Styrene maleic acid-encapsulated paclitaxel micelles: antitumor activity and toxicity studies following oral administration in a murine orthotopic colon cancer model

Abstract

Oral administration of paclitaxel (PTX), a broad spectrum anticancer agent, is challenged by its low uptake due to its poor bioavailability, efflux through P-glycoprotein, and gastrointestinal toxicity. We synthesized PTX nanomicelles using poly(styrene-co-maleic acid) (SMA). Oral administration of SMA-PTX micelles doubled the maximum tolerated dose (60 mg/kg vs 30 mg/kg) compared to the commercially available PTX formulation (PTX [Ebewe]). In a murine orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 mg/kg and 60 mg/kg reduced tumor weight by 54% and 69%, respectively, as compared to the control group, while no significant reduction in tumor weight was observed with 30 mg/kg of PTX (Ebewe). In addition, toxicity of PTX was largely reduced by its encapsulation into SMA. Furthermore, examination of the tumors demonstrated a decrease in the number of blood vessels. Thus, oral delivery of SMA-PTX micelles may provide a safe and effective strategy for the treatment of colon cancer.

Keywords:

• oral delivery
• anticancer nanomedicine
• CT-26
• enhanced permeability and retention (EPR) effect
• HUVEC
• antiangiogenic

Supplementary materials

Figure S1 The organ weight of the mice after treatment with MTDs of SMA-PTX micelles and PTX (Ebewe).

Notes: For the single-dose toxicity, the mice were administered a single dose of SMA-PTX micelles 120 mg/kg or PTX 60 mg/kg. For the repeated-dose toxicity, the mice were administered either SMA-PTX micelles 60 mg/kg or PTX 30 mg/kg every alternate day for 15 days. The (A) liver, (B) spleen, (C) kidney, (D) heart, and (E) lung weights were described as a percent of body weight. n=3 for all the treatment groups. The organ weight was analyzed using a one-way ANOVA coupled with Bonferroni post hoc test with *P<0.05 as the required statistical significance.

Abbreviations: MTD, maximum tolerated dose; SMA, poly(styrene-co-maleic acid); PTX, paclitaxel; ANOVA, analysis of variance.

Table S1 Plasma ALT activity and creatinine levels after treatment with single and repeated MTDs of SMA-PTX micelles and PTX

Acknowledgments

This work has been supported by 2014 University of Otago Research Grant (110273.01.R.LM) to KG.

Disclosure

The authors report no conflicts of interest in this work.