Design and evaluation of albumin nanoparticles for the delivery of a β-tubulin polymerization inhibitor

One of the major limitations of chemotherapy in cancer treatment is the side effects of anti-cancer drugs, which are due to their toxicity, their non-selective distribution and their action on cancer and normal dividing cells. The ultimate goal of this study is to develop a novel delivery system for the potent and cytotoxic compound CCI-001 to protect it from degradation, help its transport throughout the body, improve its therapeutic efficacy and reduce its harmful side effects. Albumin, one of the most abundant proteins in blood plasma, has shown to be non-toxic, non-immunogenic, biocompatible and biodegradable. Furthermore, it strongly interacts with both hydrophilic and hydrophobic compounds. Therefore, it is an ideal and versatile substance to fabricate nanoparticles for drug delivery. The albumin carrier could specifically target the desired site of action due to the recognition by the albumin receptors, gp60 and SPARC, which are overexpressed in tumours. The uniqueness of using albumin lies in the facts that it is a natural component of our body and it can potentially provide both passive and active targeting, without the use of any external ligands. CCI-001, a tubulin polymerization inhibitor, which has been synthesized and patented in the Department of Oncology, University of Alberta, Edmonton, Canada, has shown potent anti-cancer activity in various cancer cell lines, in vitro (IC50s of 3.28 and 4.29 nM in pancreatic and bladder cancer, respectively). Moreover, CCI-001 has been particularly effective in cancer cells resistant to paclitaxel. However, its applications are limited by its extremely low water solubility, poor uptake into the tumour site and non-selective distribution and uptake by healthy cells. These limitations can reduce the efficacy of the compound and also could cause undesirable side effects, upon in vivo administration. In the current study, CCI-001 was loaded into serum albumin, both bovine and human, generating CCI-001-BSA and CCI-001-HSA nanoparticles, using a modified version of the desolvation method. Already formed and crosslinked albumin nanoparticles were incubated overnight at 37°C with different drug solutions. The obtained CCI-001-loaded albumin nanoparticles were assessed for particle size, zeta potential, drug loading, release, morphology and cell toxicity against SW620 and HCT116 colorectal cancer cell lines. The spherical nanoparticles were negatively charged (zeta potential of ~ -30 mV) and had an average diameter of ~ 130 nm, with a narrow size distribution. The in vitro release of CCI-001 from the albumin nanoparticles showed a sustained release pattern over 24-25 hours without any initial burst release, compared to the fast release of the free drug. Due to the extremely high lipophilicity of the drug (solubility in water at pH 7.4 of 0.007 mg/mL), the drug loading resulted to be around 6 μg/mg albumin, which is still high enough to be tested on the cell lines investigated, due to the extremely high cytotoxicity of the compound. In fact, cellular toxicity studies of the CCI-001-loaded albumin nanoparticles showed a similar activity to the free drug, with IC50s even slightly lower in the cancer cell lines investigated. These data support the advantages of the potential use of these versatile nanoparticles as drug carriers in biological systems. However, the formulation of such CCI-001-loaded albumin nanoparticles could be further improved for future animal of human studies.