Development Of A Bone Targeted Paclitaxel Nanocrystal Formulation For Treatment Of Tumor Bone Metastasis

Multidrug resistance (MDR) is one of the major barriers for chemotherapy treatment of many cancers. However, some non-ionic surfactants, for example Brij, have been shown to restore the sensitivity of MDR cells to such drugs. Bone is among the most common sites of metastasis in cancer patients and overexpressing multidrug resistance related genes were found in some metastatic or invasive cancer cells. Thus we aimed to develop a drug delivery system both targeting to tumor bone metastasis microenvironment and overcoming drug resistance. Previously, Brij 78 was reported to stabilize paclitaxel nanocrystals (PNCs) and to overcome P-gp mediated multidrug resistance. Then we designed and synthesized a pamidronate-modified Brij 78 (Pa-Brij78) as a bone targeting surfactant. Using Pa-Brij78, we fabricated the Pa surface functionalized paclitaxel nanocrystals (Pa-PNCs). The sizes of Pa-PNCs with different ratios of PTX to Pa-Brij78 were all less than 200 nm, and the PDCs were less than 0.3, suggesting monodispersity of the nanocrystals. The nanocrystal-formulations were designed to target bone through Pa specific interaction with hydroxyapatite (HA), a major component of bone and to overcome chemoresistance through Brij78. The Pa-PNCs exhibited a stronger HA binding affinity than non-targeted Brij78/PTX nanocrystals (B-PNCs). Furthermore, our data indicate that the Pa-PNCs were able to bind to HA even under the physiological calcium concentration in human serum. Similar to B-PNCs, Pa-PNCs partially overcome drug resistance in resistant breast cancer MCF-7/adr cells. Finally, in vitro efficacy study showed that bone targeted Pa-PNCs induced higher cytotoxicity to cancer cells which were co-cultured with HA than non-targeted B-PNCs. In conclusion, the novel Pa-PNCs is a promising drug delivery system which has the potential to treat tumor bone metastasis.