Innovative theranostic hydrogels for targeted gastrointestinal cancer treatment

Tang, Min; Song, Junzhou; Zhang, Shuyi; Shu, Xiaolei; Liu, Shuang; Ashrafizadeh, Milad; Ertas, Yavuz Nuri; Zhou, Ya; Lei, Ming

doi:10.1186/s12967-024-05749-9

Review
Open access
Published: 27 October 2024

Innovative theranostic hydrogels for targeted gastrointestinal cancer treatment

Min Tang¹^na1,
Junzhou Song²^na1,
Shuyi Zhang³^na1,
Xiaolei Shu⁴,
Shuang Liu⁵,
Milad Ashrafizadeh ORCID: orcid.org/0000-0001-6605-822X⁶,
Yavuz Nuri Ertas^7,8,
Ya Zhou¹ &
…
Ming Lei⁹

Journal of Translational Medicine volume 22, Article number: 970 (2024) Cite this article

1919 Accesses
Metrics details

Abstract

Gastrointestinal tumors are the main causes of death among the patients. These tumors are mainly diagnosed in the advanced stages and their response to therapy is unfavorable. In spite of the development of conventional therapeutics including surgery, chemotherapy, radiotherapy and immunotherapy, the treatment of these tumors is still challenging. As a result, the new therapeutics based on (nano)biotechnology have been introduced. Hydrogels are polymeric 3D networks capable of absorbing water to swell with favorable biocompatibility. In spite of application of hydrogels in the treatment of different human diseases, their wide application in cancer therapy has been improved because of their potential in drug and gene delivery, boosting chemotherapy and immunotherapy as well as development of vaccines. The current review focuses on the role of hydrogels in the treatment of gastrointestinal tumors. Hydrogels provide delivery of drugs (both natural or synthetic compounds and their co-delivery) along with gene delivery. Along with delivery, hydrogels stimulate phototherapy (photothermal and photodynamic therapy) in the suppression of these tumors. Besides, the ability of hydrogels for the induction of immune-related cells such as dendritic cells can boost cancer immunotherapy. For more specific cancer therapy, the stimuli-responsive types of hydrogels including thermo- and pH-sensitive hydrogels along with their self-healing ability have improved the site specific drug delivery. Moreover, hydrogels are promising for diagnosis, circulating tumor cell isolation and detection of biomarkers in the gastrointestinal tumors, highlighting their importance in clinic. Hence, hydrogels are diagnostic and therapeutic tools for the gastrointestimal tumors.

Introduction

Cancer is a prominent contributor to global mortality, with around 9.6 million deaths attributed to cancer in 2018, out of a total of 18.1 million of diagnosed cases. Furthermore, up to 43.8 million cancer cases suffer from relapse within five years or less [1,2,3]. The most common tumor types in men are lung, prostate, colorectal, gastric and liver cancers, while breast, colorectal, lung, cervical and thyroid tumors are common among the females. According to the data, one in five of the males and one in six of females are diagnosed with tumor during their life [2]. Among them, one-in-eight men and one-in-eleven women cannot overcome this disease in their longevity [4]. The incidence rate of cancer has shown an increase in most the countries. The survival rate of cancer patients is low because of the late diagnosis and restricted access to therapeutics, which are more prevalent in developing countries [4]. Currently, there are a number of therapeutics for human tumors, including surgical resection, immunotherapy, chemotherapy, radiotherapy, targeted therapy and hormonal therapy [2, 5]. However, these therapeutic modalities are associated with adverse impacts affecting the life quality of patients. Moreover, the resistance to therapeutics is another hurdle towards the anticancer activity of chemotherapy drugs [5]. Therefore, oncological research has been directed towards the development novel therapeutics for the cancer [6], and the development of biomedical materials is among them.

