A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders

Abstract

Gels are attractive candidates for drug delivery because they are easily producible while offering sustained and/or controlled drug release through various mechanisms by releasing the therapeutic agent at the site of action or absorption. Gels can be classified based on various characteristics including the nature of solvents used during preparation and the method of cross-linking. The development of novel gel systems for local or systemic drug delivery in a sustained, controlled, and targetable manner has been at the epitome of recent advances in drug delivery systems. Cross-linked gels can be modified by altering their polymer composition and content for pharmaceutical and biomedical applications. These modifications have resulted in the development of stimuli-responsive and functionalized dosage forms that offer many advantages for effective dosing of drugs for Central Nervous System (CNS) conditions. In this review, the literature concerning recent advances in cross-linked gels for drug delivery to the CNS are explored. Injectable and non-injectable formulations intended for the treatment of diseases of the CNS together with the impact of recent advances in cross-linked gels on studies involving CNS drug delivery are discussed.

Keywords: central nervous system; cross-linked gels; injectable cross-linked gels; non-injectable cross-linked gels; spatial drug delivery.

Figure 1

The blood-brain barrier and drug transporters in the capillary endothelial cells. (Blue arrows: Flow of molecules through influx transporters into the brain parenchyma from the blood vessel; Red arrows: Outward flow of molecules through efflux transporters from the brain parenchyma to the blood vessel) [Adapted from [17] in terms of the Creative Commons Attribution License (CC BY 3.0)].

Figure 2

Classifications of cross-linked gels based on the nature of solvents.

Figure 3

Chemical structures and molecular weights (MW) of naturally derived polymers used in the manufacture of cross-linked gels.

Figure 4

Chemical structures and molecular weights (MW) of various synthetic polymers used to manufacture cross-linked gels.

Figure 5

Chemical structures and molecular weights (MW) of various natural crosslinkers used to manufacture cross-linked gels.

Figure 6

Chemical structures and molecular weights (MW) of various synthetic crosslinkers used to manufacture cross-linked gels.

Figure 7

The various mechanisms of cross-linking that result in gelation [Obtained and reproduced without any changes from [87] and The Royal Society of Chemistry in accordance with Creative Commons Attribution License (CC BY)].

Figure 8

Schematic of the composition of nanocomposite cross-linked gels with a hydrogel dispersion matrix and drug-loaded nanoparticles. [Obtained and re-produced without any changes from [172] and Nanomaterials MDPI in accordance with Creative Commons Attribution License (CC BY 4.0)].

Figure 9

Schematic of drug release from nanogels in response to various stimuli [Obtained and reproduced without any changes from [183] and Gels MDPI in accordance with Creative Commons Attribution License (CC BY 4.0)].

Figure 10

Pictorial illustration of the in-situ gel formation following the administration of drug loaded cross-linked gel for CNS conditions. Key: IN = Intranasal injection; IC = Intracranial; SC = Subcutaneous Injection, IV = Intravenous and IS = Intraspinal.