Deciphering the Impact of Hyaluronic Acid Grafting Density and Molecular Weight on Paclitaxel Liposome in CD-44 Receptor Targeting

Abstract

Purpose

The biggest challenge in developing efficacious anticancer formulations is to improve their targeting specificity and reducing toxicity. For this purpose, HA anchored paclitaxel liposomes (HA-PTX-LIP) were fabricated using synthesized conjugate HA-DSPE (HA Molecular Weight- 12, 76, and 160–200 kDa).

Methods

Maximum in vitro cell targeting was observed with 160–200 kDa HA-PTX-LIP compared to 11 and 76 kDa HA-PTX-LIP, indicating HA’s MW-dependent HA-CD44 binding and internalization. Further, the effect of grafting density (HA/L ratio- μg HA-DSPE/μmol Lipid) of 160–200 kDa HA-DSPE on tumor targeting was evaluated in vitro at three different levels (low-20 μg/μmol, mid-50 μg/μmol, and high- 100 μg/μmol).

Results

HA/L -100 exerted the highest in vitro tumor-targeting potential. Upon in vivo evaluation, 160–200 kDa HA-PTX-LIP (HA/L-100) exhibited 18.11 and 27.4-fold improved AUC and MRT, respectively, compared to the marketed formulation. Moreover, it showed improved biodistribution with less organ AUC (liver, spleen, and kidney) when compared with the marketed formulation. A significant reduction in ROS generation suggested decreased tumor incidence. Compared to the control and marketed formulations, the modified liposome showed increased targeting potential in the in vivo antitumor efficacy on the ovarian tumor model, resulting in a 4.88 and 2.81-fold reduction in tumor volume. Compared to the control and commercial formulations, tumor weight was also reduced by 1.48 and 1.11-fold. Animal survival was 100 percent with 160–200 kDa HA-PTX-LIP (HA/L-100) without significant weight loss.

Conclusion

The findings suggest the possibility of rationalizing HA's molecular weight and grafting density for efficient in vivo ovarian tumor targeting.

Graphical Abstract