The biomedical application of nano- and micro-materials in disease therapy has been of importance. These materials can propose new insights for disease therapy, especially cancer treatment, including cancer diagnosis, phototherapy, immunotherapy, improving gene therapy, boosting chemotherapy and significant reduction in tumorigenesis [7,8,9,10,11]. The current issues in cancer therapy, including drug resistance and the side effects of therapeutics, can be solved by such materials through the specific delivery of drugs and genes as well as high accumulation at the tumor site. Moreover, there is a need for the encapsulation of cargoes, including genes, to protect against degradation by enzymes. Therefore, there are many reasons for the development of materials in cancer therapy. Hydrogels are three-dimensional physical or chemical polymeric networks possessing hydrophilic groups [12]. Although hydrogels are not soluble in water, they are can absorb and swell in water, providing a number of characteristics, including biocompatibility, viscoelasticity and specific mechanical strength [13,14,15]. Hydrogels have been significantly applied in drug delivery and tissue engineering [16,17,18]. Both natural and synthetic organic polymers can be used for the development of hydrogels. In the recent years, natural hydrogels have been mainly comprised of polymers, and an example is collagen, which is one of the most common natural hydrogel materials and has been applied for skin and blood vessel reconstruction [19, 20]. Furthermore, natural-based hydrogels (such as hydrogels developed from fibrin and alginate) have been popular as safe structures in wound healing and drug delivery. The application of natural hydrogels in drug delivery can be limited due to their elasticity and easy degradation in vivo [21, 22].

The application of hydrogels in cancer is exponentially growing regarding the promise provided by these structures in tumor elimination. Upon incomplete radiotherapy suppression, the injectable hydrogels containing OK-432 and doxorubicin can be administered to increase anticancer immunotherapy through STING upregulation [23]. Injectable hydrogels can also be prepared from ferritin and oxidized dextran to increase tumor penetration through active transcytosis and promote anticancer immunotherapy [24]. In addition to accelerating cancer immunotherapy [25,26,27] and vaccine development [28], hydrogels can be used for photothermal therapy [29] and drug delivery [30]. Moreover, stimuli-responsive hydrogels, including NIR- and pH-sensitive hydrogels, can be used in cancer therapy [31].

Gastrointestinal (GI) tumors are among the most malignant diseases posing major threat to human health and providing high mortality and morbidity. There are significant challenges in the treatment of GI tumors, requiring novel strategies in their suppression. First of all, there is a complicated and dense tumor microenvironment (TME) preventing the entrance of bioactive molecules and therapeutics to this region, reducing the penetration of drug. As a result, the nanostructures have been introduced for the drug delivery in GI tumor therapy [32]. Moreover, the conventional therapeutics used for GI tumors suffer from specific delivery and may cause damage to healthy tissues. Due to the malignant behavior of GI tumors, they have the potential to develop resistance to conventional therapeutics including radiotherapy [33], chemotherapy [34] and immunotherapy [35, 36]. Therefore, the new strategies should be introduced for GI tumor therapy that nanoarchitectures are among them [37]. In addition, there are challenges in the diagnosis of GI tumors that nanoparticles can aim in improving diagnosis of patients [38]. Regarding these challenges in the treatment of GI tumors and promises of hydrogels, the present review has been dedicated to understanding the application of hydrogels for the treatment of gastrointestinal cancers as a major threat to human health, and such hydrogels can mediate drug delivery and increase anticancer activity along with reversing drug resistance. The development of hydrogels and their stimuli-responsive kinds can improve the fight against digestive tumors. Figure 1 represents an overview of the application of hydrogels for the treatment of gastrointestinal tumors.

