reduction sensitive nanosystems for tumor targeted imaging and therapy
Nanomedicines have shown great advantages in cancer therapy as they enhance the efficacy of traditional therapeutic agents by improving their in vivo biodistribution. Based on a wide range of nanomaterials, various nanotherapeutic platforms such as drug conjugates, lipid-based nanocarriers and polymer-based nanocarriers have been established, and some of them even have been approved for clinical cancer care. Among these nanotherapeutic platforms, polymer-based nanomedicines have received increasing attention due to their small size, stealth properties and excellent biocompatibility, allowing long circulating times in the bloodstream. In addition, easy chemical modification of polymer-based nanocarriers with ligands capable of specifically binding receptors that are overexpressed in cancer cells endows them with active-targeting ability to tumors.
However, despite the fact that significant progress has been made in the past decades, the therapeutic benefits of nanomedicines are still limited since they have to go through several steps to exert their pharmacological effects. In general, when applied in vivo, nanomedicines should remain stable in the blood circulation, selectively accumulate in tumor tissue, penetrate into deep regions of tumors, efficiently internalize into cancer cells and finally rapidly release their anticancer agents. Notably, the last step is of key importance for achieving the efficacy of nanomedicines, while it is also the problem with present nanomedicines, which often have inefficient drug release in tumor tissue or inside tumor cells.
In order to overcome these barriers, in our study, we design and evaluate novel reduction-sensitive polymer-based nanomedicines for improved tumor-targeted imaging and therapy. The use of ligands (mono or dual) for targeting the nanosystems to the tumors and uptake by cells in the tumor have been described as well as the release of drugs from a nanosystem designed to release the drug in the tumor area by an external trigger. The in vivo performance of the nanomedicines described in this thesis including the stability, tumor targeting efficiency and antitumor efficacy have been evaluated using various tumor models. Notably, the multifunctional docetaxel-loaded reversibly-crosslinked micelles are stable in the circulation, have long circulation time, efficiently accumulate in tumor area, penetrate deep in the tumor tissue and rapidly release drug in intracellular reductive environment, leading to superior tumor inhibition effect. We are convinced that in the future advanced nanomedicines, either by themselves or by a combination with other methods like surgery, irradiation, hyperthermia and immune therapy will significantly improve cancer therapy.
