A facile method for synthesizing water-soluble and superior sustained release anti-HIV prodrug SCs–d4T

• Sulphonated chitosan–stavudine (SCs–d4T) was mildly synthesized with SO3·Py complex.
• SCs–d4T demonstrated superior anti-HIV activity and sustained release ability.
• SCs–d4T showed superior water-solubility (106-bold of chitosan-stavudine solubility).
• The mainly released d4T-P-H revealed ~ 55-fold higher anti-HIV activity than stavudine.

To efficiently deliver stavudine (d4T) for AIDS therapy, chitosan–stavudine conjugate (Cs–d4T) was synthesized. However, its poor water-solubility limited its clinical application. In this study, a sulphonated chitosan–stavudine conjugate (SCs–d4T) was synthesized with a mild SO3·Py complex sulphonation strategy. Chemical characteristics and morphology of Cs–d4T and SCs–d4T were performed by NMR, XRD, FTIR, ICP-AES and SEM. SCs–d4T demonstrated satisfactory solubility (106-bold of Cs–d4T solubility), good anti-HIV activity (6-fold of d4T anti-HIV activity), and well sustained release ability. The major release product O-isopropyl-5′-H-phosphonate of d4T (d4T-P-H) showed higher anti-HIV activity than d4T. For further evaluating the influence of linker and sulphonation strategy on anti-HIV activity, chitosan grafted with d4T by succinyl linker (Cs–sd4T) and SCs–d4T sulphonated by oleum were also prepared. The result showed that the O-isopropyl monophosphate linker of Cs–d4T and SO3·Py complex sulphonation strategy revealed higher anti-HIV activity than succinyl linker of Cs–sd4T and oleum sulphonation strategy, respectively.

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