Poly(vinyl alcohol) potentiating an inert D-amino acid-based drug for boron neutron capture therapy.

Since the discovery of D-amino acids, they have been considered inactive and have not been used as potent drugs. Here, we report that simple mixing with poly(vinyl alcohol) (PVA) unleashed latent potentials of D-amino acids in boron neutron capture therapy (BNCT). PVA formed boronate esters with seemingly useless boronated D-amino acids and induced tumor-associated amino acid transporter-superselective internalization and prolonged intracellular retention, accomplishing complete cure of tumors. The superselective internalization was achieved by switching the internalization pathway from ineffective pass through the transporter to the transporter-mediated endocytosis. The acidic environment in the endo-/lysosome dissociated the boronate esters and elicited the stealthiness of the drugs, preventing their externalization and prolonging intracellular retention time. In a subcutaneous tumor model, this system accomplished surprisingly high tumor-selective accumulation that could not be achieved by conventional approaches and induced drastic BNCT effects. PVA may be a unique material to unlock potentials of seemingly inert molecules.