Glycyrrhetinic Acid-Modified Norcantharidin Nanoparticles for Active Targeted Therapy of Hepatocellular Carcinoma

Abstract

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been confirmed to have a good anti-tumor effect against hepatocellular carcinoma (HCC). However, its use is limited by its poor water solubility and low tumortargeting efficacy. In the present study, an active-targeted drug delivery nanoplatform was designed to deliver NCTD using a glycyrrhetinic acid (GA)-decorated copolymer (mPEG-PCL-PEI-GA, MPG). The NCTD-loaded polymeric nanoparticles (MPG/NCTD) formed by self-assembly in water exhibited a mean hydrodynamic diameter of roughly 89 nm. In vitro studies revealed that GA-conjugated nanoparticles (AT NPs) had superior cytotoxicity and higher targeting efficacy on HepG2 cells compared to non-conjugated nanoparticles (Non-AT NPs, NAT NPs). Determination of cell apoptosis and cell cycle phase showed that AT NPs resulted in increased cell apoptosis and a distinct increase in the G2 phase (65.30 ± 3.52%, P < 0.01) and S phase (46.39 ± 1.39%, P < 0.01). Evaluation of in vivo anti-tumor activity showed that the AT NPs significantly inhibited tumor growth and prolonged survival of tumor-bearing mice. The expression of Ki-67 and CD31 revealed that AT NPs inhibited cell proliferation and resulted in a decreased microvessel density (MVD). The results indicated that NCTD-loaded GA-modified nanoparticles may have great potential in HCC-targeted therapy.

Insight into norcantharidin, a small-molecule synthetic compound with potential multi-target anticancer activities

“…NCTD has the disadvantages of poor water solubility, short half-life and low tumor targeting efficiency, which limits its clinical application [132,176]. Therefore, a variety of NCTD analogues have been developed to improve the clinical applicability and efficacy.…”

Targeted pharmacokinetics of polymeric micelles modified with glycyrrhetinic acid and hydrazone bond in H22 tumor-bearing mice

“…The active targeting is a common strategy which is achieved mainly via grafting specific ligands to the delivery system. 21 Another copolymer modified with GA (GA-PEG-PLA) has been synthesized. The double amino-terminated PEG (H 2 N-PEG-NH 2 ) was obtained when PEG was chlorinated, azidated, and catalytic hydrogenated.…”

“…Many GA-modified nano-carriers showed selective binding to the corresponding receptors on liver and liver cancer tissues developing higher drug accumulation with better anti-hepatoma activity. 20–22…”

Olaparib nanoparticles potentiated radiosensitization effects on lung cancer

“…Recent studies have shown that the importance of nanoparticle size will greatly affect the metabolism of nanoparticles: ,200 nm of nanoparticles will result in a longer blood circulation time, favorable stability, lower cytotoxicity, and greater absorptive capacity due to EPR effect. 13,34,35 In addition, the sustained slow drug release as shown by Ola-NPs could be attributed to…”

“…10,11 Degradable polymer nanomaterials play an important role in the transmission system of antitumor drugs. 12,13 Among them, two block polymers methoxy poly (ethylene glycol)-poly (e-caprolactone) (MPEG-PCL) with a core-shell structure has become a promising carrier of nanoscale drugs due to its biodegradability and sustained drug release properties. 14 MPEG-PCL has a hydrophobic core (PCL) for connecting with hydrophobic drugs, and the hydrophilic shell (PEG) contributes to the dissolution of the polymeric micelle.…”