Arginine‐Modified Nanostructured Lipid Carriers with Charge‐Reversal and pH‐Sensitive Membranolytic Properties for Anticancer Drug Delivery

Abstract

The ability to escape endo/lysosomal trafficking is critically important to prevent entrapment of nanomedicines in lysosomes and to achieve maximum therapeutic efficacy of drugs delivered to cells through endocytosis. In this study, a novel pH-sensitive chitosan carrier with the ability to reverse its charge during endo/lysosomal trafficking is developed as a way of improving lysosomal disruption. N-Arginine-N-octyl chitosan (AOCS) is synthesized by grafting l-arginine onto carboxymethyl chitosan. The AOCS is used to modify the surface of nanostructured lipid carriers (NLC) to prepare pH-sensitive charge-reversal lysosomolytic nanocarriers (ANLC). The ANLC is loaded with 10-hydroxycamptothecin (HCPT). The results show that ANLC is able to reverse surface zeta potential from negative to positive at lysosomal pH, which contributes to improved release of encapsulated drugs into cytoplasm. The lysosomolytic capability of ANLC is confirmed by confocal microscopy and transmission electron microscopy. In vitro studies demonstrate that the anticancer activity of HCPT-loaded ANLC is improved when compared with HCPT-NLC and free HCPT. In vivo pharmacokinetics and tissue distribution analysis show improved delivery of HCPT-ANLC to subcutaneous Heps mouse liver tumors and greatly improved antitumor activity. The results present ANLC as a promising drug delivery carrier for improved antitumor therapy.

Surface Charge Reversible Polymeric Micelle‐Laden Hydrogels for Drug Delivery and 3D Cell Culture

“…To ensure the distribution of DOX in the cells, channel intensities of DOX and Hoechst 33 258 were captured through Zeiss ZEN 2.3 image analysis software. The result in Figure d indicates that DOX mainly distributes in the cytoplasm since DOX is hydrophobic . As a control, we performed the experiment using DOX∙HCl cultured with the cells and gained the confocal microscopy image as shown in Figure S7, Supporting Information.…”

Chitosan-Based Nanomaterials for Drug Delivery

“…Chitosan derivatives mainly originate from the modification of hydroxyl and especially the free amino of chitosan skeleton [ 45 ]. The chitosan decorated with different functional groups yields desired products with excellent properties, and the effort about chitosan modification has given much assistance for its wide use in biomedical field [ 17 ].…”

Advances in Stimulus‐Responsive Polymeric Materials for Systemic Delivery of Nucleic Acids

“…Cellular organelles, such as the cytoplasm, endosomes, lysosomes, endoplasmic reticulum, Golgi bodies, mitochondria and nuclei, all maintain their own characteristic pH (Figure 2) [10]. Delivery and release of NAs into the cytoplasm (siRNA, mRNA) or nucleus (plasmid DNA) is a crucial step and a major challenge during intracellular delivery [11]. The majority of nanosized particles are internalized by the process of endocytosis.…”

“…This physiological property of solid tumors has been widely used in the design of stimulus-responsive drug and NA delivery systems. For example, pH-triggered charge-conversion of nanoparticles (NPs) was reported to enhance the cellular uptake of NAs [11]. Agmatine- and arginine-chitosan conjugates, CS-DM-Agm [11a] and N-arginine-N-octyl chitosan [11b], which were utilized to transport siRNA or anti-cancer drugs, changed from being negatively charged to positively charged in the slightly acidic extracellular environment of the tumor.…”