and it disturbs the equilibrium. The system tries to maintain the disturbed equilibrium by absorbing active ingredient from the sponge particle into the vehicle and subsequently the absorption from the vehicle into the skin. This continues until the vehicle is exhausted. Even after the vehicle is dried, the sponge particulate matter remaining on the skin surface (Stratum corneum) will continuously deliver the active ingredient to the skin. This results in sustained release action^10,58. Fig.3 explains the drug release mechanism from topical preparation. Chemical and physical properties of entrapped drug molecules, sponge characters (like pore diameter, pore volume, and its elasticity), vehicle characters (like physical and chemical nature of the vehicle, into which the sponges are finally scattered) greatly influence the release of drug from nanoparticles. External factors like pressure, temperature, the solubility of the drug too play a very important role. Pressure or rubbing enhances the release of active from sponges onto the skin when used externally^11,34,36,69.

Fig. 3. Drug release mechanism from NSs

3. PHARMACEUTICAL APPLICATIONS OF NSs:

3.1. Solubility enhancement of drugs:

Drugs having poor solubility will lead to poor bioavailability. Enhancing the effectiveness of such drugs has been one of the of the significant problems. But revolution in the field of nanoformulations has tackled the problem to some extent. NSs being one among the various nanoformulations too have successfully been formulated to enhance the solubility. These help in increasing the solubility by increasing the amorphous nature of the drug and masking the hydrophobic groups of the drug. Itraconazole¹⁵, Efavirenz⁷⁰, Resveratrol⁴⁶, Paclitaxel⁶⁶, Camptothecin⁴⁴ and Telmisartan⁷¹ are few examples of which solubility was increased by using NSs approach.

3.2. Delivery vehicle for enzymes, biocatalyst, antibodies, proteins, and vaccines:

Industrial applications of biocatalysts are increasing day by day due to evolution in genetic modifications that can easily increase the specificity, stability, and economy of these enzymes. Researchers reported that NSs could carry and release these biocatalysts or enzymes efficiently to the target site without loss in its modification, breakdown, and inactivation, thereby meeting the increasing demands for novel and efficient carrier system. Thus it also improves it's in vivo stability^23,72. Maintaining the native structure of proteins during processing as well as long term storage is one of the greatest problems associated with its formulation and development. For example, Bovine serum albumin (BSA) proteins’ is unstable in the solution. Therefore, it has to be stored in the lyophilized state. In addition to this, several studies reveal that these proteins undergo reversible denaturation during the process and attains a conformation slightly deviating from the original one. Development of NSs is one the best option to overcome this problem, as it can help in increasing stability by encapsulating the proteins in NSs^23,26,73.

3.3. Targeted drug delivery:

Two main reasons for the failure of conventional anticancer therapy or chemotherapy are either failure of the drug to reach the tumor site or low solubility or metabolism of drug or attack by the immune system before they exhibit their action at the target site. Employing NSs based delivery can help tackle these problems to some extent. Researchers from Vanderbilt University came out with an antineoplastic drug encapsulated NSs, which could stop the advancement of tumor growth up to three to five times of any other conventional methods. Paclitaxel is one the best example of an anticancer drug, which was formulated into the nanosponge and showed required activity at the target site^23,66,74. Doxorubicin is another relevant examples for targeted delivery to the cancerous cells which can be modified as glutathione-responsive cyclodextrin based nanosponges of doxorubicin. This modified moiety helped in reduction of tumor development by releasing the drug at target site⁷⁵. NSs can also act as flexible carriers to convey active ingredients by using various administration routes such as ocular, pulmonary and nasal routes. Researchers claim that these NSs can be employed to deliver small interfering ribonucleic acid (RNA) or antiviral drugs successfully into the lungs and nasal epithelia, meaning this research can specifically target viruses like respiratory sinctial virus, influenza virus, and rhinovirus which causes respiratory tract infections (RTI). This technology can also be used against the Hepatitis B Virus (HBV), Herpes Simplex Virus (HSV) and Human Immune Virus (HIV), respectively⁵⁰.

