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Abstract: Stimuli-responsive nanoparticles (NPs) have been receiving much attention as a drug-delivery vehicle for therapeutic applications; once internalized into cells, the intracellular fate of NPs and their drug release behavior in response to local stimuli must be understood for efficient delivery of therapeutics. In this study, we prepared pH-responsive doxorubicin (DOX)-loaded NPs, made of N-palmitoyl chitosan bearing a Cy5 moiety (Cy5–NPCS), as an anticancer delivery device. The results of our molecular dynamic simulations showed that the ability of Cy5–NPCS to self-associate offered the close proximity between the donor (DOX) and the acceptor (Cy5) required for Förster resonance energy transfer (FRET), while the pH-driven structure transition prescribed the on-to-off switch of the energy transfer. The caveolae-mediated pathway played a major role in the internalization of NPCS NPs. Using the concept of FRET, we found that the DOX fluorescence in the cytosol was first seen when NPCS NPs were present in the slightly acidic early endosomes. Following NPCS NPs trafficking into a more acidic organelle (late endosomes/lysosomes), a more evident release of DOX into the cytosol was observed; the released DOX was then gradually accumulated in the cell nuclei, leading to a significant cytotoxicity. Understanding the fate of NPs with respect to their intracellular localization and drug release behavior is crucial for the rational design of drug carriers. [Copyright &y& Elsevier]

Abstract: In-situ forming hydrogels triggered by environmental stimuli have emerged as a promising injectable strategy targeted for various biomedical applications. However, several drawbacks associated with temperature-stimulated hydrogels have been reported. Employing a hydrophobically-modified chitosan (N-palmitoyl chitosan, NPCS), we developed a pH-triggered hydrogel system which showed a rapid nanostructure transformation within a narrow pH range (pH 6.5–7.0). NPCS in an aqueous environment was found to be a shear-thinning fluid and exhibited an instant recovery of its elastic properties after shear thinning, thereby making it an injectable material. Additionally, aqueous NPCS, an associating polyelectrolyte, can be rapidly transformed into hydrogel triggered simply by its environmental pH through a proper balance between charge repulsion and hydrophobic interaction. This in-situ hydrogel system was shown to be nontoxic. Subcutaneous injection of aqueous NPCS (pH 6.5) into a rat model resulted in rapid formation of a massive hydrogel at the location of injection. The implanted hydrogel was found to be degradable and was associated with an initial macrophage response which decreased with time as the degradation proceeded. These results suggested that the developed NPCS hydrogel may be used as an injectable drug/cell delivery system. [Copyright &y& Elsevier]