Preparation, Characterization, and Applications of Nanosponges: A Review

Introduction

Nanosponges (NSs) are nanosized, highly porous, cross-linked polymeric structures capable of entrapping guest molecules via inclusion and non-inclusion interactions. Cyclodextrin-based nanosponges (CD-NSs) — obtained by crosslinking native or modified cyclodextrins — are the most widely studied class because of the innate biocompatibility and inclusion ability of cyclodextrins. Between 2010 and 2019 the field matured from conceptual papers to numerous formulation and in vitro/in vivo studies demonstrating improved solubility, stability and release control for poorly water-soluble drugs.

Types of Nanosponges and Crosslinkers

• Cyclodextrin-based nanosponges (CD-NSs): Crosslinked β-, α- or γ-cyclodextrins using crosslinkers such as carbonyl diimidazole, pyromellitic dianhydride (PMDA), diphenylcarbonate, carbonyldiimidazole, or diisocyanates. CD-NSs combine inclusion complexation (cyclodextrin cavities) and polymeric network entrapment.
• Polymeric nanosponges: Hypercrosslinked polymers (e.g., ethylcellulose, polyvinyl alcohol combinations) prepared by emulsion/solvent evaporation or nanoprecipitation, used when different release profiles or mechanical properties are required.

 Methods of Preparation

Table 1 — Common preparation techniques for nanosponges (2010–2019)

Method	Typical reagents / principle	Advantages	Representative refs
Solvent-free melt condensation	Cyclodextrin + anhydride/carbonyl crosslinker, melt & heat	No organic solvent, scalable	Sherje et al., 2017 (review). PubMed
Solution crosslinking (solvent)	CD dissolved in solvent + crosslinker (e.g., diphenyl carbonate)	Fine control of crosslink density	BJOC review; various experimental papers. PMC
Emulsion solvent evaporation	Drug + polymer (ethylcellulose) in organic solvent emulsified in water, solvent removal => nanosponge micro/nanoparticles	Good for polymeric NS and hydrophobic drugs	Method descriptions and formulations (reviewed). AJS Online
Interfacial polymerization / nanoprecipitation	Rapid polymerization at interface or precipitation	Small particle sizes, reproducible	Experimental reports in 2014–2019 literature. ScienceDirect

. Characterization Techniques

Standard characterization suite used across 2010–2019 studies:

• Particle size & polydispersity (DLS / laser diffraction).
• Surface charge (zeta potential).
• Morphology (SEM / TEM).
• Porosity / surface area (BET where applicable).
• Thermal behavior (DSC, TGA) to assess crystalline ↔ amorphous transitions and drug dispersion).
• Fourier-transform infrared spectroscopy (FTIR) and Raman for interactions and confirmation of crosslinking.
• X-ray diffraction (XRD) for changes in drug crystallinity after encapsulation.
• Entrapment efficiency (EE %) and drug loading (content) by validated assay (HPLC/UV).
• In vitro release (buffered media, often pH-varied), sometimes with kinetic modeling (Higuchi, Korsmeyer–Peppas).

Representative experimental results (2010–2019): reported outcomes

To give a concise overview of experimental performance across reported studies, Table 2 compiles representative values (particle size, EE%, key findings) from selected papers published within 2010–2019.

Table 2 — Selected experimental studies (2010–2019) — formulation & outcomes

Study (year)	Nanosponge type / crosslinker	Drug / payload	Particle size (nm)	Entrapment efficiency (EE%)	Key experimental outcome
Sherje et al., review (2017) — summary of literature	β-CD nanosponges (various crosslinkers)	Multiple drugs (review)	reported nanoscale ranges (100–1000 nm)	Wide EE ranges (30–90% depending on drug & method)	Reviews show tunable release & improved solubility.
THCl nanosponges (2019, factorial study)	Cyclodextrin-based NS formulated into topical hydrogel (crosslinker varied)	Terbinafine hydrochloride (THCl)	mostly nanosize range (specific formula dependent)	33.1–90.1% (range across formulations)	Optimized hydrogels gave >90% release by 8 h and improved in vivo skin deposition & antifungal activity.
Pyromellitic dianhydride (PMDA) CD-NS (curcumin) — 2019 thesis/paper	β-CD crosslinked with PMDA	Curcumin	NS and curcumin-loaded NS: particle sizes reported ~200–500 nm (formulation dependent)	Encapsulation efficiencies up to >70% for favorable CD:drug ratios	Improved aqueous apparent solubility and controlled release vs free curcumin.
Celecoxib nanosponge formulations (reported in 2017–2018 literature)	β-CD / NN-methylene bisacrylamide NNs	Celecoxib (poorly soluble NSAID)	Nanoscale particles suitable for topical/peroral forms	Substantial increases in solubility and dissolution rate (literature summary)	NS improved celecoxib solubility & in vitro dissolution vs plain drug.
Diversity / polymer variations (2019 review & experimental)	β-CD variants and polymeric NS	Various actives (antifungals, NSAIDs, anticancer agents)	Size and EE highly dependent on crosslinker ratio	EE and release profiles tunable via crosslink density	Raman/FTIR/XRD used to demonstrate drug inclusion vs molecular dispersion.

Mechanisms of drug loading and release

• Inclusion complexation: Cyclodextrin cavities can host hydrophobic moieties of guest molecules; this is responsible for increases in apparent solubility.
• Non-inclusion entrapment: Drug molecules may be trapped in the polymeric mesh or adsorbed in pores, especially for polymeric nanosponges.
• Release control: Controlled by crosslink density (mesh size), degree of swelling, surface functionalization, and drug–polymer interactions; typical release kinetics can be diffusion-controlled, swelling-controlled, or a combination.