Hydrogels: basics and oncological application

Wichterle and Lim, in 1960, used the word hydrogel for the first time to describe the material they developed from poly-2-hydroxyethylmethacrylate (PHEMA), which is a synthetic biocompatible material used in contact lens applications [39]. Then, the PHEMA lenses were distributed in Western Europe in 1962, despite poor availability and acceptance. However, PHEMA lens very soon received approval from FDA [40]. Until now, hydrogels have been used as contact lenses, particularly in soft lenses developed from silicon hydrogels. Furthermore, extensive applications in biomedicine, especially in tissue engineering and wound healing, have been observed [41, 42]. Their application in wound healing is due to their ability to provide a moist environment and prevent the spread of fluids to other regions of skin tissue. Currently, several of their commercial forms are available, including DermaFilm^®, Kaltostat^®, Condress^®, and Sofargen^® [43]. Moreover, a number of them have been embedded with bioactive compounds, including iodine or zinc ions, to improve their antimicrobial and cleansing features, respectively [40]. The clinical applications of hydrogels for the treatment of human diseases have also been followed. Perseris^®, Sublocad^® and Azasite^® are several clinically used hydrogels for the treatment of diseases including schizophrenia, analgesia, and bacterial conjunctivitis, respectively [44]. Hydrogels can be categorized based on their composition, crosslinking, configuration, and source. For crosslinking, hydrogels can be developed through chemical or physical crosslinking. For composition, they can be developed from homopolymers, co-polymers, semi-IPN and IPN. From the source standpoint, hydrogels can be natural, synthetic, or hybrid. From the configuration standpoint, they can be amorphous, crystalline and semi-crystalline [45]. The common application of natural-based hydrogels is related to the delivery system development and tissue scaffolds because of their degradability and biocompatibility. The benefits of natural hydrogels include favorable biocompatibility, minimal toxicity, and natural degradation, while their cons include weak mechanical features and potential for immunogenicity. Synthetic hydrogels are mainly utilized in controlled drug release and regenerative medicine, offering precise control over physical and chemical properties. Their benefits include adjustable characteristics, including pore size and degradation rate, robust mechanical strength, while their cons include toxicity and less biocompatibility compared to natural hydrogels. Hybrid hydrogels possess the features of both natural and synthetic hydrogels using in drug delivery systems and tissue engineering. Their benefits include improved mechanical properties and biocompatibility, customizable features, whereas their cons include complicated synthesis and potential issues with batch-to-batch consistency. Amorphous hydrogels are promising in wound dressings and contact lenses due to their flexible and soft nature. Their benefits include favorable water content and conformability to various shapes, while they suffer from lower mechanical strength and structural integrity. Crystalline hydrogels are utilized in load-bearing applications, including cartilage replacements due to their structured networks. Their benefits include improved mechanical strength and stability, while their cons are decreased swelling capability and flexibility, which might limit their use in some biomedical applications. Semi-crystalline hydrogels are deployed for drug delivery systems that require a balance between mechanical properties and fluid dynamics. Their benefits include improved mechanical strength and water absorption capabilities, while their cons include complicated manufacturing processes. More information regarding the synthesis of hydrogels can be found in these reviews [46,47,48,49,50].

Until now, multiple studies have shown the different strategies utilized for the preparation of the hydrogels [14, 51,52,53,54,55,56,57,58,59,60]. The polymerization method is the first strategy for the development of hydrogels. A number of polymerization methods, including free-radical polymerization, can be utilized for hydrogel synthesis that is simple and efficient. Another strategy is the crosslinking method, which can occur as physical crosslinking using hydrogen bonding and ionic interactions, or chemical crosslinking using covalent bonding to improve the mechanical stability and functionality of hydrogels. Notably, the monomers used for the synthesis of hydrogels are of importance and can affect hydrogel characteristics. As an example, acrylic acid and its derivatives have been extensively used in the synthesis of hydrogels due to the high water absorbance ability and adjustable mechanical features. Both natural and synthetic polymers including alginate, chitosan, poly(vinyl alcohol) and polyacrylamide can be used for the synthesis of hydrogels. In order to develop biocompatible hydrogels, the synthesis of these materials using a green approach is suggested. Furthermore, stimuli-responsive hydrogels (sensitive to pH, temperature, light and magnetic field) and nanocomposite hydrogels (adding nanostructures into the structure of hydrogels) have been developed for biomedical applications.

