¹⁷⁷Lu-labeled high-density lipoprotein nanocapsules loaded with doxorubicin for multimodal therapy of tumors over expressing SR-B1 receptors

Doxorubicin (DOX) is one of the most effective drugs for the treatment of solid and hematological malignancies. However, like other chemo drugs, it causes adverse effects in most patients due to its low specificity for tumor cells, which induces severe toxicity in different organs, particularly the heart. One of the current lines of cancer research focuses on the development of new therapeutic products, which interact at a molecular or cellular scale, to diagnose, prevent and treat the disease. Many of these products, such as nanocapsules, use combined therapies to generate a positive synergy greater than the sum of the separate treatments, with less toxicity and greater efficacy. Tumor cells have a high demand for cholesterol and cholesterol esters to maintain the integrity and proliferation of the cell membrane, which is why they over express the SR-B1 receptor, responsible for internalizing the cholesterol contained in high-density lipoprotein (HDL), through reverse cholesterol transport. The present thesis focuses on the development of nanocapsules for the transport of DOX based on reconstituted HDL (rHDL) from synthetic lipids. Similar to endogenous HDL, these rHDL nanocapsules specifically target the SR-B1 receptor, which reduces the side effects of DOX. The multimodal loading capacity of rHDL was utilized to prepare lutetium-177-loaded rHDL/DOX nanocapsules. This radionuclide emits β- and γ radiation, so in addition to its excellent radio toxic effect, it allows acquiring in vivo images of the site where it accumulates (theranostic radionuclide). Like any β- emitter, when ¹⁷⁷Lu is in a dielectric medium such as tissue, it produces Cerenkov radiation capable of photosensitizing DOX. In this way, it can also be used as a light source in photodynamic therapy (PDT) and obtain a multimodal chemotherapy-radiotherapy-PDT theranostic system whose accumulation site can be visualized by optical or nuclear imaging. The results obtained indicate that the rHDL/DOX/¹⁷⁷Lu nanocapsules have great potential to apply multimodal therapy since they maintain the specific recognition by the SR-B1 receptors present in tumor cells, allowing the dosage of DOX to be reduced (which induces less cardiotoxicity), and show a therapeutic effect superior to the application of the treatments separately. (author)