Charge Reversible and Mitochondria/Nucleus Dual Target Lipid Hybrid Nanoparticles To Enhance Antitumor Activity of Doxorubicin.

The experiment aims to increase antitumor activity while decreasing the systemic toxicity of doxorubicin (DOX). Charge reversible and mitochondria/nucleus dual target lipid hybrid nanoparticles (LNPs) was prepared. The in vitro experimental results indicated that LNPs released more amount of DOX in acidic environment and delivered more amount of DOX to the mitochondria and nucleus of tumor cells than did free DOX, which resulted in the reduction of mitochondrial membrane potential and the enhancement of cytotoxicity of LNPs on tumor cells. Furthermore, the in vivo experimental results indicated that LNPs delivered more DOX to tumor tissue and significantly prolonged the retention time of DOX in tumor tissue as compared with free DOX, which consequently resulted in the high antitumor activity and low systemic toxicity of LNPs on tumor-bearing nude mice. The above results indicated that charge reversible mitochondria/nucleus dual targeted lipid hybrid nanoparticles greatly enhanced therapeutic efficacy of DOX for treating lung cancer.

Mitochondria and Nucleus Dual Delivery System To Overcome DOX Resistance.

Doxorubicin (DOX) is a broad-spectrum chemotherapy drug to treat tumors. However, severe side effects and development of DOX resistance hinder its clinical application. In order to overcome DOX resistance, DOX/TPP-DOX@Pasp-hyd-PEG-FA micelles were prepared by using newly synthesized comb-like amphiphilic material Pasp-hyd-PEG-FA. Drug released in vitro from micelles showed a pH-dependent manner. DOX/TPP-DOX@Pasp-hyd-PEG-FA induced more apoptosis in KB cell and MCF-7/ADR cell than DOX@Pasp-hyd-PEG-FA. Confocal laser scanning microscopy experiment indicated that DOX/TPP-DOX@Pasp-hyd-PEG-FA delivered TPP-DOX and DOX to the nucleus and mitochondria of the tumor cell simultaneously. Thus, DOX/TPP-DOX@Pasp-hyd-PEG-FA could significantly damage the mitochondrial membrane potential. DOX/TPP-DOX@Pasp-hyd-PEG-FA markedly shrinked the tumor volume in tumor-bearing nude mice grafted with MCF-7/ADR cell as compared with the same dose of free DOX. DOX was mainly accumulated in tumor tissue after DOX/TPP-DOX@Pasp-hyd-PEG-FA was injected to tumor-bearing nude mice by tail vein. After free DOX was injected to tumor-bearing nude mice by tail vein, DOX widely distributed through the whole body. Therefore, mitochondria and nucleus dual delivery system has potential in overcoming DOX resistance.

pH-Triggered Surface Charge Reversed Nanoparticle with Active Targeting To Enhance the Antitumor Activity of Doxorubicin.

PLGA nanoparticles are widely used in tumor targeting drug delivery systems. However, the naked PLGA nanoparticles (NNPs) not only have low drug loading but also can be rapidly removed from blood circulation by the immune system. The aim of this study was to prepare pH-triggered surface charge reversed lipid hybrid PLGA nanoparticles (LNPs) to enhance drug loading and drug delivery efficiency. CHO-Arg-His-OMe and FA-PEG-DSPE were synthesized to modify PLGA nanoparticles to prepare LNPs. The drug loading and encapsulation rate of LNPs were greatly improved as compared with NNPs. In pH 7.4 medium, doxorubicin (DOX)-loaded LNPs showed negative charge and released DOX slowly. In pH 5.0 medium, DOX-loaded LNPs exhibited positive charge and released DOX quickly. DOX-loaded LNPs delivered more DOX to the nucleus of KB cells and MBA-MD-231/ADR cells than did free DOX. In addition, DOX-loaded LNPs significantly inhibited the proliferation of KB cells and MBA-MD-231/ADR cells. Compared with free DOX, the same dose of the DOX-loaded LNPs delivered more DOX to tumor tissue. Thus, DOX-loaded LNPs significantly inhibited the growth of tumor in tumor-bearing nude mice and obviously reduced the systemic toxicity of DOX. In conclusion, pH-triggered surface charge reversed DOX-loaded LNPs significantly enhanced the antitumor activity of DOX in vitro and in vivo. DOX-loaded LNPs had great potential in tumor targeted chemotherapy.

In vitro and in vivo antitumor activity of a novel pH-activated polymeric drug delivery system for doxorubicin.

BACKGROUND: Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue. METHODS: A pH stimuli-sensitive conjugate based on polyethylene glycol (PEG) with covalently attachment doxorubicin via hydrazone bond (PEG-hyd-DOX) was prepared for tumor targeting delivery system. While PEG-DOX conjugates via amid bond (PEG-ami-DOX) was synthesized as control. RESULTS: The synthetic conjugates were confirmed by proton nuclear magnetic resonance (NMR) spectroscopy, the release profile of DOX from PEG-hyd-DOX was acid-liable for the hydrazone linkage between DOX and PEG, led to different intracellular uptake route; intracellular accumulation of PEG-hyd-DOX was higher than PEG-ami-DOX due to its pH-triggered profile, and thereby more cytotoxicity against MCF-7, MDA-MB-231 (breast cancer models) and HepG2 (hepatocellular carcinoma model) cell lines. Following the in vitro results, we xenografted MDA-MB-231 cell onto SCID mice, PEG-hyd-DOX showed stronger antitumor efficacy than free DOX and was tumor-targeting. CONCLUSIONS: Results from these in vivo experiments were consistent with our in vitro results; suggested this pH-triggered PEG-hyd-DOX conjugate could target DOX to tumor tissues and release free drugs by acidic tumor environment, which would be potent in antitumor drug delivery.