Synergistic Dual-Ligand Doxorubicin Liposomes Improve Targeting and Therapeutic Efficacy of Brain Glioma in Animals

Abstract

Therapeutic outcome for the treatment of glioma was often limited due to low permeability of delivery systems across the blood-brain barrier (BBB) and poor penetration into the tumor tissue. In order to overcome these hurdles, we developed the dual-targeting doxorubicin liposomes conjugated with cell-penetrating peptide (TAT) and transferrin (T7) (DOX-T7-TAT-LIP) for transporting drugs across the BBB, then targeting brain glioma, and penetrating into the tumor. The dual-targeting effects were evaluated by both in vitro and in vivo experiments. In vitro cellular uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could not only target endothelial and tumor monolayer cells but also penetrate tumor to reach the core of the tumor spheroids and inhibit the growth of the tumor spheroids. In vivo imaging further demonstrated that T7-TAT-LIP provided the highest tumor distribution. The median survival time of tumor-bearing mice after administering DOX-T7-TAT-LIP was significantly longer than those of the single-ligand doxorubicin liposomes and free doxorubicin. In conclusion, the dual-ligand liposomes comodified with T7 and TAT possessed strong capability of synergistic targeted delivery of payload into tumor cells both in vitro and in vivo, and they were able to improve the therapeutic efficacy of brain glioma in animals.

Targeted delivery of transferrin and TAT co-modified liposomes encapsulating both paclitaxel and doxorubicin for melanoma

“…DSPE-PEG 3500 -Tf was synthesized in the mixed solvent as described previously (Zong et al, 2014a). DSPE-PEG 3500 -Mal (1 equiv) were reacted with Tf-SH (1.5 equiv) in the mixed solvent of CHCl 3 /MeOH (V:V ¼ 2:1) containing 3-fold molar excess of triethylamine in darkness at room temperature with stirring for about 48 h, and the reaction was traced by TLC until DSPE-PEG 3500 -Mal was completely consumed.…”

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…The distribution of gold NPs in MCTS could be precisely assessed with transmission electronic microscopy (TEM), 60,61 while fluorescence microscopy was successfully applied for the detection of dye-labeled NPs. In this case, the NPs are either labeled with fluorescent probes, 34,57,62-64 specific dyes or loaded with fluorescent drugs such as doxorubicin (DOX), 58,[65][66][67][68] Oregon Green 488 Taxol, 20 or porphyrin-based photosensitizers (PSs). 59,69 Estimation of drug concentration in MCTS could be done by high-performance liquid chromatography (HPLC), 20 flow cytometry or chemical extraction with successive fluorescence measurements.…”

“…20,34,58,59,62,64,70 NP penetration can also be evaluated in intact fixed MCTS [64][65][66] or in intact living MCTS by using confocal laser scanning microscopy. 34,71 An important lesson to draw from these experiments has been the excellence of the MCTS model to determine the main factors hindering or favoring NP penetration.…”

“…73 NP diffusion in MCTS could also be improved by addition of cell-penetrating peptides on the NP surface such as RDG, 87,88 TAT or MPG. 64,65 It has been demonstrated that MPG-modified poly(d,l-lactic-co-glycolic acid) (PLGA) NPs exhibited a greater fluorescence intensity and a higher incorporation and diffusion in HeLa spheroids compared to unmodified PLGA NPs. 64 Another modification affecting the carrier surface is the addition of a targeting moiety to address the cargo to specific tissue.…”

“…The authors demonstrated a deeper NP penetration into the cell spheroid and an improved therapeutic effect of glioma tumors in animals. 65 Another possibility to achieve a higher NP penetration into MCTS was assessed by coadministration of the NP with the peptide iRGD, thus facilitating the NP extravasation and distribution. 88 The coadministration of a basic liposomal formulation of Taxol together with the iRGD peptide produced a threefold increase in drug accumulation and penetration into MCTS as compared with other liposomes or micelles especially designed to improve drug delivery in MCTS.…”