28The growing demand for efficient chemotherapy in many cancers requires novel approaches in 29 target-delivery technologies. Nanomaterials with pH-responsive behavior appear to have 30 potential ability to selectively release the encapsulated molecules by sensing the acidic tumor 31 microenvironment or the low pH found in endosomes. Likewise, polyethylene glycol (PEG)-32 and poloxamer-modified nanocarriers have been gaining attention regarding their potential to 33 improve the effectiveness of cancer therapy. In this context, DOX-loaded pH-responsive 34 nanoparticles (NPs) modified with PEG or poloxamer were prepared and the effects of these 35 modifiers were evaluated on the overall characteristics of these nanostructures. Chitosan and 36 tripolyphosphate were selected to form NPs by the interaction of oppositely charged 37 compounds. A pH-sensitive lysine-based amphiphile (77KS) was used as a bioactive adjuvant. 38The strong dependence of 77KS ionization with pH makes this compound an interesting 39 candidate to be used for the design of pH-sensitive devices. The physicochemical 40 characterization of all NPs has been performed, and it was shown that the presence of 77KS 41 clearly promotes a pH-triggered DOX release. Accelerated and continuous release patterns of 42 DOX from CS-NPs under acidic conditions were observed regardless of the presence of PEG 43 or poloxamer. Moreover, photodegradation studies have indicated that the lyophilization of NPs 44 improved DOX stability under UVA radiation. Finally, cytotoxicity experiments have shown 45 the ability of DOX-loaded CS-NPs to kill HeLa tumor cells. Hence, the overall results suggest 46 that these pH-responsive CS-NPs are highly potent delivery systems to target tumor and 47 intracellular environments, rendering them promising DOX carrier systems for cancer therapy. 48 Keywords: chitosan nanoparticles; doxorubicin; in vitro release; in vitro cytotoxicity; lysine-49 based surfactant; pH-sensitivity 50