ACS Nano. 2016 May; 10(2):5720-29.

Interfacial Cohesion and Assembly of Bioadhesive Molecules for Design of Long-Term Stable Hydrophobic Nanodrugs Towards Effective Anticancer Therapy

 Guizhi Shen1,2, Ruirui Xing1,2, Ning Zhang1, Chengjun Chen1, Guanghui Ma1, Xuehai Yan1,2,* 

1State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China

2Center for Mesoscience, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China



The majority of anticancer drugs is poorly water soluble and thus suffers from rather low bioavailability. Although a variety of delivery carriers have been developed for bioavailability improvement, they are severely limited by low drug loading and undesired side effects. The optimum delivery vehicle would be a biocompatible and biodegradable drug nanoparticle of uniform size with a thin but stable shell, making it soluble, preventing aggregation and enabling targeting. Here, we present a general strategy for the rational design of hydrophobic drug nanoparticles with high drug loading by means of interfacial cohesion and supramolecular assembly of bioadhesive species. We demonstrate that the pathway is capable of effectively suppressing and retarding Ostwald ripening, providing drug nanoparticles with small and uniform size and long-term colloidal stability. The final complex drug nanoparticles provide higher tumor accumulation, negligible toxicity, and enhanced antitumor activity, superior to commercial formulations. Our findings demonstrate that local, on-demand coating of hydrophobic nanoparticles is achievable through cooperation and compromise of interfacial adhesion and assembly. 

KEYWORDS: Hydrophobic drugs, Nanoengineering, Interfacial assembly, Ostwald ripening suppression, Drug delivery. 

PMID: 27223166



Cancer remains one of the deadliest diseases known ever known, despite remarkable advances in our knowledge of the fundamental biology and hopeful trends. There has not been a significant increase in overall patient survival for many types of cancer toward observation of WHO. So, how to efficiently fight against tumor prolonging the lifetime and quality of cancer patients is a challenging but urgent pursuit.

Until today, chemotherapeutics remains the mainstream cancer treatment. However, the lack of effective chemotherapeutic options remains a major bottleneck, and many anti-tumor drug candidates identified through high-throughput screenings do not possess sufficient solubility, stability and safety to be bioavailable. To increase their bioavailability, many drug carrier systems in nanometer size range (nanotherapeutic) including nanocrystal, liposomes, polymer micelles, dendrimers, and polymeric-drug conjugate have been developed in effort to overcome the aforementioned transport barriers.

Among the drug carrier systems, direct nanoengineering of pure hydrophobic drugs for formation of colloidal nanoparticles has been emerging as a promising platform due to the advantages of ultra-high drug loading and lowered toxicity. However, a lot of nanocrystalline drug formulations cannot be approved for medical usage for intravenous injection, which rather demands long-term stability and high tolerance adaptive to physiological environment such as in the blood vessel.

To inhibit drug dissolution, aggregation, solid-state transformation and retard subsequent Ostwald ripening that leads to a potentially detrimental change in the particle size distribution, most of these drug nanoparticles need to stabilize by nonionic surfactants, polymeric macromolecules or block copolymers. Without suitable anchors, these protective agents are not suited to stabilize some hydrophobic drugs, such as Paclitaxel. So, how to efficiently prevent their further growth into larger crystals or agglomerates due to Ostwald ripening is a highly desired, but still challenging.

In recent years, some bio-adhesion phenomenon provides inspiration for the design of synthetic adhesives in a variety of application. Researchers found that the non-coded aromatic 3, 4-dihydroxy-l-phenylalanine (DOPA) amino acid has a pivotal role in unique adhesive properties and the catechol moiety is the key parts suggested by molecular studies of DOPA. Polyphenol, another kind of compound that has a high density of catechol groups, reveals the adhesiveness as well. Phenolic compounds are widely distributed in the daily diet, such as coffee, red wine, fruit juice and tea. It reported that a natural polyphenol, tannic acid, can coordinate with iron ions to form thin films on various particulate substrates ranging from inorganic, organic to biological particle templates. And the film formation process was completed instantaneously.

Inspired largely by the robust adhesion of catechol-containing molecules in nature and their versatile coatings, we wonder that whether it could be used for preparing hydrophobic drug nanoparticles with long-term colloidal stability? So, we first select paclitaxel (PTX), a clinically approved broadly used anticancer drug as the typical hydrophobic model drug for the proof-of-principle study. We selected PTX as the model drug for two following reasons, i) It still remains a formidable challenge to obtain PTX nanoparticles with long-term colloidal stability due to its extremely poor water-solubility and continuing ripening and recrystallization. ii) It is convenient to evaluate their effective therapies compared to the commercial formulation of PTX (such as Taxol). The results showed that the strategy we present in this work is facile and generally-suited for design and preparation of hydrophobic drug nanoparticles with high drug loading. This is decisively advantageous compared to many present delivery nanocarriers, suffering from fairly low drug-to-carrier ratio and thus unfavorable side effects and high costs as well. The hydrophobic drug nanoparticles are capable of better reaching the desired target site (tumor) via the EPR effect. Due to the higher tolerated dosage of the therapeutic effect, the tumor can be effectively eradicated and tumor recurrence can be inhibited. 



fig1Fig. 1. (a) A mussel clinging to a clay slab, attached by an array of thin filaments called byssus threads. (b) Complexation state of Ferric ion with pyrogallol moieties. (c) Schematic for stabilized hydrophobic drug nanoparticles. 


Importance of the study: We develop a strategy to investigate how the driving force for Ostwald ripening of hydrophobic drug nanoparticles can be inhibited by balancing the interfacial cohesion and assembly of bioadhesive molecules, unraveling the mechanism for effective inhibition of Ostwald ripening and ultimate termination of further particle growth. Such well-designed hydrophobic nanodrugs provide more opportunities for application of drug delivery and antitumor therapy.



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3)                  Liu, K.; Xing, R. R.; Zou, Q. L.; Ma, G. H.; Möhwald, H.; Yan, X. H. Simple Peptide-Tuned Self-assembly of Photosensitizers Towards Anticancer Photodynamic Therapy. Angew. Chem. Int. Ed. 2016, 55, 3036-3039.



This work was supported by “National Natural Science Foundation of China (Project Nos. 21522307, 21473208, 91434103 and 81402871), the Talent Fund of the Recruitment Program of Global Youth Experts, Beijing Natural Science Foundation (No. 7154220), the CAS visiting professorships for senior international scientists (Project No. 2016VTA042) and the Chinese Academy of Sciences (CAS).



Prof. Dr. Xuehai Yan


State Key Laboratory of Biochemical Engineering,

Institute of Process Engineering (IPE), Chinese Academy of Sciencesc (CAS),

P.O. Box 353, Beijing, 100190, PR China. 




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