Polymer Drug Delivery Dystems for Effective Therapy and Modulation of Tumor Microenvironment

Polymer drug delivery systems represent a promising strategy of tumor treatment leading to complete control over the tumor not compromised by significant systemic toxicity. Conjugation of a low-molecular-weight drug to a synthetic polymer carrier enables targeted drug delivery to tumor tissue/cells via Enhanced Permeability and Retention (EPR) effect. Water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) is a suitable drug carrier, allowing creation of conjugates with various structures, molecular weight, and with tuneable drug content and release. The conjugates show significantly extended circulation time, preferential tumor accumulation, and limited side toxicity of the drug. HPMA-based conjugates carrying cancerostatic drugs proved excellent anti-tumor capacity in experimental murine models. Complete tumor regression together with development of anti-tumor immune response, ensuring long-term resistance against the original tumor, was documented in EL4 T cell lymphoma model following the treatment with HPMA copolymer conjugates carrying doxorubicin or docetaxel. The anti-tumor immune response, which is co-responsible for the therapeutic outcome, was demonstrated as a treatment-dependent activation of dendritic cells, by the presence of specific CD8⁺ T cells in the spleen, and immune infiltrate within the tumor.

Vasodilators such as nitric oxide (NO) enhance the EPR effect by increasing the blood flow. Three HPMA-based conjugates of nitroesters were prepared as NO donors with the aim to achieve their tumor-selective accumulation and generation of NO, resulting in EPR enhancement, thereby potentiating accumulation of co-administered macromolecular cancerostatics. The NO donors release NO upon endocytosis by tumor cells, and can synergize with the polymer-bound cancerostatics. Together, we demonstrate that HPMA can be successfully explored as a drug delivery system for targeted chemotherapy of tumors as well as modulation of tumor microenvironment.

Supported by Czech Science Foundation, Projects 14-12742S and 301/12/1254.