Evaluation of the anticancer potential of CD44 targeted vincristine nanoformulation in prostate cancer xenograft model: a multi-dynamic approach for advanced pharmacokinetic evaluation

Abstract

Abstract The in vivo anticancer potential of vincristine (VC) loaded, thiolated chitosan-based nanoformulation (NFs) with an outer hyaluronic acid (VC-loaded in TCs-HA) coating was studied in prostate cancer (PC) xenograft in the immunosuppressed rat model induced by PC3 cell lines. Our previous study has already reported the in vitro efficacy of the said NFs. The ADMET Predictor (TM) Cloud version 10.4.0.5, 64-bit, was used to simulate VC's physicochemical and pharmacokinetic parameters. The percentage of encapsulation efficiency of VC by direct and indirect methods was 81.5 and 90%, respectively. Plasma samples from healthy rats showed improved pharmacokinetic and bioavailability profiles of NFs compared to VC injection via HPLC. The haemolytic analysis of NFs showed two times lesser toxicity to red blood cells. Xenograft rats showed maximum tumour volume up to 235 ± 0.02 mm3 with increased body weight, and it was reduced by 56 ± 0.01 to 107.3 ± 0.03 mm3 during the whole treatment by NFs compared to pure VC. The histopathology of the NFs group showed less malignancy with angiogenesis and significantly less metastasis to the liver and kidney. ELISA showed high expression of apoptotic biomarkers, including Bax, cleaved Caspase 3, and cleaved PARP, while the expression of BCL2, Caspase 3, COX-II, NFκB, and TNF-α was reduced. Immunohistochemical analysis also revealed that post-NF administration, cytoplasmic expressions of TNF-α and COX-II were reduced, as were nuclear expressions of NFκB. Thus, the prepared chemotherapeutic NFs were a comparatively potent oncolytic agent, safe with lesser off-target toxicity, and had an improved pharmacokinetic and bioavailability profile.

Keywords

• ADMET predictor
• Haemolytic analysis
• HPLC analysis
• Immunosuppression
• Nanoformulation
• Prostate cancer model