Injectable nano-composite hydrogels based on hyaluronic acid-chitosan derivatives for simultaneous photothermal-chemo therapy of cancer with anti-inflammatory capacity

Abstract

Nowadays, the photothermal therapy (PTT) has received widespread attention and research by rapidly killing tumors with local high temperature. However, due to the irregular edges of tumor and the blurred boundary between normal and necrotic tissues, the desirable treatment cannot be achieved by the single PTT, and excessive heat will cause serious inflammation in local tissues. Herein, an injectable composite hydrogel is prepared by the oxidized hyaluronic acid (OHA) and hydroxypropyl chitosan (HPCS) via the imine bonds, which is employed as the delivery substrate for functional substances. In the gel medium, the mesoporous polydopamine (MPDA) nanoparticles are incorporated as the high efficiency photothermal agent and a reservoir of DOX, which can achieve the good photothermal conversion performance and pulsed drug release. Besides, the addition of the curcumin-cyclodextrin host-guest inclusion complex (CUR@NH₂-CD) in the composite hydrogel could reduce the inflammation caused by PTT. The composite hydrogel shows favorable the Hepa1–6 tumor inhibition in vivo by virtue of the comprehensive effect of the admired photothermal efficacy of MPDA, chemotherapy of DOX and anti-inflammatory of CUR. It can be predicted that the composite hydrogel has a broad prospect in the field of comprehensive therapy for tumor.

Introduction

Nowadays, the morbidity and mortality of malignant tumor, which severely threaten human life, are gradually increasing every year (Cullin, Azevedo Antunes, Straussman, Stein-Thoeringer, & Elinav, 2021; Hanahan & Weinberg, 2011; Martínez-Reyes & Chandel, 2021). For the treatment of malignant tumor, it is a challenge to achieve the effective and radical curative effect (Kong, Cheng, Wang, Fang, & Hwang, 2021; Lu et al., 2022; Morad, Helmink, Sharma, & Wargo, 2021; Propper & Balkwill, 2022). At present, the cancer treatments mainly include radiotherapy, surgery, chemotherapy (Debela et al., 2021). However, the surgery can not completely remove the cancer tissues, and the risk of cancer metastasis and recurrence appears (Li et al., 2020). Besides, the traditional radiotherapy or chemotherapy cause varying degrees of damage to the surrounding normal tissues and cells, and have serious side effects (Ahles & Saykin, 2007; Kaur, Hurwitz, Krishnan, & Asea, 2011; Wang et al., 2021). Therefore, it is urgent to design the innovative method to improve the curative effect and reduce the incidence of adverse in the process of treatment.

The photothermal therapy (PTT) mediated by nanomaterials is a new technology that can inhibit tumor growth by irradiating photosensitive nanomaterials with the near-infrared ray (NIR) light (Deng, Shao, & Zhao, 2021; Han & Choi, 2021; Li et al., 2021; Liu, Pan, & Liu, 2020; Zhi, Yang, O'Hagan, Zhang, & Donnelly, 2020). Compared with traditional treatments, the PTT has advantages of minimal invasiveness and therapeutic efficiency. Before the treatment, the specialized nanomaterials with admired photothermal conversion performance are injected directly into and gathered near the tumor tissue, which can convert light into heat to kill tumor cells or indirectly cause tumor cell apoptosis (Liu, Bhattarai, Dai, & Chen, 2019). When the temperature of the tumor site reaches 42 °C or above, the tumor cell death caused by the thermal ablation occurs (Knavel & Brace, 2013; Ma et al., 2022). However, the PTT usually requires a high-power density to maintain the higher temperature of tumor site, which may induce local inflammatory response. The inflammatory cells and leukocytes are induced by inflammation around the tumor microenvironment (TME), which suppresses antitumor immunity. Inflammatory factors produced by necrotic cells shape the TME to cancer cell favor, and stimulate tumor regeneration, causing that the therapeutic effect of tumor was significantly reduced. As a result, it is worthwhile and urgent to explore new strategies to restrain the inflammatory response generated by PTT in order to improve the efficacy of tumor treatment.

