Catechin Functionalized Cationic Lipopolymer for Biomedical Applications as Internal Tissue Adhesive and Anticancer Drug Carrier

Abstract

Catechin is a flavonoid compound mainly derived from plants that has been widely studied due to its various physicochemical and biological properties. The most critical of the catechin is the catechol motif on the freely rotating phenyl ring. Physiochemically, catechol groups can adhere to different surfaces in wet environments through hydrogen bonding, coordination, covalent bonding, etc. Thus, catechins containing catechol moieties have the potential to be used in the preparation of tissue adhesives. Biologically, catechins have many beneficial properties for human health such as anti-oxidation, anti-cancer, anti-diabetic, and neuroprotective properties, etc. In particular, in the anticancer field, many researchers have studied the possible anti-cancer mechanisms and applications of catechins over the years.

However, whether applied to tissue adhesives or drug delivery, catechins should be used in combination with macromolecules. Because the monomeric form of the catechol moiety does not provide sufficient cohesive force to bond two surfaces when preparing bioadhesives. And in drug delivery systems, the use of catechins in combination with macromolecules with transfection ability can greatly improve their bioavailability. In this thesis, we have explored the applications of catechins as functional groups that provide adhesion and bioactivity, respectively, in the fabricating of tissue adhesives and delivery systems. In addition, electrostatic interactions between oppositely charged polyelectrolytes can form coacervation at high concentrations and micelles at low concentrations, respectively. Therefore, we found that the polymeric cationic liposomes, cholesterol chloroformate-modified polyethyleneimine (PEI-Chol), were an excellent candidate for preparing tissue bioadhesive that required drainage, or for constructing drug delivery systems that need certain transfection ability. Herein, catechins were utilized as different functional motifs in association with cationic liposomes with electrostatic interactions to create biomaterials for various applications.

Firstly, using catechins as adhesion providers for preparing tissue adhesives for internal use. Due to the safety issue and poor underwater adhesion of current commercially available bioadhesives, they are hard to apply to in vivo physiological environments and more diverse medical use conditions. In recent years, lots of bioadhesives based on mussel-inspired chemistry have been prepared, and catechol groups were the most critical part for applying underwater adhesion. While fewer studies have been reported for catechins in adhesive than for the commonly used dopamine. In addition, the waterproofing of the bioadhesives was another major issue, that may limit their use in physiological body fluid environments. In this part, we designed a novel and facile bioadhesive for underwater medical applications based on the coacervation of electrostatic interactions and hydrophobic interactions, with the introduction of catechin as providers of catechol moieties for adhesion to surrounding tissues. The orange-colored bio-adhesive, named PcC, was generated within seconds by mixing catechin-modified chondroitin sulfate (CSCC) and PEI-Chol with agitation. In vitro mechanical measurements proved that this novel PcC bio-adhesive was superior in underwater adhesion performance when applied to cartilage. Animal experiments in the rat mastectomy model and rat cartilage graft implantation model have demonstrated its potential for diverse medical purposes, such as closing surgical incisions, reducing the formation of seroma, and tissue adhesive applied in orthopedic or cartilage surgery.

Secondly, using catechins as bioactive functional motifs for preparing the drug delivery system for cancer or other diseases treatment. It has been reported that catechins have cancer cell-selective apoptosis-inducing properties, especially at high concentrations, while having no effect on normal cells. Alternatively, this cancer cell-selective apoptosis-inducing properties of catechins were positively correlated with the concentrations, that is, it depends on the efficient intracellular delivery. Herein, a nano-scaled micellar composite, named Ac/Pc, composed of catechin functionalized cationic lipopolymer and serum albumin was constructed. Cationic liposomes, catechin-modified PEI-Chol (Pc), tended to accumulate in the pulmonary microvasculature due to electrostatic effects, as well as were able to deliver the micellar system intracellularly. catechin-bovine serum albumin (Ac), Albumin in the system acted as a biocompatible anti-plasma absorbent and can form complexes with positively charged Pc under electrostatic interactions, facilitating to prolong the in vivo retention time of the micellular complexes. The physicochemical properties of the nano-micellar complexes were characterized, and the antitumor properties of low concentrations of grafted catechins were confirmed by ROS, caspase-3, and cell apoptosis measurements. The role of each functional module, cationic polymeric liposome, and albumin, was revealed by cell penetration, in vivo imaging, etc. assays. This multicomponent micellar nanocomposite has the potential to become an effective vehicle for the treatment of lung diseases such as COVID-19, lung tumors, sepsis-induced lung injury, etc.

In summary, firstly, we utilized the unique properties of catechins to fabricate a tissue bioadhesive PcC that could be used in underwater conditions. This study provided a facile method for preparing bioadhesives with stronger water resistance based on the coacervation of electrostatic interactions and hydrophobic interactions, and catechins could have more stable adhesion in the air. Animal experiments showed the PcC bioadhesive has the potential for seroma prevention and coating grafts to enhance host-graft adhesion. Secondly, we established a nanoscale multicomponent micellar complex Ac/Pc to obtain lung targeting and cancer cell-selective apoptosis-inducing properties, which proved that the grafting of catechins onto cationic polymeric liposomes was an effective method to boost bioavailability. Results of animal assays revealed the respective functions of each component. We hope that our attempts in these two research directions will provide insight into the multiple unique properties of catechins and broaden their biomedical applications to create more valuable products.

Date of Award	31 Jul 2023
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Dongan WANG (Supervisor)