A visible and controllable porphyrin-poly(ethylene glycol)/α-cyclodextrin hydrogel nanocomposites system for photo response

Highlights

• The visible hydrogel disassembly was tracked in vivo by fluorescence imaging.

• MWNTs can control the hydrogel disassembly due to its photothermal effect.

• The photo response merged remote controlling and visualization of the hydrogel.

Abstract

The real-time controlling and tracking of the evolution and status of the hydrogel are important challenges for accurate and precise assessments. In this article, a visible and controllable hydrogel nanocomposites system for photo response was designed and developed based on a thermosensitive porphyrin-poly(ethylene glycol)/α-cyclodextrin hydrogel loaded with multi-walled carbon nanotubes (PPEG-MWNTs/α-CD). The PPEG-MWNTs/α-CD hydrogel was simply self-assembled with a carbon nanotubes dispersed porphyrin-poly(ethylene glycol) solution and an aqueous solution of α-cyclodextrin by homogeneous stirring. The structure and the optical and photothermal abilities of the hydrogel nanocomposites system were characterized in vitro. Moreover, the controlled disassembly of the hydrogel was monitored in real time by in vivo fluorescence imaging after subcutaneous injection using mice as models. The results demonstrated that the hydrogel disassembly can be efficiently accelerated under laser irradiation with the loading of carbon nanotubes by fluorescence imaging visualization. With the advantages of the photo response, fluorescence imaging tracking and photothermal remote controlling were combined into the hydrogel nanocomposites system.

Introduction

Hydrogels are hydrophilic polymer networks that can be similar to the structure of natural tissues. Their unique function and structure have led to the increased applications of hydrogels in fields ranging from drug delivery to tissue engineering (Ashley, Henise, Reid, & Santi, 2013; Li, Rodrigues, & Tomas, 2012). As a functional hydrogel, a thermosensitive hydrogel can exert a sol-gel transition in response to a change in temperature, which permits its beneficial injectability and enables control over the stability, viscosity, mechanical strength and degradation profiles (Dang et al., 2017; Park, Park, Lee, & Na, 2017). These significant advantages make hydrogels desirable for medical applications, thus they are currently receiving a great deal of attention. The cyclodextrin and poly(ethylene glycol) inclusion is a special complex that forms via the host-guest interaction, and this complex has attracted attention as a biomaterial in drug delivery or tissue engineering due to its simple preparation, abundant drug loading ability and beneficial biocompatibility (Cugovčan et al., 2017, Li et al., 2016). A thermosensitive hydrogel based on cyclodextrin and poly(ethylene glycol) inclusion can be easily self-assemble by adjusting the components (Cui et al., 2014, Lin et al., 2017). Due to the dependence of structure and function, the hydrogel evolution in vivo is a crucial issue to be illustrated and revealed for the developments and applications of cyclodextrin/poly (ethylene glycol) hydrogels. Real-time tracking the hydrogel disassembly and status are important challenges for accurate and precise assessment. Besides, it is an issue worth considering to control the self-assembly and disassembly of the hydrogels for the intended requirement. The combination of tracking hydrogel evolution in real time and remote controlling the structural change of hydrogel provides a novel strategy for the investigation of cyclodextrin/poly (ethylene glycol) hydrogel.

Visualization of biomedical materials in vivo can be performed by medical imaging, which is an advanced tool for accurate tracking and monitoring in vivo (Appel, Anastasio, Larson, & Brey, 2013; Nam, Ricles, Suggs, & Emelianov, 2015). Fluorescence imaging has gained considerable attention for non-invasive visualization in living subjects due to its unique advantages including high sensitivity, low radiation, non-invasiveness and long-term monitoring (Etrych et al., 2016, Hilderbrand and Weissleder, 2010, Piper et al., 2013). In vivo fluorescence imaging has made great progress in the fields of medical diagnosis and imaging guiding, such as tumor diagnosis, inflammation monitoring, surgical imaging guiding, and tissue repair therapy and drug delivery tracking (Kruger et al., 2014; Lin, Huang, Chen, & Zheng, 2016; Schadlich, Kempe, & Mader, 2014; Selvam, Kundu, Templeman, Murthy, & Garcia, 2011). In our previous reports, several drug delivery systems and implants were monitored in real time and tracked successfully by fluorescence imaging (Dong, Wei, Chen et al., 2016; Dong, Wei, Liu, Lv, & Qian, 2016; Liang et al., 2017). The imaging results demonstrated the feasibility and superiority of fluorescence imaging in visualizing the release and distribution of the drug as well as the location, evolution of materials in vivo. Among the fluorescence imaging techniques, fluorescence tags play a vital and decisive role in the imaging effect and quality. Porphyrin is an advanced fluorescent tag with beneficial biocompatibility beyond that of other fluorescent dyes as a component of hemoglobin, which gives it unique advantages in fluorescence diagnosis and tracking (Lovell et al., 2011, Rieffel et al., 2015). Fluorescent probes and fluorescent hydrogels based on porphyrins were successfully designed and developed by our group for tumor diagnosis and drug delivery tracking (Dong, Wei, Lu, Liu, & Lv, 2016; Lv, Mao, & Liu, 2014; Lv, Lu, Wu, & Liu, 2011). In particular, a fluorescent polymer with the porphyrin core in the polymer backbone exhibited unique superiority over other fluorescent probes and enormous potential in imaging tracking, because the porphyrin that was conjugated on the polymer backbone could avoid the early selective breakage of the ectogenic fluorescent tags and afford minimal adverse effects on the biotissues (Dong, Wei, Liu et al., 2016, Lv et al., 2014). Accordingly, the porphyrin based hydrogel is a suitable visible biomaterial for in vivo fluorescence tracking.