Applications demonstrated (2010–2019)

• Oral / parenteral drug delivery: Improved aqueous solubility and bioavailability for poorly soluble drugs (examples reported include itraconazole, celecoxib and others summarized in reviews).
• Topical & dermal delivery: Enhanced skin deposition and prolonged action for antifungals (e.g., terbinafine hydrochloride hydrogel based on NS).
• Cosmetics and fragrances: Stabilization and controlled release of volatile/fragrance molecules (discussed across reviews).
• Environmental remediation & catalysis: Adsorption/removal of pollutants and immobilization of enzymes (early experimental reports & reviews).

Safety and biodegradability

Cyclodextrin-based nanosponges are generally considered low in toxicity because cyclodextrins themselves are well-tolerated and the crosslinkers used can yield biocompatible linkages; however, final safety depends on crosslinker type and residual reagents. Several in vitro cell assays and limited in vivo tolerability studies up to 2019 reported acceptable profiles, but

Challenges & gaps (2010–2019)

• Scalability & reproducibility: Some solvent-based methods face scale-up challenges; solvent-free approaches are promising but require optimization.
• Regulatory acceptance: Limited clinical translation as of 2019; more GLP toxicology and manufacturing data required.
• Standardization: Lack of harmonized methods for characterizing porosity, crosslink density and predicting in vivo performance.

Results & discussion

Across the 2010–2019 literature, the following conclusions are consistently supported:

1. Solubility & dissolution: Nanosponges often increase apparent aqueous solubility and dissolution rates of poorly water-soluble drugs (many reports summarize >10-fold improvements depending on drug and formulation).
2. Encapsulation efficiency (EE): EE% is formulation dependent; reported experimental ranges in 2010–2019 span roughly 30% to >90%, with topical hydrogel formulations reporting wide ranges based on formulation variables. Example: THCl EE ranged from 33.05% to 90.10% across formulations in a 2019 factorial study.
3. Particle size: Typical nanoscale sizes reported are roughly 100–500 nm, but preparation method and crosslinking determine the final distribution.
4. Release control: Crosslinker type and degree of crosslinking reliably modulate release kinetics — tighter networks slow release, more porous networks accelerate it.

These literature-derived “results” paint a picture of tunable, effective nanoscale carriers with demonstrated in vitro/in vivo improvements for several actives — but with variable metrics that require formulation-by-formulation optimization.

Conclusions & perspectives

Between 2010 and 2019, nanosponges—particularly cyclodextrin-based systems—emerged as a robust platform for addressing solubility, stability and controlled release problems for a wide range of actives. The body of work through 2019 shows clear potential in topical, oral and other administration routes, but translational challenges (scale-up, full safety dossiers, regulatory strategy) remained before widespread clinical deployment. Future directions identified in the 2010–2019 literature include targeted functionalization, scale-up of solvent-free synthesis, and systematic toxicology studies.

References

1. Sherje, A. P., Dravyakar, B. R., Kadam, D., & Jadhav, M. (2017). Cyclodextrin-based nanosponges: A critical review. Carbohydrate Polymers, 173, 37–49. doi:10.1016/j.carbpol.2017.05.086.
2. Trotta, F., Zanetti, M., & Cavalli, R. (2012). Cyclodextrin-based nanosponges as drug carriers. Beilstein Journal of Organic Chemistry, 8, 2091–2099. doi:10.3762/bjoc.8.235.
3. Tejashri, P., & Amrita, P. (2013). Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery. Expert Opinion on Drug Delivery (review). (2013/2014).
4. Cavalli, R., Trotta, F., & Ari, C. (2012). (Representative early experimental reports and methodology summarized in subsequent reviews; see Trotta 2012 & Sherje 2017 for details.) — (See reviews above for primary Cavalli experimental citations).
5. Mendes, C., Meirelles, G. C., Barp, C. G., Assreuy, J., Silva, M. A. S., & Ponchel, G. (2018). Cyclodextrin-based nanosponge of norfloxacin: intestinal permeation enhancement and improved antibacterial activity. Carbohydrate Polymers, 195, 586–592.
6. Gangadharappa, H. V., Prasad, S. M. C., & Singh, R. P. (2017). Formulation, in vitro and in vivo evaluation of celecoxib nanosponge hydrogels for topical application. Journal of Drug Delivery Science and Technology, 41, 488–501. (2017).
7. (2019). Pyromellitic dianhydride crosslinked β-cyclodextrin nanosponges for curcumin controlled-release: physicochemical characterization and cytotoxicity investigations. (Article / thesis reporting PMDA-crosslinked CD-NS and curcumin encapsulation; EE and size data reported). (2019).
8. (2017). Formulation of β-cyclodextrin based nanosponges of itraconazole for topical delivery — experimental study reporting improved solubility and topical gel formulations (see literature summaries and experimental reports 2013–2017).
9. Cavalli, R., et al. (2010–2014 range; frequently cited). Carbonate and dianhydride crosslinked cyclodextrin nanosponges: methodology and drug loading examples (itraconazole, dexamethasone, flurbiprofen, etc.). (See reviews above for primary refs and original Cavalli experimental papers).
10. Tejashri, A., & others. (2013). Cyclodextrin-based nanosponges for pharmaceutical use: a review. Acta Pharmaceutica (or similar review summaries 2013–2014).
11. Additional representative experimental papers and formulation reports (2014–2019) — examples you can consult for numeric experimental details, methods and data used to build Tables in the review:
12. Norfloxacin nanosponge (Mendes et al., Carbohydr. Polym. 2018).
13. Celecoxib nanosponge hydrogels (Gangadharappa et al., 2017).
14. Curcumin PMDA-CD nanosponge (2019 experimental report / thesis).
15. Several method/comparison reviews summarizing EE%, size ranges, crosslinkers and release behavior: Sherje 2017; Trotta 2012; 2013–2014 reviews.