A new core–shell-type nanoparticle loaded with paclitaxel/norcantharidin and modified with APRPG enhances anti-tumor effects in hepatocellular carcinoma

Abstract

Nanoparticle delivery systems have been shown to improve the therapeutic efficacy of anti-cancer drugs, including a variety of drugs for the treatment of hepatocellular carcinoma (HCC). However, the current systems show some limitations, and the delivery of more effective nanoparticle systems for anti-HCC drugs with better targeting ability are needed. Here, we created paclitaxel (PTX)/norcantharidin (NCTD)-loaded core–shell lipid nanoparticles modified with a tumor neovasculature-targeted peptide (Ala-Pro-Arg-Pro-Gly, APRPG) and investigated their anti-tumor effects in HCC. Core–shell-type lipid nanoparticles (PTX/NCTD-APRPG-NPs) were established by combining poly(lactic-co-glycolic acid) (PLGA)-wrapped PTX with phospholipid-wrapped NCTD, followed by modification with APRPG. For comparison, PTX-loaded PLGA nanoparticles (PTX-NPs) and PTX/NCTD-loaded core–shell-type nanoparticles without APRPG (PTX/NCTD-NPs) were prepared. The in vitro and in vivo anti-tumor effects were examined in HepG2 cells and tumor-bearing mice, respectively. Morphological and release characterization showed that PTX/NCTD-APRPG-NPs were prepared successfully and achieved up to 90% release of PTX in a sustained manner. Compared with PTX/NCTD-NPs, PTX/NCTD-APRPG-NPs significantly enhanced the uptake of PTX. Notably, the inhibition of proliferation and migration of hepatoma cells was significantly higher in the PTX/NCTD-APRPG-NP group than those in the PTX-NP and PTX/NCTD-NP groups, which reflected significantly greater anti-tumor properties as well. Furthermore, key molecules in cell proliferation and apoptosis signaling pathways were altered most in the PTX/NCTD-APRPG-NP group, compared with the PTX-NP and PTX/NCTD-NP groups. Collectively, PTX/NCTD-loaded core–shell lipid nanoparticles modified with APRPG enhance the effectiveness of anti-HCC drugs and may be an effective system for the delivery of anti-HCC drugs.

Recent Advances in Nanotechnology-Based Targeted Delivery Systems of Active Constituents in Natural Medicines for Cancer Treatment

“…The modification of APRPG on the nano-formulations can considerably increase the effect of the first-level drug targeting by means of active targeting. It can actively deliver the drug to the tumor tissue and improve the effectiveness of chemotherapy [106][107][108]. After Borneol and musk, belonging to aromatic resuscitation herbs in natural medicines, can be used to modify nano-preparations acting on the brain, which can increase drug distribution in the brain and improve the brain targeting of the formulation [101][102][103].…”

“…The modification of APRPG on the nano-formulations can considerably increase the effect of the first-level drug targeting by means of active targeting. It can actively deliver the drug to the tumor tissue and improve the effectiveness of chemotherapy [106][107][108]. After intravenous administration, APRPG-modified nanoparticles loaded with PTX and norethindrone were concentrated at the cancer site of mice and effectively inhibited the growth of ectopic solid tumors in tumor-bearing mice (the inhibition rate of APRPPG-modified nanoparticles group and non-targeted nanoparticles group were 78.67% and 62.98%, respectively) (p < 0.01), suggesting that APRPG could deliver chemotherapeutic drugs more effectively to tumor tissues through active targeting [108].…”