Revitalizing Colchicine: Novel Delivery Platforms and Derivatives to Expand Its Therapeutic Potential

Abstract

Colchicine is a potent alkaloid with well-established anti-inflammatory properties. It shows significant promise in treating classic immune-mediated inflammatory diseases, as well as associated cardiovascular diseases, including atherosclerosis. However, its clinical use is limited by a narrow therapeutic window, dose-limiting systemic toxicity, variable bioavailability, and clinically significant drug-drug interactions, partly mediated by modulation of P-glycoprotein and cytochrome P450 3A4 metabolism. This review explores advanced delivery strategies designed to overcome these limitations. We critically evaluate lipid-based systems, such as solid lipid nanoparticles, liposomes, transferosomes, ethosomes, and cubosomes; polymer-based nanoparticles; microneedles; and implants, including drug-eluting stents. These systems ensure targeted delivery, improve pharmacokinetics, and reduce toxicity. Additionally, we discuss chemical derivatization approaches, such as prodrugs, codrugs, and strategic ring modifications (A-, B-, and C-rings), aimed at optimizing both the efficacy and safety profile of colchicine. Combinatorial nanoformulations that enable the co-delivery of colchicine with synergistic agents, such as glucocorticoids and statins, as well as theranostic platforms that integrate therapeutic and diagnostic functions, are also considered. These innovative delivery systems and derivatives have the potential to transform colchicine therapy by broadening its clinical applications while minimizing adverse effects. Future challenges include scalable manufacturing, long-term safety validation, and the translation of research into clinical practice.

Keywords: codrug; colchicine; drug delivery systems; immune-mediated inflammatory diseases; prodrug.

Figure 1

Chemical structure of colchicine (adapted from [28]).

Figure 2

Mechanism of action of colchicine (adapted from [28]).

Figure 3

The diversity of colchicine delivery systems.

Figure 4

Synthesis of thiocolchicine and 1,2,3-demethylthiocolchicine (adapted from [27]).

Figure 5

Variation of the C-1 substituent of colchicine (adapted from [27]).

Figure 6

Synthesis of 4-chloro-, 4-bromo-, and 4-iodocolchicine (adapted from [169]).

Figure 7

Synthesis of deacetylthiocolchicine from thiocholcine derivative (adapted from [27]).

Figure 8

Synthesis of triazoles derived from colchicine, allocolchicine, and N-acetylcolchinol (adapted from [27,187]).

Figure 9

Examples of colchicinoids synthesized by “click” conjugation (adapted from [186,188]).

Figure 10

Structural modifications carried out on colchicine to produce 7-triazoles of 10-N-methylaminocolchicine (adapted from [190]).

Figure 11

Synthesis of N-acetylcolchinol from colchicine (adapted from [27]).

Figure 12

Substitution with thiomethyl groups in C-10 (adapted from [195]).

Figure 13

Colchicine derivatives with amino or related functional groups at C-10 (adapted from [196]).