Hydrogels are hydrophilic polymer networks formed by covalent bonds, van der Waals force or physical entanglement cross-linking, etc. They possess complex three-dimensional structures, strong water absorption and retention properties, and reversible swelling behavior [1]. According to different preparation materials, hydrogels include two types: synthetic polymer based hydrogels (SP hydrogels) and natural polymer based hydrogels (NP hydrogels). SP hydrogels are generally formed through the polymerization of small molecule monomers [2]. NP hydrogels are prepared from natural polymers, such as cellulose, starch, collagen, and sodium alginate. Natural polymers have attractive advantages such as wide sources, renewability, good biocompatibility, and biodegradability. Therefore, NP hydrogels have become promising materials for preparing drug carriers [3].

As the most widely distributed and abundant polysaccharide in nature, cellulose is a linear homopolymer formed by repeatedly connecting β-d-glucopyranosyl units through (1, 4) glycosidic bonds [4]. To improve its performance and expand its application range, various cellulose derivatives have been developed [5]. As an important cellulose derivative, hydroxypropyl methylcellulose (HPMC) is commonly used in the preparation of drug delivery systems due to its good solubility [6].

Polysuccinimide (PSI) is a cyto- and biocompatible polymer susceptible to enzymatic degradation under physiological conditions. It can be facilely modified because of its highly reactive succinimide rings [7]. PSI and its derivatives have been used to prepare biomaterials such as drug delivery systems and supports for enzymes [8].

Poly(ethyleneimine) (PEI) is a synthetic polymer with strong cationic properties and biocompatibility [9]. Due to the presence of a large number of amino groups in PEI, the performance of biomaterials can be improved after the addition of PEI, which contributes to their applications in many fields, such as drug delivery, cell fixation, wound dressings, and tissue engineering. In addition, the primary amines of PEI can adsorb protons to carry positive charges, producing electrostatic interactions with negatively charged bacterial surfaces, resulting in bacteria inactivation and death [10].

Therefore, HPMC, PSI, and PEI are ideal raw materials to fabricate smart hydrogels. Smart hydrogels can respond to external stimuli (pH, temperature, and electric field, etc.), which have been widely applied in biomedical fields [11]. Especially, pH and temperature-responsive hydrogels have received great attention, because pH and temperature changes can be easily controlled and are widely present in nature and the human body [12]. The pH and temperature of the tumor sites are also different from those of the healthy tissues, therefore, the development of temperature and pH sensitive drug controlled release carriers is of great significance [13,14]. Additionally, the type of chemical reaction used for forming crosslinking points has a direct impact on the properties and applications of the hydrogels. Therefore, great attention has been paid to the development of some new reactions for preparing hydrogels. Among them, click reaction is widely applied in the preparation of hydrogels due to its modularization, rapidity, high efficiency, and mild conditions. At present, the types of click reactions are constantly expanding [6]. In our experiment, we found that hydrogels could form rapidly in water via a fast, efficient and mild amino-succinimide reaction under open-air conditions, which was in line with the characteristics of click reaction. Therefore, we tried to fabricate cellulose based thermosensitive and pH sensitive hydrogels through amino-succinimide click reaction in water.

On the other hand, the performance of hydrogels can be effectively improved by forming a semi-interpenetrating network (semi-IPN) structure. Semi-IPN hydrogels contain a linear polymer chain and a crosslinked polymer network. There is no covalent bond between these two polymers. Their synergistic effect can not only improve the mechanical strength, but also improve the drug encapsulation and controlled release characteristics of semi-IPN hydrogels [15].

In the present work, a dual thermo- and pH-sensitive semi-IPN hydrogel was fabricated by introducing a temperature-sensitive cellulose derivative into the network formed through the ring-opening reaction of PSI with PEI. First, poly(N-vinylcaprolactam) containing terminal carboxyl groups (PNVCL-COOH) was prepared. Afterward, a thermosensitive cellulose derivative (HPMC-PNVCL) was synthesized by modifying HPMC with PNVCL-COOH. Partially ring-open PSI with good water solubility (PSI-TRIS) was obtained by modifying PSI with tris(hydroxymethyl)aminomethane (TRIS). Finally, HPMC-PNVCL, PSI-TRIS, and PEI were dissolved in water to obtain semi-IPN hydrogels through ring-opening reaction of PSI-TRIS and PEI. The temperature and pH responsive behavior of semi-IPN hydrogels was systematically analyzed by evaluating the swelling ratios at different temperatures and pH values. Their drug release behavior was investigated using 5-fluorouracil (5-Fu) as a model drug and the drug release mechanism was explored using zero-order model, first-order model, Higuchi model, and Korsmeyer-Peppas kinetic model.