Malignant tumors are one of most threatening diseases causing irregular death of humans. Although a lot of efforts have been performed, this problem remains unsolved up to date [1], [2], [3]. The chemotherapy is one of the most popular treatments for tumors, however, most of these chemotherapeutic drugs are also toxic to the living body. For example, the DOX is well known to be cardiac toxic [4], the Cisplatin and paclitaxel could cause nephrotoxicity [5], allergic reactions and neurosuppression respectively [6], etc. Mostly, the toxicity of the drugs was caused by burst and nonspecific release of the drugs to the living body, and the sustained release and targeted delivery could reduce the acute toxicity of the drugs to improve the antitumor efficacy. As a result, controlled release of the anti-tumor drugs drew great attentions in past decades [7], [8], [9], [10], [11], [12], [13]. Among the drug release systems, the biodegradable hydrogels are the most attractive since they could degrade in vivo to avoid possible side effects [14], [15], [16], [17], [18]. Generally, biodegradable hydrogels were designed form biomass like cellulose [19], [20], [21], [22], chitosan [23], [24], [25], [26], [27], [28], hyaluronic acid [29], [30], poly(amino acid) [31], [32], etc. [33], [34], [35]. However, as another important biobased polymer, pectin did not gain enough attention in hydrogel preparation like other biopolymers [33], [36]. The vicinal diol on pectin could be oxidized into aldehyde group to prepare Schiff-based cross-linked hydrogels [37]. These results proved the pectin is also very useful in hydrogel fabrication for bioapplications.

Besides the hydrogels as drug loading carrier, the loaded drugs are more important and co-loading of specific drugs to enhance the therapeutic effect of DOX is extremely expected.On the basis broad-spectrum anticancer drug DOX loading, co-loading of a specific anticancer drug to enhance the therapeutic effect of DOX is extremely expected. Limonin is a natural compound extract from the citrus plant of Rutaceae family [38] with a variety of biological activities including analgesic, anti-inflammatory, anti-anxiety, insecticidal, and anti-viral activities [39]. Recent research revealed the limonin is a potent inhibitor of TMEM16A ion channel which is specific high-expressed in many tumor tissues including lung cancer, head and neck squamous carcinoma and colorectal cancer [40], [41]. High expression of TMEM16A is closely related to tumor generation, deterioration, metastasis, and prognosis [42], [43]. Moreover, the TMEM16A inhibition can effectively inhibit the proliferation, migration, and invasion of lung cancer cells and promote cancer cell apoptosis [44], [45]. As a result, the limonin is expected to suppress lung cancer by targeting TMEM16A and the limonin has great potential application in lung cancer therapy.

To reduce the acute biotoxicity of the DOX by burst release and prolong the anti-tumor efficacy, the DOX was coupled onto the pec-Ald to prepare pec-AD in this research. With lower DOX component with covalent connection, the hydrogel showed moderate lung cancer therapy and high biosafety. Moreover, limonin as a lung cancer targeting medicine was loaded into the hydrogel to form a multi-targeted drug delivery system. The result showed the hydrogel formed fast with good mechanical property fit for injectable application. The combination of DOX and limonin showed serious biotoxicity while the hydrogel loaded drugs greatly reduced the toxicity with the therapeutic efficacy well preserved. As a result, the pectin based self-healing hydrogel with coupled DOX and limonin loading could have great potential application in lung cancer therapy in the future.