Polymer System for Controlled Drug Delivery and Release of All-Trans Retinoic Acid

All-trans retinoic acid (ATRA) is used as an anti-cancer chemotherapeutic to treat patients with acute promyelocytic leukemia. Due to ATRA ability to drive differentiation of immature granulocytes into mature ones, ATRA was also tested as a drug capable of restricting the suppressive capacity of myeloid-derived suppressor cells (MDSC) in tumor microenvironment.

Hydrophobicity of ATRA is one of the major disadvantages of its medicinal use. With the aim to increase solubility and enable delivery and controlled release of ATRA within the place of action, we have designed and synthesized several water-soluble polymer carriers based on N-(2-hydroxypropyl)methacrylamide copolymers. Various keto-group-containing polymer carriers were prepared and used for the attachment of hydrazide derivative of ATRA via pH-sensitive hydrazone bond. This bond is rather stable in neutral pH (pH 7.4, model of blood stream) but it is hydrolyzed in mild acidic condition with pH 5 – 6 (model of tumor microenvironment).

In vitro tests in a cell line HL-60, corresponding to immature granulocytes, showed that hydrazide form of ATRA keeps its biological properties. The HPMA-based conjugates, the ATRA and its hydrazide derivative induced an increase in expression of CD11b granulocyte marker on the surface of the treated cells and restricted their proliferation in a concentration-dependent manner as evidenced by ³H-thymidine incorporation method and detection of overall viability of cells by MTT. The preliminary data showed that this conjugates could be used as an immunomodulator to decrease the suppressive activity of MDSC. Moreover, the conjugates were also able to decrease proliferation of human T cell lymphoma Jurkat, murine T cell lymphoma EL4 or murine 4T1 breast carcinoma cell lines.

This work was supported by Czech science foundation (grant NO.P301/11/0325).