3.4. In the topical drug delivery:

The nanosponge based drug delivery is widely used for the treatment of various topical infections which ranges from bacterial to fungal infections. There are various examples of drug which are widely used for the topical drug delivery in various treatment conditions. The adsorption of econazole nitrate, an antifungal agent, was found to be insignificant, and its effective therapy required a large number of active ingredients to be incorporated. Econazole nitrate loaded NSs hence formulated was found to be highly effective. This was produced by emulsion solvent diffusion method followed by loading those NSs in the hydrogel, which served as a local storehouse and facilitated sustained release action^23,41,53. Voriconazole nanosponges incorporated in the gel was used for the treatment of topical infections⁵⁸. Cephalexin loaded into the nanosponges and incorpotated into the hydrogel was found to be useful in different topical problems such as diabetic foot infection, urinary tract information and soft and skin tissue infection⁵⁹.

3.5. As a carrier for calcium delivery:

Most of the marketably available phosphate binders for treating hyperphosphatemia produce many toxic effects, which include bone disease, aluminium, soft tissue calcification, and hypercalcemia. Pravin Shende et al. formulated and characterized enteric-coated cyclodextrin-based calcium carbonate NSs that could bind efficiently to free phosphate ions and release calcium in a controlled manner. According to the report, the cross-linking enhances the stability and helps achieve controlled release of calcium. All these make it suitable to treat hyperphosphatemia without any side effects⁷².

3.6. To provide stability:

NSs can selectively trap a few families of protein molecules from the blood, hence can be used in safeguarding those proteins from undergoing enzymatic degradation⁷⁴.

3.7. Ocular delivery:

Glaucoma is a chronic disease that is associated with the risk of vision loss. Several methods are in use to increase patient compliance, but very poor adherence to these drugs acts as a major barrier. The efficacy of NSs encapsulated compounds was studied in glaucoma therapy by Lambert et al., concluding that one injection of NSs could convey ocular antihypertensive molecules effectively in a continuous, linear fashion for around thirty-two days. They even reported that these formulations are effective at targeting retinal ganglion cell (RGC) that get degenerated in glaucoma patients⁷⁶.

3.8. Indetoxification and reduction of superbug infection:

The present detoxification platforms such as antisera, monoclonal antibodies, small molecule inhibitors, etc., exhibit their action by targeting the toxins based on their molecular structures. Recognizing the need for personalized treatment for different diseases, Che-Ming J. Hu et al., came out with biomimetic toxin NSs, which could act as a toxin decoy in vivo. This NSs were found to be capable of absorbing those toxins which damaged the membranes. After absorbing, they could divert the toxins away from the cellular targets, thereby preventing toxin-mediated hemolysis. According to the report, this biologically inspired toxin NSs can be employed to nurse a large number of diseases and injuries caused by pore-producing toxins, which are the most widely found protein toxins in nature till date. They even observed that these NSs could clearly reduce the noxious effects of staphylococcal α-hemolysin and reported that this approach could be used to battle drug-resistant contaminations/infections such as methicillin-resistant Staphylococcus aureus infections. They claim - One red blood cells (RBC) membrane can be utilized to blanket more than or around 3,000 of these stealthy NSs (fully loaded with poison) which can be safely discarded via liver³³.

3.9. Biomedical applications:

Oxygen plays a major role in both hospitals and medical industries, storing of which seems to be challenging at times. A novel attempt to solve this problem was made by designing carbonate NSs based on cyclodextrins which could form inclusion complexes with various gases like carbon dioxide, methylcyclopropene, and oxygen. These NSs carrying oxygen can be used to deliver oxygen in hypoxic conditions^22,23,41.

4. List of patents filed for NSs:

There are some patents available on recent inventions based on NSs. List of few patents on methods of obtaining NSs is as described in Table 2.

CONCLUSION:

