Photosensitive targeted nanocarriers for selective delivery of photodynamic therapy


de las Heras Guilarte, Elena 


This thesis reports the study of active-targeting nanocarriers as drug delivery systems for photodynamic therapy for cancer purposes. Poly‐(D,L‐lactide‐co‐glycolide) (PLGA) nanoparticles and mesoporous silica nanoparticles (MSNPs) are the two nanovehicles of different nature employed. The vehiculization of drugs through nanodelivery systems can overcome limitations that conventional delivery experiences, such as increasing its selectivity. In this regard, the major limitation of any cancer therapy lies on the difficulty to precisely control the localization of the drug in the tumor tissue and not in a healthy one. In order to improve this drawback, the delivery of drugs through nanocarriers can actively-target to tumor cells by grafting targeting ligands to the nanosystem that can recognize and bind to surface receptors overexpressed by these cells. In this thesis, two active-targeting ligands have been explored: the c(RGDfK) peptide and the Cetuximab antibody. First, PLGA nanoparticles with the photosensitizer ZnTriMPyP covalently attached and grafted with the c(RGDfK) peptide have been developed. Their physicochemical and photophysical properties have been studied, as also assessing their phototoxic activity. Covalent binding of the hydrophilic ZnTriMPyP to the surface of PEG-coated PLGA nanoparticles improves the phototoxicity and dark toxicity of the nanosystem compared to related nanocarriers with the photosensitizer occluded. The conjugation of c(RGDfK) peptide provides an enhancement in photodynamic action against tumor cells expressing the v3 integrin receptor but does not prevent damage to cells lacking this integrin. Secondly, immuno-photo-nanocarriers have been explored. For this, PEG-coated MSNPs decorated with phthalocyanine and Cetuximab have been synthesized. The physicochemical, photophysical and photobiological properties have been studied. Initially, this nanosystem has been prepared with the novel phthalocyanine ZnPcSMP, however, it is strongly aggregated and its photosensitizing ability is quenched when it is covalently attached to MSNPs. In contrast, the phthalocyanine IRDye700DX maintains its ability to generate singlet oxygen and thus the nanosystem achieves photodynamic action in cells. Furthermore, the conjugation of Cetuximab improves the aqueous dispersibility of these nanoparticles and enables their internalization in cells according to the EGFR expression level. Lastly, chemo-immuno-photo-nanocarriers have been developed. PEG-coated MSNPs grafted with phthalocyanine, Cetuximab and Doxorubicin have been designed to allow the release on-demand of the antineoplastic agent triggered by light. They have been characterized in terms of their physicochemical and photophysical properties, as also evaluating their phototoxicity in vitro. The attachment of small amounts of Doxorubicin onto nanoparticle surface induces a reduction in their singlet oxygen production ability and photodynamic activity. In contrast, with higher concentrations of Doxorubicin, the nanocarrier shows efficient and selective photokilling of EGFR-expressing cells mainly through singlet oxygen-induced cleavage of the Doxorubicin. Therefore, this novel triply functionalized nanosystem is an effective and safe nanodevice for light-triggered on-demand Doxorubicin delivery.




Nonell Marrugat, Santiago 
Agut Bonsfills, Montserrat  


IQS SE - Química Analítica i Aplicada

Date of defense