The application of hydrogels in cancer therapy has opened a new gate for tumor suppression. Hydrogels have been shown to be beneficial for tumor microenvironment (TME) remodelling [61], immunotherapy [62, 63], vaccine development [64], drug delivery [65, 66], nanoparticle and drug co-delivery [67] and phototherapy [68]. Hydrogels can be developed from pectin and carboxymethyl to deliver silibinin, impairing the progression of lung tumor in vivo and impairing the function of TMEM16A ion channel [69]. Despite using oral vaccines, their clinical application due to the safety issues is under question. Therefore, chitosan-sodium alginate microcapsules have been developed to encapsulate engineered bacteria and protect against the conditions in the stomach. Moreover, the dissolution of the microcapsules can lead to the release of bacteria in the intestine periodically, improving cancer immunotherapy [70]. Another function of hydrogels is related to the stimulation of macrophages, increasing their phagocytic activity, and promoting systemic cancer immunotherapy [71]. Hydrogels can accelerate cancer phototherapy, and for this purpose, injectable nanocomposite hydrogels have been developed based on alginate-Ca²⁺ to provide melittin-assisted Ca²⁺ overload for increasing photothermal-mediated tumor ablation [72]. One of the interesting points of hydrogels in cancer chemotherapy is their potential for the slow release of drugs such as doxorubicin [73]. This can potentiate chemotherapy and prevent drug resistance in cancer cells. The presence of tumor cells at TME can cause cancer relapse, and therefore, immunomodulatory DNA hydrogels comprised of PD-L1 aptamers can be developed to sense cancer cells for monitoring postoperative tumor relapse [74].

Hydrogels in the treatment of gastrointestinal cancers

Colorectal cancer

One of the most common digestive tumors is colorectal cancer (CRC), where up to half of the CRC patients can develop metastasis into the liver and lung [75, 76]. The conventional therapeutics for CRC include surgical resection, radiation, and chemotherapy [77]. However, chemotherapy or surgery cannot significantly improve the survival of CRC patients. Therefore, the development of new strategies, mainly based on hydrogels, can improve the treatment of CRC. Hydrogels have been developed from the chemical crosslinking of hyaluronic acid (HA) and carboxymethyl cellulose sodium (CMCNa) and then loaded with oxaliplatin. These hydrogels can reduce intra-abdominal adhesion after chemotherapy. Moreover, the slow release of oxaliplatin from these hydrogels was observed to release drug via diffusion. The in vivo experiment was performed on an SD rat model, where the suppression of intra-peritoneal adhesion was provided by the hydrogels [78]. In this regard, hydrogels have been developed from HA and CMCNa through crosslinking, and then a double emulsion strategy was utilized to develop oxaliplatin-embedded Poly-(d,l-lactide-co-glycolide) (PLGA) microparticles. The PLGA microparticles had a size and zeta potential of 1100.4 nm and 77.9%, respectively. The microparticle-embedded hydrogels were able to release drug in a prolonged manner and they improved the pharmacokinetic profile of oxaliplatin. These hydrogels provided protection of damaged tissues against peritoneal adhestion [79]. However, the function of hydrogels is more than the regulation of abdominal adhesions; they can exert anticancer activities. Studies have shown that polysaccharides-based hydrogels are promising candidates for prolonged drug delivery because of their biocompatibility and high swelling [80,81,82]. Alginate (Alg) is one of the polysaccharides with common use capable of supporting the drugs against the gastric juice and providing intestinal delivery of drug [83]. In this regard, hydrogels have been prepared from Alg and CMC via crosslinking with Ca²⁺. Then, methotrexate (MTX)-loaded CaCO₃ (CaCO₃/MTX) and aspirin (Asp) are co-entrapped in the hydrogels. These hydrogels provide the protection of MTX in stomach and small intestine and deliver it to the colorectum [84]. Therefore, they are promising candidates in cancer therapy through the delivery of chemotherapy drugs.

