Crystalline Nanoparticles of Water-Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs.

We herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC-11, composed of four molecular baskets linked to four trivalent aromatic amines via amide groups. The cage is tetrahedral in shape and similar in size to small proteins (Mw = 8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While twenty-four carboxylates at the outer surface of CBC-11 render it soluble in aqueous phosphate buffer (PBS) at pH = 7.0, the amphiphilic nature prompts its assembly into nanoparticles (d = 250 nm, DLS). Cryo-TEM examination of nanoparticles revealed their crystalline nature with wafer-like shape and hexagonally arranged cages. Nanoparticulate CBC-11 traps anticancer drugs irinotecan and doxorubicin with each cage binding up to four drug molecules in a non-cooperative manner. The inclusion complexation resulted in nanoparticles growing in size and precipitating. In media containing mammalian cells (HCT 116, human colon carcinoma), IC50 value of CBC-11 was above 100 mM. While this work presents the first example of a large covalent organic cage operating in water at the physiological pH and forming crystalline nanoparticles, it also demonstrates its biocompatibility and potential to act as a polyvalent binder of drugs for their sequestration or delivery.