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

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 (PTX NC@CS-Fmoc). The PTX NC@CS-Fmoc exhibited rodlike shapes with an average hydrodynamic size of 173.6 ± 0.7 nm (PDI = 0.11 ± 0.04) and a drug loading of up to 31.3 ± 0.6%. Next, PTX NC@CS-Fmoc was subjected to lyophilization in the absence of cryoprotectants for long-term storage, and after redispersion, PTX NC@CS-Fmoc displayed an average hydrodynamic size of 205.3 ± 2.9 nm (PDI = 0.15 ± 0.01). In murine Panc02 cells, PTX NC@CS-Fmoc showed higher internalization efficiency than that of PTX nanocrystals without CS modification (PTX NC@F127) (P < 0.05) or that of CS-Fmoc micelles (P < 0.05). Moreover, PTX NC@CS-Fmoc appeared to accumulate in both lysosomes and Golgi apparatus, while CS-Fmoc micelles accumulated specifically in the Golgi apparatus. In the orthotopic Panc02 tumor-bearing mice model, PTX NC@CS-Fmoc showed higher tumor-specific accumulation than CS-Fmoc micelles, which also demonstrated comparable tumor growth inhibition as to Nab-PTX. Overall, the CS-Fmoc-derived nanocrystals represent a neat and viable formulation strategy for targeted chemotherapy with great potential for translational studies.