Hyaluronic acid capped cubosomes co-loaded with antitumor agents towards the treatment of colorectal cancer

Colorectal cancer (CRC) is the 3rd most lethal type of cancer-linked deaths worldwide. Combination chemotherapy offers a better therapeutic response against CRC than single drug therapy. The purpose of this study was to successfully encapsulate Capecitabine (CAP) and Regorafenib (REG) in liquid crystal nanoparticles or cubosomes (CUBs) matrix for targeting CRC following intravenous (IV) administration. Active targeting of the CUBs was achieved by surface capped hyaluronic acid (HA) owing to its binding affinity with complex differentiation (CD-44) receptors on cancer stem cells. The HA-capped REG-CAP co-loaded CUBs (HA-REG-CAP-CUBs) were prepared via the Top-bottom method and optimized using Design Expert^®. The optimized formulation had a mean particle size of 196.1 ± 1.4 nm, polydispersity index (PDI) of 0.231 ± 0.03, zeta potential (ZP) of -25.5 ± 5.2 mV and entrapment efficiency (%EE) of REG and CAP was 78.56 ± 2.1% and 76.48 ± 2.5%, respectively. Morphological studies revealed uniform distribution and smooth cubic texture of the CUBs. Solid state characterizations suggested no interactions among the ingredients of the prepared system. The HA-REG-CAP-CUBs showed a significantly reduced HCT116 (4.39 ± 1.30%) and H29 (2.39 ± 0.53%) cell viability in 48 h. The pharmacokinetics study revealed a controlled release profile of CAP and REG with excellent biodistribution and prolonged plasma circulation over 48 h, thereby leading to 20.3 ~ and 10.2 ~ fold improved bioavailability, respectively. Histopathological studies demonstrated the safety of the HA-REG-CAP-CUBs towards vital organs in an animal model. It is concluded that HA capped CUBs may be suitable carriers for the targeted delivery of combinational antitumor drugs.