What Makes Cyclodextrin Polymers the Future of Advanced Drug Carriers?

Cyclodextrin polymers (CDPs) have been of great interest in drug delivery because of their structural and functional versatility. Such polymers bring the inclusion and smart functionality of CDs with the smart functionality of polymers and can be used for a variety of purposes in the controlled, targeted, and stimuli-responsive delivery of therapeutics. CDPs can be categorized into four main structural types: CD-based polyrotaxanes (CD-PRs), grafted CD polymers (G-CDPs), cross-linked CD polymers (C-CDPs), and star-shaped CD polymers (star-CDPs). Each of these structural types demonstrates unique properties, making them suitable for various advanced drug delivery strategies.

CD-PRs as Drug Carriers

CD-PRs consist of CD molecules threaded onto linear guest polymers, with bulky end groups capping the polymer chains to prevent CD dethreading. This threaded architecture endows CD-PRs with distinctive features, including multivalent hydroxyl groups that regulate drug release rates and the dynamic mobility of CDs along the polymer chain axis, enhancing interaction with biological receptors. CD-PRs have shown excellent biocompatibility and chemical diversity, making them suitable carriers for specific drugs. The PR prodrug (PR-TPGS-HCPT) obtained by attaching D-α-tocopheryl PEG-1000 succinate (TPGS) and 10-hydroxycamptothecin (HCPT) to an α-CD-based PR exerted anticancer effects, and can, therefore, be used as an anticancer drug.

Fig.1 Structure of PR-TPGC-HCPT and findings from in vitro and in vivo experimental studies^[1].

Drug encapsulation in CD-PRs typically involves either direct attachment to the CD cavity or physical entrapment within micellar or vesicular structures formed by the polymers. The size and molecular weight of the aggregates significantly influence drug delivery efficiency. Furthermore, stimuli-responsive bonds and degradable linkages integrated into CD-PRs enable precise control over drug release in response to environmental cues, such as pH, temperature, or light, while enhancing intracellular targeting through receptor-mediated endocytosis.

G-CDPs as Drug Carriers

G-CDPs are formed by grafting CDs onto polymer backbones or substrates, creating a platform that enhances system biocompatibility and facilitates drug loading through host-guest interactions. G-CDPs can self-assemble into micelles or vesicles with tunable hydrophilic-hydrophobic ratios, enabling the formation of controlled drug carriers with tailored sizes.

These polymers have been utilized to prepare advanced nanocomposites, such as β-CD-grafted mesoporous silica particles (MSPs). In these systems, CDs act as molecular gates to retain drugs within the MSP matrix, releasing them under stimuli like ultraviolet light or glutathione. For example, β-CD-grafted MSPs have demonstrated efficacy in the controlled release of doxorubicin (DOX), exhibiting spatiotemporal release characteristics suitable for targeted chemotherapy of hepatocellular carcinoma.

Fig.2 MSP-CD coupling strategies investigated for controlled drug release.^[2].

C-CDPs as Drug Carriers

C-CDPs are synthesized through the cross-linking of CDs with co-monomers, forming either insoluble gel networks or nanoscale hydrogels. These cross-linked structures provide robust platforms for drug encapsulation, offering enhanced stability, solubility, and bioavailability of active compounds.

Nanoscale C-CDPs, such as those formed from β-CD and pyromellitic dianhydride, exhibit superior oral bioavailability for drugs like rosuvastatin, demonstrating favorable pharmacokinetics in vivo. Similarly, epoxy-amine cross-linked C-CDPs have been applied to encapsulate poorly soluble drugs like sorafenib, resulting in reduced systemic toxicity and increased therapeutic efficacy. However, the specific localization of drugs within the CD cavity or the cross-linked network often remains unclear, necessitating further investigation into encapsulation mechanisms.

Fig.3 Schematic description of the C-CDP, AdRGD and DOX assembly^[3].

Star-CDPs as Drug Carriers

Star-CDPs feature a CD core with multiple polymer arms, offering a unique architecture for drug delivery. These polymers can form stable unimolecular micelles with desirable properties, such as biodegradability, stimuli-responsiveness, and controlled drug release.

For example, star-shaped CDPs constructed from β-CD cores and amphiphilic block copolymers, such as poly(ε-caprolactone) (PCL) and polyethylene glycol (PEG), exhibit enhanced drug encapsulation efficiency and pH-triggered release behaviors. These micelles have shown promise for delivering hydrophobic drugs like DOX, achieving sustained release with minimal cytotoxicity. The molecular weight and arm composition of star-CDPs significantly influences micelle size, encapsulation efficiency, and drug loading capacity.

Fig.4 Schematic illustration of the design of β-CD-based amphiphilic block copolymers using ROP and the subsequent ATRP and the formation of unimolecular micelles in water for drug delivery.^[4].

Comparative Overview of CDP Types

The following table highlights the distinguishing characteristics of the four CDP types and their applications as drug carriers.

Future Perspectives

CDPs exhibit tremendous potential as advanced drug carriers due to their structural diversity and functional versatility. G-CDPs, C-CDPs, and star-CDPs, with their vacant CD cavities, enable efficient drug encapsulation and controlled release through host-guest chemistry. Meanwhile, CD-PRs leverage the multivalent hydroxyl groups of CDs and the dynamic mobility of their threaded architecture to achieve selective and stimuli-responsive drug delivery.

Emerging trends suggest that unimolecular carriers, such as star-CDPs, represent the next frontier in drug delivery due to their robustness, resistance to environmental changes, and prolonged circulation in vivo. The grafting of functional molecules, such as tumor-targeting ligands, onto CDPs further expands their therapeutic scope, making them ideal candidates for precision medicine applications. Continued research into optimizing CDP designs, enhancing biocompatibility, and elucidating encapsulation mechanisms will undoubtedly advance the clinical translation of these innovative drug carriers.

It should be noted that our our products and services are for research use only, not for clinical use.