X-ray visible microspheres derived from highly branched biodegradable poly(lactic acid) terminated by triiodobenzoic acid: Preparation and degradation behavior

Highlights

• X-ray opaque highly branched poly (lactic acid) were synthesized by using triiodobenzoic acid as end-capping agent.

• The synthesized highly branched poly (lactic acid) exhibited high radiopacity performance with high molecular weight.

• Non-invasive micro-CT imaging biodegradable embolic microspheres were developed.

• In vitro degradation behavior of X-ray opaque microspheres was traced.

Abstract

Biodegradable polyesters with X-ray visibility for biomedical applications have attracted increasing attention. We herein reported a facile method of end-chain functionalization to prepare highly branched linear-comb poly (lactic acid) (Lc-PLA) using triiodobenzoic acid (TIBA) as end-capping and X-ray contrast agent. Three branch lengths of iodinated linear-comb poly (lactic acid) (I-Lc-PLA_30k, I-Lc-PLA_50k, and I-Lc-PLA_70k) were successfully synthesized and then microspheres with well-controlled size (average size ~180 μm) were prepared. By micro-CT testing, the results showed that shorter branch length of PLA contributed more iodinated end-group functionalized sites, leading a relatively high iodine content and excellent radiopacity. After terminated with TIBA, glass transition temperature and thermal stability of I-Lc-PLA polymers were greatly improved. During the in vitro hydrolytic degradation of three months, the molecular weight, iodine content, surface microstructure and micro-CT radiopacity of these microspheres were investigated. The degradation results showed that I-Lc-PLA_50k possessed sufficient iodine content and high household unit values, suggesting a well-maintained radiopacity of I-Lc-PLA. Therefore, this work proposed a highly branched I-Lc-PLA microspheres with promising CT-imaging capacity, which could be used as a long-term embolic material.

Introduction

The interventional embolization therapy (i.e. transcatheter embolization) has become common treatment with minimal invasive for various diseases in recent years. Advances in interventional materials, such as X-ray opaque biodegradable polymers, have led to the development of novel preclinical embolic agents. Generally, there were two methods to obtained radiopaque polymers, including physical mixing and chemical bonding method. Due to the limitations of physically mixed method (such as leakage, fuzzy imaging, systematic toxicity, etc.), synthesis of radiopaque biodegradable polymer by covalent bonding with iodinated moieties became an attractive approach. Among these synthetic routes, various kinds of iodinated polymers with functional radiopaque groups were synthesized by methods of copolymerization of iodinated monomers [[1], [2], [3], [4], [5], [6]] or grafting of iodinated onto polymer backbones [[6], [7], [8], [9], [10], [11]], which endowed inherent X-ray visibility and showed great potential in interventional therapy.

Among these iodinated polymers, only a few research focused on the iodination of poly (lactic acid) due to limited function sites for iodinated functional groups, which brought challenges of functionalization of PLA backbone [12]. In our previous work [13], PLA diols was used as the soft segment to prepare radiopaque iodinated poly (lactic acid)-polyurethane (I-PLAU) with intrinsic X-ray visibility by “chain extension method”. The I-PLAU materials were developed towards embolic microspheres, which was targeting for the embolization therapy with low cytotoxicity and good X-ray radiopacity. Recently, another facile method was introduced to synthesize iodinated linear and star PLA by terminating with contrast agent triiodobenzoic acid (TIBA), which possessed high X-ray radiopapcity with three iodine atoms per molecule [14]. However, even the star 4-arm structure of PLA only provide four terminals reacted with TIBA as end-capped agents, which cannot offer higher radiopacity for embolization materials.

PLA materials with highly branched architectures have attracted much attention [[15], [16], [17], [18], [19]], because such series of branched-structure PLA affords multi-end of functional sites to be used for further functionalization. Up to now, kinds of highly branched linear-comb poly (lactic acid) (Lc-PLA) have successfully synthesized by our groups [[20], [21], [22], [23], [24]]. The Lc-PLA, which was a kind of branched PLA with a linear backbone and randomly distributed branches of PLA, was expected to have multi-terminal hydroxyl groups and used as the functional site with further functionalization [23,24].

Hence, the purpose of this study is to obtain high iodine content of highly branched Lc-PLA and evaluate the potential applications as long-term embolization agents. Firstly, Lc-PLA with different branch lengths were synthesized, and then terminated with TIBA using end-group functionalization method. The molecular structure and thermal performance were examined and investigated. Based on the synthesized I-Lc-PLA materials, we further fabricated I-Lc-PLA microspheres via the emulsion-solvent evaporation method. Micro-CT scanning was used to detect the radiopacity of these I-Lc-PLA microspheres. Moreover, in vitro hydrolytic degradation process was studied by the molecular weight, iodine content and Micro-CT radiopacity of the microspheres in phosphate-buffered saline (PBS) solution at body temperature (37 °C) for 3 months. This work provided a simple route to synthesize inherently radiopaque PLA materials with both high molecular weight and good radiopacity performance, which could ensure the radiopacity microspheres work as long-term embolization agents.