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

Abstract

The application of natural small products with selfassembly 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.

Research progress on self-assembled nanodrug delivery systems

“…Combined administration of amylin containing OA-GA can effectively reduce the liver injury caused by amylin. 118 Through hydrogen bonding and hydrophobic interaction, Wang et al combined ursolic acid (UA) and PTX to form a stable and highly drug-loaded nanocomposite (UA-PTX NPs). UA-PTX NPs extend the plasma half-life and effectively prevent rapid drug leakage in the body.…”

“…Combined administration of amylin containing OA-GA can effectively reduce the liver injury caused by amylin. 118…”

Supramolecular assemblies based on natural small molecules: Union would be effective

“…Moreover, in different liquids, self-assembled glycyrrhetinic acid from Glycyrrhiza glabra and OA from Lantana camara produced spherical objects and vesicles or fibrils to form supramolecular gels, respectively [ 34 , 35 ]. Besides, sumaresinolic acid from Melastoma candidum and echinocystic acid from Albizzia julibrissin had been identified as spherical or irregular NPs [ 36 , 37 ]. Ursolic acid (UA) presented in the leaves of Plumeria rubra were proved to aggregate into stable self-assembly in the form of supramolecular gel or nanocrystal which could improve its solubility and anticancer activity in vitro [ [38] , [39] , [40] ].…”

“… Compound Structural formula Micromorphology Macroscopic Phase Ref. Betulinic acid Fibrillar network Gel [ 23 ] Betulin Flower-like fibrillary network Gel/colloidal suspension [ 26 ] Liquidambaric acid Fibrillar network Gel [ 17 ] Lupeol Rod/lamellae/fibrillar network Gel [ 16 ] Arjunolic acid Vesicle Gel [ 31 ] Maslinic acid Vesicle Viscous suspension [ 33 ] Corosolic acid Vesicle Gel/colloidal suspension [ 32 ] Oleanolic acid Vesicle/fiber Gel [ 34 ] Glycyrrhetinic acid Sphere/petal Gel [ 35 ] Sumaresinolic acid Sphere NP [ 36 ] Echinocystic acid Irregular NP [ 37 ] Ursolic acid Vesicles/tubes/fibers/flowers/sphere/layer Gel/colloidal suspension/nanocrystal/NP [ [38] , [39] …”

“…More results of hybridization suggested that OA/BA, glycyrrhetinic acid/liquidambaric acid and liquidambaric acid/lupeol could be co-assembled to form new uniform NPs mainly driven by hydrophobic interaction and hydrogen bond. Further studies in vitro and in vivo have substantiated the existence of synergistic effects in the co-assemblies in tumor treatment [ 22 , 37 ]. However, not every effort of co-assembly would be productive.…”