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- Development of IR780 based nanoparticles for photothermal therapy of breast cancerPublication . Alves, Cátia Gomes; Correia, Ilídio Joaquim Sobreira; Diogo, Duarte Miguel de MeloDespite all the efforts that have been done, cancer remains as one of the most common and deadliest diseases in the whole world. Surgery can be an effective strategy to treat this disease if the cancer is diagnosed at an early stage. In a more advanced stage of this disease, chemotherapy and radiotherapy are the most applied therapeutic strategies. However, these conventional approaches lack efficacy and selectivity towards cancer cells, causing several side effects in the patients such as hair loss, nausea, and severe weakness. These drawbacks of the clinically available therapeutics highlight the urgent need for developing new anticancer approaches with greater efficacy and safety. To face this challenge, the nanomaterials’ mediated phototherapy is one of the most promising strategies. Regarding this therapeutic modality, it is important to consider two main aspects: i) the physicochemical properties of the nanomaterials (e.g., size, corona composition) and ii) the optical properties of the laser (e.g., wavelength, intensity) and of the therapeutic agent (e.g., molar extinction coefficient, photothermal and photodynamic efficiencies). In what concerns the first point, the nanomaterials’ size, charge, shape, and corona composition play an important role in their ability to reach the tumor site. Classically, the optimization of the nanomaterials’ size has been intensively pursued to allow these nanostructures to accumulate at the tumor site by exploiting the tumor’s leaky vasculature (i.e., to take advantage from the so-called Enhanced Permeability and Retention effect). However, recently it was unveiled that dynamic vents (also known as eruptions) occur spontaneously at the tumor vasculature, facilitating nanostructures extravasation into the tumor site. This new phenomenon led to a paradigm shift, and thus, currently, researchers are focused on the optimization of the nanoparticles’ corona for improving their tumor uptake (i.e., to increase their blood circulation time and hence their likelihood to benefit from these dynamic vents). To improve the nanostructures’ blood circulation time and favor their tumor uptake, these nano-systems have been mainly coated with poly(ethylene glycol) (PEG). However, recently it was uncovered that PEGylated nanomaterials suffer from the Accelerated Blood Clearance phenomenon. Therefore, at the time of the first administration of PEGylated nanomaterials, anti-PEG antibodies are created. Then, these anti-PEG antibodies mediate the rapid clearance of the PEGylated nanoparticles in subsequent administrations. Due to the immunogenicity displayed by PEG-based coatings, it is crucial to develop and validate novel materials capable of improving the nanostructures’ biological properties. The efficacy of nanomaterials-based phototherapies also depends on the optical properties of the laser and of the photoresponsive agent. In this regard, the use of near infrared (NIR; 750-1000 nm) light is of utmost importance since it does not interact significantly with major body components (e.g., water, melanin, collagen) and achieves a high penetration depth (up to about 2 cm). Moreover, the laser power density and irradiation time can also affect the therapeutic outcome. In this way, phototherapies based on NIR light-responsive nanomaterials have been showing promising results. In this type of therapy, after the nanomaterials’ tumor uptake, this zone is irradiated with NIR light. Upon interaction with this radiation, the nanomaterials can produce a temperature increase (photothermal therapy) and/or reactive oxygen species (photodynamic therapy), which cause damages on cancer cells. Among the several NIR light responsive agents, IR780 stands out due to its high versatility. This prototypic heptamethine cyanine has multimodal properties since it can be used for both photothermal therapy and photodynamic therapy as well as for imaging applications (IR780 emits fluorescence in the NIR). However, this small molecule presents acute toxicity and low solubility, hindering its direct application in cancer therapy. In this way, encapsulating IR780 in nanomaterials can be pursued to surpass these disadvantages. However, most of the IR780-based nanomaterials have been produced using PEG in their corona. Considering the recent studies demonstrating the immunogenicity of PEGylated nanostructures, it is of utmost importance to develop new IR780-based nanoparticles that are functionalized with PEG alternatives. In this way, the main goal of the workplan developed during this Doctoral thesis was to validate the potential of novel materials, based on sulfobetaine methacrylate (SBMA) and Poly(2-ethyl-2-oxazoline) (PEtOx), in the coating of nanostructures incorporating IR780 for application in cancer photothermal therapy. This thesis includes two chapters presenting research work. In the first research work (Chapter 3), Bovine Serum Albumin (BSA) was grafted with SBMA, for the first time, being this polymer (SBMA-BSA) employed to encapsulate IR780 through the nanoprecipitation technique (IR/SBMA-BSA NPs). The produced nanoparticles presented an ideal size (≈ 96 nm) and surface charge (≈ -9 mV) for cancer-related applications. As importantly, the SBMA functionalization improved the colloidal stability of the nanostructures in different media as well as their uptake by breast cancer cells. In the phototherapeutic assays, the IR/SBMA-BSA NPs in combination with NIR light could decrease the cancer cells’ viability to just 12 %. In the second research work (Chapter 4), a novel amphiphilic PEtOx-IR780 conjugate was produced. For that, the cyclohexenyl ring of IR780 was chemically attached to thiol-terminated PEtOx (PEtOx-IR conjugate). Afterwards, PEtOx-IR and D-α-tocopheryl succinate (TOS) were combined through the nanoprecipitation technique, yielding PEtOx-IR/TOS NPs. These nanoparticles presented a size (≈ 190 nm) and surface charge (≈ -8 mV) compatible with anticancer applications. As importantly, the PEtOx-IR/TOS NPs also presented an optimal colloidal stability. The PEtOx-IR/TOS NPs could be successfully internalized by cancer cells. In the phototherapeutic assays, the combination of PEtOx-IR/TOS NPs with NIR light could decrease the viability of breast cancer cells (2D in vitro cancer models) to 9 %, and the heterotypic breast cancer spheroids’ (3D in vitro cancer models) viability was also reduced to just 15 %. Overall, the results obtained in this thesis validate the potential of SBMA-brushes and PEtOx in the coating of IR780-based nanomaterials. Moreover, these novel IR780-based nanomaterials also displayed a good in vitro performance, highlighting their potential for cancer photothermal therapy.