Novel Antibody-Targeted Liposomes for the Treatment of Solid Tumors

In the last decades, several advances have been made in cancer treatment leading to improved patient survival, although certain types of cancer remain very difficult to treat. Surgical resection and radiation therapy are highly effective against primary lesions. Disseminated disease however remains the main cause of cancer related mortality. Chemotherapy has been effective against various cancer types, but is often marred by adverse effects and the development of drug resistance, which eventually leads to withdrawal of patients from chemotherapeutic treatments. Nanomedicine can be used to encapsulate chemotherapeutics and thus protect the healthy tissue from adverse effects. In addition, the specificity of nanomedicine can be increased with a range of targeting modalities, such as antibodies or antibody fragments. The goal of this thesis was to bring these two concepts together to improve drug delivery by developing nanomedicine specifically targeted against certain cancer antigens.

As one of the earliest nanomedicine, liposomes have been used as drug-delivery systems and have shown to eradicate conventional side effects of chemotherapeutics. Whereas so-called nanobodies, or single-domain antibodies, are the smallest functional antibody constructs, which are known for escaping detection in the body and do not trigger an immune response. The combination of nanobodies and liposomes creates a platform, which is long-circulating, highly specific and stealth-like in vivo, and ideal for loading with chemotherapeutics. In this thesis, we have shown that targeting with nanobodies offers many advantages compared to conventional targeting ligands and can be used as novel imaging tools against prostate cancer. Moreover, these nanobodies could be used in combination with drug-loaded liposomes where they were effective in inhibiting tumor growth.

Furthermore, we have investigated the role of the tumor microenvironment and morphology in the uptake of liposomes in vivo and the use of radioactive labeled liposomes has shown that tumor heterogeneity is a major limiting factor in tumor uptake. Fortunately, the use of mild hyperthermia, as a pretreatment to increase the permeability of the tumor vasculature, increased liposomal uptake in the tumor. Moreover, thermosensitive liposomes can be used which, upon a hyperthermia trigger, release their chemotherapeutic contents at the target site. Collectively, the results of this thesis describe and provide insights into the pitfalls and possibilities of targeted nanomedicine.