At present, the photothermal nanomaterials including inorganic and organic nanomaterials (Chen et al., 2019; Hu, Cheng, & Zhang, 2018; Lv, He, Wang, & Zhu, 2021; Wei, Zhang, Zhang, Wei, & Su, 2019) can be transformed and modified for the application of tumor imaging, drug loading, and etc. (Bian et al., 2021; Zhang, Li, Zhao, & Liu, 2018; Zhen, Pu, & Jiang, 2021). Polydopamine (PDA) is a kind of multifunctional biomimetic polymer material (Jin, Wang, Lin, & Jiang, 2020; Lynge, van der Westen, Postma, & Städler, 2011; Yang et al., 2021) which has broadband light absorption and photothermal conversion performance similar to natural melanin (Dai et al., 2017; Liu et al., 2020; Liu, Pan, & Liu, 2020; Zeng et al., 2018). In addition, the morphology and microstructure of PDA can be regulated by changing the polymerization method, and the mesoporous polydopamine (MPDA) nanoparticles were acquired by the organic template method (Shu et al., 2021; Wang et al., 2019). Compared with other photothermal materials, the MPDA nanoparticles hold the advantages of simple preparation, strong adhesion, high specific surface area, and good biocompatibility (Zhu et al., 2021). Furtherly, the MPDA nanoparticles can also be used as reservoirs to adsorb chemotherapeutic drug such as doxorubicin (DOX) by π-π interactions (Hak, Ravasaheb Shinde, & Rengan, 2021).

However, PTT disrupts the integrity of cell membranes, releasing intracellular components, which induce inflammatory responses. It mimics tumor regeneration and hinders subsequent treatment. As a natural polyphenol, the curcumin (CUR), which is extracted from the rhizome of turmeric, has extensive pharmacological activities such as anti-inflammatory, anti-liver fibrosis, antioxidant (Maheshwari, Singh, Gaddipati, & Srimal, 2006). However, due to the unadmired insolubility in water, CUR had a low bioavailability in the clinical application (Mahmood, Zia, Zuber, Salman, & Anjum, 2015). It will bring the hope in the comprehensive treatment of tumors by improving the solubility of CUR in the aqueous solution and unify modified CUR and photothermal chemotherapy (Mansouri et al., 2020).

With the mild gelation process and admired self-healing ability, the injectable hydrogels based on the imine bonds (Schiff base) have been widely studied. In order to achieve the network of hydrogel, the aldehyde groups were introduced into polymers by chemical modification or oxidation, which could react with the amino-containing polymers via the imine bonds. For instance, Wei et al. prepared a series of injectable, self-healing hydrogels through the aldehyde group modified polyethylene glycol and chitosan derivatives, which could widely be used in 3D cell culture, cell therapy, or tissue engineering (Fu et al., 2022; Gao et al., 2019; Xie et al., 2017; Yang et al., 2012). Besides, it has become the common strategy that sodium periodate was used to oxidize polysaccharides to obtain aldehyde bio-based derivatives, such as dextran, sodium alginate, hyaluronic acid, pectin and starch (Mo, Xiang, & Chen, 2021; Pandit, Mazumdar, & Ahmad, 2019). Subsequently, these reactive polysaccharide derivatives could be employed to construct the gel system via dynamic imine bonds with the components having amino functionality, which included cystamine, branched polyethyleneimine, gelatin, chitosan and derivatives (Li et al., 2020; Li, Fu, Duan, Zhu, & Fan, 2022; Shen, Yeh, Chiu, Wang, & Yeh, 2022). Among them, the injectable hydrogel based on all-natural components possessed prominent advantages due to favorable biocompatibility and biodegradation, which could be widely applied in cell culture and drug delivery, providing ideal minimally invasive and non-invasive treatments for cancer, nervous system and cardiovascular diseases.

In this study, an injectable composite polysaccharide-based hydrogel was achieved by the oxidized hyaluronic acid (OHA) and hydroxypropyl chitosan (HPCS) as the functional substrate (Scheme 1). The MPDA nanoparticles loaded in the hydrogel were acted as the high efficiency photothermal agent and a reservoir of DOX (DOX@MPDA). Besides, the cyclodextrin derivative (NH₂-CD) was employed to improve the solubility of CUR through the formation of the host-guest inclusion complex (CUR@NH₂-CD). The photothermal conversion performance, pulsed drug release, inflammatory factors, and the comprehensive efficacy of the composite gel were analyzed by in vitro and in vivo tumor experiment. The whole-natural hydrogel was employed as a carrier to load various functional components to achieve efficient and simultaneous photothermal therapy, and pulsed drug release. The addition of CUR@NH₂-CD in the composite hydrogel not only inhibits the tumor, but also reduces the inflammation caused by PTT. It can be believed that the strategy for the composite hydrogel blazes a trail in the field of comprehensive therapy for tumor.