Transferrin-Conjugated pH-Responsive γ-Cyclodextrin Nanoparticles for Antitumoral Topotecan Delivery

Abstract

In this study, we developed γ-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a γ-cyclodextrin (γCD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed γCDP-(DMA/PEG-Tf) NPs. These γCDP-(DMA/PEG-Tf) NPs are effective in entrapping topotecan (TPT, as a model antitumor drug) resulting from the ionic interaction between pH-responsive DMA and TPT or the host–guest interaction between γCDP and TPT. More importantly, the γCDP-(DMA/PEG-Tf) NPs can induce ionic repulsion at an endosomal pH (~6.0) resulting from the chemical detachment of DMA from γCDP, which is followed by extensive TPT release. We demonstrated that γCDP-(DMA/PEG-Tf) NPs led to a significant increase in cellular uptake and MDA-MB-231 tumor cell death. In vivo animal studies using an MDA-MB-231 tumor xenografted mice model supported the finding that γCDP-(DMA/PEG-Tf) NPs are effective carriers of TPT to Tf receptor-positive MDA-MB-231 tumor cells, promoting drug uptake into the tumors through the Tf ligand-mediated endocytic pathway and increasing their toxicity due to DMA-mediated cytosolic TPT delivery.

Development of biocompatible electrostatic‐repulsive microparticles for local tumor treatment

“…The carboxyl groups of HA (500 mg) were aminated with ADH (1.15 g), DCC (270 mg), NHS (150 mg), and TEA (1 mL) in DMSO (25 mL) at 25 °C for 3 days 22 . To remove the unreacted chemicals, the resulting solution was transferred to a pre‐swollen dialysis membrane (Spectra/Pro® MWCO 2 K) and dialyzed in DMSO for 2 days and then in distilled water for 2 days 4,16,17,22 . After dialyzing, this solution was lyophilized, producing aminated HA (aHA).…”

“…After the reaction, the unreacted chemicals were removed through dialysis in 5 mM Na 2 B 4 O 7 aqueous solution for 3 days, and lyophilized. The chemical structure of the obtained aHA‐DMA was analyzed using a 300 MHz nuclear magnetic resonance spectroscopy (NMR Spectrometer, Bruker, Billerica, MA, USA) 4,17,22,27 …”

“…The zeta potential of the PLGA MP samples was confirmed using Zetasizer 3000 (Malvern Instruments, Malvern, UK) for each sample (1.0 mg/mL) dispersed in PBS (pH 7.4 or 6.8, 150 mM) 8,9,11,16,17,22 . To determine the DOX encapsulation content in the PLGA MPs, the DOX‐encapsulated PLGA MPs dissolved in DMSO was measured using a microplate reader (Bio‐Tek, Winooski, VT, USA) 22 .…”

“…Therefore, we intend to develop biospecific signal‐responsive microparticles using poly(D,L‐lactide‐ co ‐glycolide) (PLGA), a biocompatible polymer 10,15 . In addition, we considered the physical information that the pH of the environment outside the tumors is slightly acidic due to acidosis of tumor tissues 4,5,10,15–17 …”

“…Briefly, aHA‐DMA and DOX dispersed in aqueous system were homogenized with PLGA dissolved in dichloromethane (DCM) and then lyophilized in excess aqueous solution. We hypothesized that the DMA moieties in the PLGA(aHA‐DMA)/DOX MPs could be detached at weakly acidic pH, 3,11,17,22 leading to structural destabilization of the MPs. These physicochemical properties may be effective for the controlled DOX release due to the electrostatic‐repulsion between protonated aHA and DOX at an acidic pH (Figure 1(A)).…”