| Popis: |
Most of the chemotherapeutics employed today are facing important limitations, including the inability to provide targeted therapy and intracellular drug degradation within the lysosomal compartments. These explain why the average survival rate, throughout all cancer types, is still as low as 50%. The aim of the present thesis is to develop multifunctional AuNPs for intracellular delivery. PEGylated AuNPs were prepared via grafting poly(ethylene glycol) onto the AuNP surface. The influence of the PEG chain length and grafting densities on the colloidal stability, the grafted polymer conformation, the stealth character and the interparticle interactions have been extensively investigated. Longer chain lengths favoured the stability of the colloids in aqueous solution and the preparation of long-range and ordered assemblies via “flexible” interparticle interactions whereas shorter chain lengths led to denser layers and “hard-to-contact” spheres. Highly stable biocompatible pH-responsive AuNPs were obtained through the grafting with the anionic poly(L-lysine isophthalamide) (PLP) conjugated with L-phenylalanine at 75 mol% (PP75). The polymer pH dependent coil-to-globule conformational change was retained between pH 5-6, tuned to the endosomal pH. The AuNPs@PP75 nanohybrids demonstrated a quick and highly reversible agglomeration-deagglomeration cycle. Doxorubicin was loaded at 0.6 wt% onto the nanohybrids without compromising the overall stability in biological media and was effectively delivered into drug-resistant human uterus sarcoma cell line. The synergistic effect of the chemotherapy with photothermal treatment increased the killing efficiency by 6 folds compared to the conventional free drug. The nanohybrids were finally entrapped into pH-responsive PLP hydrogels. The composite hydrogels retained a high pH-responsive swelling behaviour and demonstrated improved mechanical properties compared to the bare hydrogel. Controlled drug release ability and biocompatibility confirmed their suitability as potential cancer therapeutics via oral administration. |
