Chondroitin Sulfate-Derived Paclitaxel Nanocrystal via π–π Stacking with Enhanced Stability and Tumor Targetability

Abstract

Nanocrystals with high drug loading have become a viable strategy for solubilizing drugs with poor aqueous solubility. It remains challenging, however, to synthesize nanocrystals with sufficient stability and targeting potential. Here, we report a novel nanocrystal platform synthesized using paclitaxel (PTX) and Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-AEEA)conjugated chondroitin sulfate (CS) (CS-Fmoc) via π−π stacking to afford a stable formulation with CD44 targetability (

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“…Regarding the 1 H NMR spectrum of CS-NH 2 (Figure S2b), structural modifications were validated at peaks of 1.95 (a, 3H, CH 3 –CONH 2 ), and 2.34 ppm (b, 4H, NH 2 (CH 2 ) 2 NHCO). As for CS-Fmoc (Figure S3b), the appearance of the signature peak at 7.33–7.99 ppm demonstrated that Fmoc-AEEA was successfully introduced into CS-NH 2 . Meanwhile, the substitution degree of Fmoc-modified CS was about 26.6%.…”

“…CS-Fmoc was synthesized via a two-step amide reaction as previously described . Briefly, 10 mL of 51.5 mg/mL CS solution was mixed with 1.342 g of EDC and 0.845 g of NHS to activate the carboxyl group, which then dripped it into the 5.58 mL ethylenediamine solution on an ice bath and stirred at room temperature for 3.5 h, then dialyzed, and lyophilized.…”

“…LD nanocomposites were prepared with a bottom-up method . Briefly, 0.3 mL of 7 mg/mL LD stock solution in anhydrous ethanol was added dropwise into 2 mL of 8 mg/mL CS-Fmoc in purified water upon stirring for 30 min.…”

“…CS-Fmoc was synthesized via a two-step amide reaction as previously described. 14 Briefly, 10 mL of 51.5 mg/mL CS solution was mixed with 1.342 g of EDC and 0.845 g of NHS to activate the carboxyl group, which then dripped it into the 5.58 mL ethylenediamine solution on an ice bath and stirred at room temperature for 3.5 h, then dialyzed, and lyophilized. Second, 4 mL of 52 mg/mL Fmoc-AEEA solution in DMF was mixed with 310.6 mg of EDC, 159.4 mg of NHS, and 9 mL of 11.1 mg/mL CS-NH 2 solution in formamide, which was then poured into the former Fmoc-AEEA solution.…”

“…As for CS-Fmoc (Figure S3b), the appearance of the signature peak at 7.33−7.99 ppm demonstrated that Fmoc-AEEA was successfully introduced into CS-NH 2 . 14 Meanwhile, the substitution degree of Fmoc-modified CS was about 26.6%.…”