The in vivo control and adjustment of the structure and status of medical materials can lead to functional changes and can enhance the therapeutic effect to meet clinical requirements. Remarkably, the remote controlled degradation or disassembly of the hydrogel in vivo introduces a new approach for advanced medical devices (Hawkins, Milbrandt, Puleo, & Hilt, 2014; Hawkins, Satarkar, & Hilt, 2009). This controllability can modulate the drug dosage and delivery time for drug delivery applications, or it can improve the degradation or disassembly profile for tissue engineering scaffolds applications according to changes in the requirements of a patient after implantation (Moncion et al., 2016, Wang et al., 2012). The hydrogels can control their rheological ability and degradation profiles depending on changes in the external environment including pH, ionic strength and temperature, or on diverse external stimuli such as ultrasound, light, electric current and magnetic field (Kang, Kim, Lee, Yoon, & Suh, 2013; Lim et al., 2015, Satarkar and Hilt, 2008). Thermosensitive hydrogels can adjust the sol or gel status in vivo depending on the change in temperature by the remote external stimuli, which can be used to optimize the function and effect for tissue repair or drug delivery.

Thermosensitive hydrogel nanocomposites systems have attracted considerable attention for remote controlled applications because of their accelerated and rapid response. Gold nanoshells, iron oxide nanoparticles, Pt nanoparticles and carbon nanotubes are several representative nanocomposites for the remote control of hydrogel degradation or disassembly based on a temperature change in the external stimuli, which manipulates the properties of the thermosensitive hydrogel nanocomposites as potential candidates for pulsatile drug delivery, tissue repair and soft actuator applications (Al-Sagur, Komathi, Khan, Gurek, & Hassan, 2017; Kwok, Tsang, Wang, & Leung, 2017; Mu, Liang, Chen, Zhang, & Liu, 2015). Of the thermosensitive hydrogel nanocomposites systems, photo responsive thermosensitive hydrogel nanocomposites systems are of great interest due to their advantages including non-invasiveness, simple manipulation and responsiveness to stimuli in a remote controlled, instant manner (Ninh, Cramer, & Bettinger, 2014). The photothermal responsive hydrogel can control the degradation or disassembly by simply adjusting the light wavelength, power density and exposure time (Céline et al., 2013; Servant, Methven, Williams, & Kostarelos, 2013). A carbon nanotubes- thermosensitive hydrogel not only can combine the thermal therapy and chemotherapy by the photothermal and synergistic effect of the sustained and controlled release, but also can improve tissue repair as a carbon nanotubes reinforced hydrogel (Céline et al., 2013, Ninh et al., 2014; Omidi, Yadegari, & Tayebi, 2017). These applications suggest that the photo responsive carbon nanotubes- thermosensitive hydrogel needs to be further developed as a controllable biomaterial.

We hypothesized that the intervention of porphyrin compound and carbon nanotubes could implement the visualization and controllability of hydrogels in vivo. In this article, a visible and controllable hydrogel nanocomposites system for photo response was designed and developed based on a thermosensitive porphyrin-poly(ethylene glycol)/α-cyclodextrin hydrogel loaded with multi-walled carbon nanotubes (PPEG-MWNTs/α-CD). Except of the function of visualization imaging, porphyrin-poly(ethylene glycol) (PPEG) enhanced the guest-host inclusion interaction of poly(ethylene glycol)/α-cyclodextrin due to its four armed structure by accelerating the rapid gelation in vivo. Moreover, it improved the dispersion of carbon nanotubes in the hydrogel nanocomposites system, which increased the photothermal efficiency of carbon nanotubes for controlling the hydrogel disassembly. With the advantages of the photo response, the hydrogel nanocomposites system enabled fluorescence imaging tracking and the ability for photothermal remote control. Multi-walled carbon nanotubes (MWNTs) manipulated the status and properties of the hydrogel nanocomposites system, and adjusted the hydrogel degradation or disassembly by the irradiation switch, achieving the in vivo controllability of the thermosensitive hydrogel. A porphyrin labeled hydrogel could be tracked in real time to determine the disassembly profiles based on the photothermal stimuli of carbon nanotubes, which allowed in vivo visualization by fluorescence imaging (Fig. 1). This ability provided an important foundation for exploring the application potential of the poly(ethylene glycol)/α-cyclodextrin hydrogel. The combination of controllability and visualization in vivo introduces a new approach to reveal the status and function of these biomedical materials in vivo.