A directed co-assembly of herbal small molecules into carrier-free nanodrugs for enhanced synergistic antitumor efficacy.

Carrier-free nanomedicines without structural modification are attractive for the development of natural small molecules (NSMs) and biomedical applications. Moreover, the combination of NSMs is expected to obtain nanomedicines with high efficacy and low side effects due to their inherent pharmacological activities and health benefits. However, poor water solubility and low bioavailability of NSMs limit their wider biomedical and clinical applications. In this study, we revealed the co-assembly properties of pentacyclic triterpenoids and constructed a series of carrier-free nanodrugs, which are co-assembled nanoparticles (NPs) formed by the combination of two NSMs via a supramolecular assembly strategy. Experimental work and simulation studies were combined to reveal the co-assembly mechanism of non-covalent interactions between NSMs. Not only do co-assembled NPs have rapid cellular uptake ability and passive targeting tumor ability based on the EPR effect, but also their constituent units could arrest the cell cycle at different stages of tumor cells and induce apoptosis, showing synergistic anti-tumor effects (CI < 0.7). Compared with self-assembled NPs and positive control, co-assembled NPs show the strongest therapeutic effect in vivo. Importantly, the co-assembled NPs highlight the unique advantages of NSMs in terms of biosafety and health benefits, and systemic toxicity and histological examination confirm that co-assembled NPs have reliable biosafety, and no side effects and nano toxicity risks were observed.

Paclitaxel and betulonic acid synergistically enhance antitumor efficacy by forming co-assembled nanoparticles.

The side effects and low bioavailability of paclitaxel (PTX) limit its clinical application. The formation of self-assembled nanomedicines without structural modification is attractive for biomedical applications. Here, we constructed a supramolecular co-assembled nanoparticles (NPs), which is formed by betulonic acid (BTA) and PTX mainly through hydrogen bond interaction and hydrophobic interaction. It not only has the characteristics of NPs but also the activity of natural small molecules (NSMs). The results of in vitro and in vivo experiments showed that BTA-PTX NPs showed excellent synergistic enhancement of anti-tumor efficacy, because BTA and PTX have different anti-tumor mechanisms. What's more, BTA-PTX NPs showed excellent biosafety and low toxicity, because BTA has impressive biological activity and biosafety. This work provides an effective and simple method to construct high efficiency and minimize side effects of NPs, which provides more possibilities for the application of NSMs in drug delivery.

Nanomedicine-Cum-Carrier by Co-Assembly of Natural Small Products for Synergistic Enhanced Antitumor with Tissues Protective Actions.

The application of natural small products with self-assembly characteristics in a drug-delivery system is attractive for biomedical applications because of its inherent biological safety and pharmacological activity, and there is no complex structural modification process. However, drug carriers with pharmacological effects have not been developed enough. Here, we report a pure natural nanomedicine-cum-carrier (NMC) drug delivery system. The NMC is formed by the direct co-assembly of two small molecular natural compounds through noncovalent interaction, and a molecular dynamics model for predicting the co-assembly of two small molecular compounds was established. The representative co-assembled NMC (oleanolic acid and glycyrrhetinic acid) not only shows excellent stability, high drug loading, and sustained release characteristics but also the co-assembled NMC formed by two small molecular compounds has a synergistic antitumor effect (CI < 0.7). After drug loading, the antitumor effect is further improved. In addition, this NMC highlights the unique advantages of active natural products in biosafety and health benefits. Compared with free drugs, it can reduce the liver damage caused by chemotherapy drugs through upregulating key antioxidant pathways. Compared to nonpharmacologically active drug delivery systems, it can reduce the risk of nanotoxicity. Taken together, this co-assembly drug-carrier system overcomes the shortcomings that pharmacologically active compounds cannot be directly applied, enhances the pharmacological activity of bioactive drug carriers, improves the antitumor efficacy, and slows down the side effects induced by chemotherapy drugs and the additional toxicity caused by long-term use of non-bioactive nanocarriers.