NSs based drug delivery can be regarded as a useful drug delivery system as it solubilizes both hydrophilic and lipophilic moieties, helps to reduce both dose and dosing frequency and also supports the personalization of drugs, thereby satisfying the majority of features of an ideal drug delivery system. NSs based drug delivery would be highly useful for drugs with a narrow therapeutic window and can even be used to treat diseases based on its severity stage. Hence, it can be used to prevent overuse and promote rational drug use. NSs based drug delivery emerged as a boon and is likely to drastically change the classical vista of drugs with low solubility. This system conquers almost all the problems associated with poor bioavailability and drug toxicity. It is possible to formulate different dosage forms of drugs complexed with NSs, and its extremely small size promotes parenteral, optical delivery successfully. Pharma industries too can significantly benefit from this if clinical trials can demonstrate its potential and efficacy for human use as it involves quite a simple production and evaluation procedures. Biotechnological products-based industries too can enjoy the fruits of this invention as this supports the delivery and sustained release of antibodies, proteins, vaccines, and enzymes. Besides its application in pharma sector, its potential applications are seen even in agriculture, veterinary, floriculture, cosmetics, agrochemistry, bioremediation, etc. Thus, there is tremendous scope for exploring NSs based delivery systems.

LIST OF SYMBOLS AND ABBREVIATIONS:

SYMBOLS:

α – Alpha; β– Beta; γ– Gamma; °C – Degree Celsius; h – Hours; μm – Micrometer

ABBREVIATIONS:

NSs- Nanosponges; 3D – Three dimensional; SnCl4 –Tin(IV) chloride ; RT – Room temperature; PVA - Polyvinyl alcohol; BSA - bovine serum albumin ; RNA - Ribonucleic acid ; HBV - Hepatitis B virus ; HSV - Herpes simplex virus; HIV - Human immune virus ; RGC - Retinal ganglion cell ; RBC - Red blood cells ; 0₂ – oxygen

ACKNOWLEDGEMENT:

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

CONFLICT OF INTEREST:

Authors declare that they donot have any conflict of interest in the content or data for the publication of the manuscript.

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Received on 26.09.2019 Modified on 24.11.2019

Research J. Pharm. and Tech. 2020; 13(7): 3536-3544.

DOI: 10.5958/0974-360X.2020.00626.5

Drug	Therapeutic Activity	NSs Vehicle	Study	References
Econazole Nitrate	Antifungal activity	Ethyl Cellulose Polyvinyl Alcohol	Irritation study on rat	41
BSA	Protein supplement	Cyclodextrin Polymer	Drug stability and release in vitro study	41
Tamoxifen	Breast Cancer	Beta Cyclodextrin	Cytotoxicity study on MCF- 7 cell line	41,42
Antisense Oligonucleotide	Cancer Therapy, Viral Infection, Pathologic Disorder	Sodium alginate, Poly C- Lysine	Pharmacokinetic study on mice	41
Camptothecin	Anticancer Activity	β-cyclodextrin	Stability and solubility enhancement	44
Tamoxifen	Hormone-related deficiency such as antiestrogenic activity	β-cyclodextrin	Solubility improvement	45
Resveratrol	Antioxidant Property	β-cyclodextrin	Drug permeation enhancement	46
Itraconazole	Antifungal Property	β-cyclodextrin and co-polyvidonum	Bioavailability and solubility improvement	15
Temozolamide	Antitumor Activity	Poly (valerolactoneallylvalerolactone) and poly(valerolactoneallylvalerolactoneoxepanedione)	Enhancement of drug release	25
Dexamethasone	Antitumor Activity	β-cyclodextrin	Drug release improvement	47
Flurbiprofen	Anti-inflammatory	β-cyclodextrin	Drug release enhancement	48
Nifedipine	Anti-hypertensive and antianginal Activity	β-cyclodextrin	Drug solubility enhancement	49
Acyclovir	Antiviral Property	Carboxylated cross linkers	Solubility and drug release improvement	50

Patent number	Description	References
WO2012147069A1	Explains a method for preparing Dextrin NSs via interfacial polymerization technique	77
US20060251561A1	Invention explaining silicon NSs, its preparation from metallurgic silicon powders	78
WO2009138998A2	Discloses a solution for problems associated with preparation of metal nanosponges, it provides a	79
US20140370422A1	Explains the preparation of metallic nanoparticles possessing a coating of a very thin protective shell of carbon as well as nano-metallic sponges	80
WO2006002814A1	Describes a method to obtain nanosponges in absence of solvent	81
EP2175847A1	Describes complexes of nanoporous polymers made of cyclodextrins containing antitumoral drugs	82
EP2294190A1	A description on cyclodextrin based NSs as carriers for various biomolecules is given	83
WO2013046165A1	Reveals the use of NSs growth, protection, conservation and disinfection of vegetable organisms	84