Final Report Summary - SMART NANOGELS (Stimuli-responsive theranostic nanogels based on hyperbranched polyglycerol) There are over 10 million new cases of cancer per year world-wide, and it still remains a difficult disease to treat and a significant cause of mortality. Nowadays, typical cancer therapies are limited to surgery, radiation, and chemotherapy. It is well known that those methods face many disadvantages, such as the damage to healthy tissues and organs. In addition, those therapies, or even a combination of them, are sometimes not enough to completely eradicate cancer. Therefore, there has been an explosive development of a variety of nanotechnology platforms to treat cancer; however, there is still a lot of research to be carried out.Nanotechnology offers the possibility to design and fabricate nanosized drug delivery systems (nanocarriers) that can encapsulate a wide variety of old and novel therapeutics. The main advantage of nanocarriers is that they can selectively target the cancerous cells and release the cytotoxic drug exactly there. On the contrary, conventional cancer treatments, such as chemotherapy, are based on the use of drugs that kill not only the cancer cells, but also the healthy ones, leading to adverse side effects such as nausea, hair-loss, extreme fatigue, and compromised immune function. In this context, the benefit of nanoparticles is that they can be used as “nano-taxis” that can deliver medication directly to the tumor without affecting healthy tissues. Moreover, nanocarriers offer several other advantages compared to conventional chemotherapy. For instance, the employment of nanocarriers protects the drug from degradation in the body, allowing oncologist to lower the amount of drug employed in the treatment.For all the above mentioned reasons, nanomedicine has the potential to drastically change how we diagnose and treat cancer. In addition, it constitutes a large industry with many companies and products worldwide, which is expected to keep on rising and to have a significant impact not only on the global health, but also on the economy. All these facts have motivated the “SMART NANOGELS” research project. The objective of this project was to synthesize different nanocarriers, in particular nanogels prepared from biocompatible polymers, with applications in cancer therapy. In addition, such nanogels were designed to be “smart”, i.e. they were engineered they can deliver their payload at a well-defined time, place, and after a specific stimulus (stimuli-responsive nanogels). Briefly, the results of this project are the following:1. We have developed new nanocarriers for the anticancer drug paclitaxel that can release the drug in a “smart” way. In particular, the drug is released by the action of some enzymes (esterases) and by the action of the acidic pH found in some cellular compartments. Notably, paclitaxel is widely used for the treatment of various carcinomas, such as ovarian and non-small cell lung cancers.2. We have synthesized “smart” polymeric nanogels that are able to shrink or swell by the action of temperature. Temperature can be used as a simple external stimulus for controlling the structural shape of these nanogels, trigger drug release, or to improve cellular targeting.3. Finally, we have gone a step further and we have designed and synthesized polymeric nanogels that are able to react to different stimuli. Such nanogels, called “multiresponsive nanogels” release the cytotoxic drug doxorubicin as a response to different biological stimuli (such as low pH and reductive environments found inside the cells), resulting in a more efficient cell proliferation inhibition in lung cancer cells.As it has been described, the proposed research project tried to achieve more advanced scientific results that hopefully could have a direct impact in society by improving the development of current nanomedicines. It intended to go a step further in the preparation of novel nanocarriers for future cancer therapy solving many current challenges and therefore contributing to the scientific development of the “state of the art”.