Development and physicochemical characterisation of a cremophor-free paclitaxel–calix[۶]arene inclusion complex with increased apparent solubility and in vitro cytotoxicity in mia-pa-ca-۲ pancreatic cancer cells

Objective(s): The current research focused on the development of a Cremophor-free Paclitaxel (PTX)–Calix[۶]arene (C۶A) inclusion complex. To determine its apparent aqueous solubility and in vitro cytotoxicity against MIA-Pa-Ca-۲ pancreatic cancer cells.Materials and Methods: An optimised PTX–C۶A inclusion complex (۳:۵ mole ratio) was synthesised through physical mixing, and the drug loading was estimated using a validated HPLC technique. The physical characterisation of the inclusion complex was performed using FTIR, DSC, XRD, FESEM, and EDX techniques. The aqueous solubility of the complexes was comparatively studied at pH ۶.۸ and ۷.۴ using the UV-visible spectrophotometer technique, and their cytotoxicity in vitro against the MIA-Pa-Ca-۲ cell line was evaluated.Results: The optimised ۳:۵ inclusion complex (IC) showed ۸۴.۷ ± ۰.۲ % (n=۳) drug content, which was calculated using the HPLC technique. The inclusion complex exhibited higher apparent aqueous solubility than free PTX at both pH ۶.۸ and ۷.۴, with a more pronounced enhancement at pH ۶.۸. XRD analysis suggested partial amorphisation of the inclusion complex, while FESEM examination revealed predominantly spherical particles with diameters ranging from approximately ۴۵–۶۰ nm. The FTIR spectra showed no significant variation in the characteristic absorption bands after ۱۲ weeks of storage, indicating no detectable changes in the characteristic FTIR profile during storage. In addition, the inclusion complex showed in vitro cytotoxic activity against MIA-Pa-Ca-۲ cells with an IC۵۰ of ۵.۶۴۱ nM, which was better than that of PTX (۶.۷۰۵ nM) and C۶A (۹.۴۹۸ nM).Conclusion: The apparent aqueous solubility of the PTX–C۶A inclusion complex was slightly higher than that of PTX, accompanied by partial amorphisation of PTX. It also showed higher in vitro cytotoxic activity against MIA-Pa-Ca-۲ cells as compared to free PTX. The overall anticancer activity of the inclusion complex could be affected by the intrinsic cytotoxicity of Calix[۶]arene; however, further investigation is needed to confirm this contribution.

کلیدواژه ها:

Calix[۶]arene ، Cremophor&ndash ، free formulation ، Paclitaxel ، Pancreatic Cancer ، Supramolecular chemistry