Design and optimization of nano-formulations for a novel colchicine derivative

Introduction: Chemotherapy is the most reliable approach to cancer treatment, but it is often associated with side effects due to anti-cancer compounds' toxicity and non-selectivity [1]. CCI- 001 is a novel colchicine derivative, computationally designed by modifying colchicine’s basic structure, that exploits the affinity with βIII-tubulin to impair the mitosis of cancer cells [1]. CCI- 001 showed lower general toxicity, increased selectivity and specificity [1]. Despite this, its applications are limited by low water solubility and poor tumor uptake. [1]. This may reduce CCI- 001 efficacy and produce undesirable side effects. To solve this issue, this contribution describes the design of new efficient transporters of CCI-001 (polymeric nanoparticles, NPs) to enhance target accumulation and reduce the off-target effects. Methods: CCI-001 was successfully loaded in core-shell pegylated NPs, using the nanoprecipitation method [2]. In detail, a poly-ε-caprolactone (PCL)-based polyurethane (NHSC2000) was solubilized in acetonitrile and precipitated in water containing a mix of phospholipids (L-α- phosphatidylglycerol, PG and 1,2 – Distearoyl- sn – glycerol – 3 – phosphoethanolamine – Poly (ethylene glycol), DSPE-PEG). In vitro efficacy of CCI-001 loaded- NPs was analyzed against 2D and 3D cultures (spheroids) of three cell lines: U87MG (glioblastoma multiforme), Mia-PaCa-2 (pancreatic adenocarcinoma) and OVCAR-3 (ovarian cancer). Results: NPs of small size (~170 nm), narrow size distribution (PDI<0.3), high stability in aqueous solution, and satisfying encapsulation efficiency (6 %) were obtained [3]. CCI-001-loaded NPs caused a significant decrease in the viability of each cell line tested. The maximum effect was exerted after 72h, at a concentration of 2,5 μM, where residual viabilities of 50%, 30%, and 26% were reached for 2D culture of U87MG, Mia-PaCa-2, and OVCAR-3, respectively (Figure 1a). NPs exhibited similar results on U-87 and Mia-PaCa-2 spheroids, while OVCAR-3 spheroids' viabilities are higher than the corresponding 2D culture (as shown in Figure 1b). Also, empty NPs did not elicit signs of toxicity on these cell lines, up to a concentration of 1 mg/ml. Conclusions: Overall, our results demonstrate that nano-formulations of CCI-001 can be obtained with satisfying loading efficacy without altering the anti-cancer effect of the drug, warranting their further investigation.