Owing to high efficacy and safety, natural medicines have found their way into the field of cancer therapy over the past few decades. However, the effective ingredients of natural medicines have shortcomings of poor solubility and low bioavailability. Nanoparticles can not only solve the problems above but also have outstanding targeting ability. Targeting preparations can be classified into three levels, which are target tissues, cells, and organelles. On the premise of clarifying the therapeutic purpose of drugs, one or more targeting methods can be selected to achieve more accurate drug delivery and consequently to improve the anti-tumor effects of drugs and reduce toxicity and side effects. The aim of this review is to summarize the research status of natural medicines’ nano-preparations in tumor-targeting therapies to provide some references for further accurate and effective cancer treatments.

Curcumin (CUR), a natural polyphenolic compound existing in plants, exhibits anticancer potential in inhibiting the growth of various types of human cancer. However, the poor aqueous solubility and low bioavailability limit its clinical applications. pH-sensitive macromolecule F68-acetal-PCL (FAP) and active targeting macromolecule F68-glycyrrhetinic acid (FGA) were designed to fabricate mixed micelles for efficient delivery of CUR. The thin film hydration method was used to prepare CUR loaded mixed (MIX/CUR) micelles. The drug loading rate (DL) of MIX/CUR micelles was 6.31 ± 0.92%, which remained stable for 15 days at 4 °C. The particle size and zeta potential of the MIX/CUR micelles were 91.06 ± 1.37 nm and −9.79 ± 0.47 mV, respectively. The MIX/CUR micelles exhibited pH sensitivity in a weak acid environment, and showed rapid particle size variation and drug release. In addition, in vitro tests demonstrated that MIX/CUR micelles induced higher cytotoxicity and apoptosis than free CUR, non-pH-sensitive F68-PCL (FBP)/CUR micelles and pH-sensitive FAP/CUR micelles in SMMC7721 and Hepa1-6 cells. Besides, mixed micelles were more effective than FBP and FAP micelles in a cell uptake experiment, which was medicated by a GA receptor. All in all, these results indicated that MIX/CUR micelles could be regarded as an ideal drug administration strategy against hepatoma carcinoma cells.

Cantharidin (CTD) has been widely used to treat hepatocellular carcinoma (HCC) in clinical practice. However, the current CTD preparations may induce hepatic and renal damage due to their non-specific distribution. Therefore, redox-sensitive polymer Pluronic F127-disulfide bond-poly(D,L-lactide) (F127-SS-PDLA) and active targeting polymer F127-glycyrrhetinic acid (F127-GA) were synthesized to prepare mixed micelles (GA/F127-SS-PDLA/CTD) for effective delivery of CTD. Fourier transform infrared (FTIR) spectroscopy and ¹H nuclear magnetic resonance (¹H-NMR) spectroscopy were used to verify the successful synthesis of F127-SS-PDLA and F127-GA. During the preparation, this study was the first to screen the density of GA by cellular uptake assay. The results indicated that mixed micelles with 10% and 15% F127-GA (weight fraction) exhibited superior cellular uptake in comparison to micelles with 5% and 20% F127-GA. GA/F127-SS-PDLA/CTD micelles prepared by thin film hydration method demonstrated excellent drug loading capacity for CTD (16.12 ± 0.11%). The particle size and zeta potential of GA/F127-SS-PDLA/CTD micelles were 85.17 ± 1.24 nm and −11.71 ± 0.86 mV, respectively. Hemolysis and stability assay showed that the mixed micelles had good blood compatibility and could remain stable for 30 days at 4 °C. The redox-sensitivity of GA/F127-SS-PDLA/CTD micelles in vitro was verified under reducing conditions through dynamic light scattering (DLS) and an in vitro drug release experiment, which showed obvious particle size variation and rapid drug release ability. In cellular experiments, GA/F127-SS-PDLA/CTD micelles could induce superior cytotoxicity, apoptosis and intracellular reactive oxygen species (ROS) levels compared with free CTD, non-sensitive F127-PDLA/CTD micelles and redox-sensitive F127-SS-PDLA/CTD micelles. The cellular uptake ability of nile red-labeled GA/F127-SS-PDLA micelles, which was evaluated via fluorescent microscope and flow cytometry, indicated that the modification of GA significantly increased micelle uptake in HepG-2 cells. Consequently, GA/F127-SS-PDLA/CTD micelles could be considered as a satisfactory drug administration strategy in the treatment of HCC.

Hydrophobic modification alters the properties of Pluronic F127 to form micelles more efficiently and enhances its drug-loading capacity. However, selecting the appropriate hydrophobic group for modification is laborious. In this paper, we propose an efficient approach for predicting key parameters to select hydrophobic groups for F127 modification prior to synthesis, in order to improve the formability and stability of the micelles. The results of nuclear magnetic resonance and isothermal titration calorimetry were utilized to establish a function for predicting the hydrophile–lipophile balance, critical micelle concentration, and Gibbs free energy of the products based on the structure of raw material. These predicted values can assist us in selecting suitable hydrophobic groups for F127 modification. Subsequently, we successfully tested our method and validated our work using pharmaceutical evaluation methods, such as appearance observation, particle size measurement, drug loading determination, equilibrium binding rate assessment, storage stability testing, and the plotting of accumulation release curves. Therefore, we suggest that our work could provide a model linking the molecular structure to properties, with the purpose of pre-selecting modification products that have advantages in micelle preparation. This can facilitate the application of F127 in preparing nano-micelles.

Correction for ‘Glycyrrhetinic acid-modified redox-sensitive polymeric mixed micelles for tumor-specific intracellular delivery of cantharidin’ by Yu Hu et al. , RSC Adv. , 2024, 14 , 28753–28767, https://doi.org/10.1039/D4RA03171G.