One of the factors determining the cellular fate is the mechanical interactions occurring between the cells and TME, which are important in metastasis and migration. The type I collagen hydrogels have been shown to affect the migration of CRC cells, and this is determined by the stiffness of the hydrogels related to the collagen concentration and gelatin temperature [85]. However, this aspect has been ignored in most of the studies and they emphasized on the development of novel hydrogels and loading different drugs or other bioactive factors in the treatment of CRC. The physical cross-linked hydrogels have been developed from ABA triblock copolymers of vitamin D-functionalized polycarbonate and poly(ethylene glycol) to deliver Avastin in the treatment of CRC. Two models of CRC, including subcutaneous and intraperitoneal metastatic tumor models, were used. These hydrogels exerted more suppressive activity on subcutaneous tumors compared to intraperitoneal models, and they preferentially accumulated at the tumor site with low accumulation in the liver and kidney. These hydrogels improved the survival rate of animal models and they suppressed metastasis [86].

One of the types of hydrogels is mucoadhesive hydrogels, which are capable of binding to mucin, as a glycoprotein generated by the cells in the mucosal tissues. The presence of functional groups, including carboxylic acids, amines, or thiols can affect the extent and strength of interaction with mucin [87, 88]. In line with this, mucoadhesive hydrogels have been developed by grafting poly(acrylic acid) (PAA) on cellulose nanocrystals (CNC) at 6, 9 and 12 CNC:PAA w/w ratios. These hydrogels possessed rheological behavior when there is mucin compared to CNC and other gels, and they can release cisplatin in a sustained way to increase suppression of CRC [89]. In another study, hydrogels were developed from chitosan and chondroitin sulfate. In order to improve chitosan solubility and hydrogel characteristics, the hydrogel synthesis was performed from ionic liquids. Then, curcumin and silver nanoparticles were loaded into hydrogels. These hydrogels, along with photodynamic therapy (PDT), demonstrated potential in the induction of cell death in CRC due to increased metal-mediated singlet oxygen. Moreover, their biocompatibility was high due to lack of impact on healthy tissues [90].

One of the strategies is loading nanostructures inside the hydrogels for CRC therapy. In this line, alginate nanostructures have been functionalized with folic acid and then embedded in hydrogels. The conjugation of folic acid to alginate nanoparticles was performed by NH₂-linkage, and they can target the folate receptor overexpressed on the surface of cancer cells. The pH-sensitive hydrogels were developed via a free radical polymerization strategy to mediate the sustained release of diferourylmethane. The pH-mediated release of drug occurred at a pH level of 7.4, and it was internalized by the tumor cells through folate receptors [91]. This system can release the nanoparticles at the tumor site and then the nanoparticles provide the controlled release of drugs to increase the anticancer potential. In another work, hydrogels were developed based on inulin, and then they were loaded with hollow MnO₂ nanocarriers containing oxaliplatin. Bacteria in colon tissue mediated the metabolism of these nanoparticles to degrade inulin and produce short-chain fatty acids to mediate immune responses and regulate microbiota, providing site-specific release of oxaliplatin and increasing ROS generation in the acidic TME [92]. It can be highlighted that hydrogels are promising factors for the delivery of chemotherapy drugs in CRC suppression. Hydrogels can also impair peritoneal carcinometastasis of the colorectal and decrease its growth [93,94,95,96,97,98,99,100]. Hydrogels are ideal candidates for the site-specific delivery of naringenin and tannic acid in CRC therapy [101, 102], emphasizing their function in natural product delivery. Moreover, hydrogels provide the prolonged release of drugs in CRC therapy [103].

Gastric cancer

Gastric cancer (GC) is another malignant of gastrointestinal tract, and it is a major public health problem [104]. GC has been mentioned as the most malignant tumor in China and the leading cause of death [105]. Surgical resection, along with chemotherapy and radiotherapy, are conventional therapies for GC [106]. However, the tumor cells can develop resistance to traditional therapies. Therefore, the application of nanoparticles for the treatment of GC has surged. Regarding this, hydrogels have been developed to deliver a number of chemotherapy drugs, including cisplatin, to improve the survival time of animal models bearing GC cells and impair proliferation and invasion [107]. Hydrogels can deliver several chemotherapy drugs to suppress GC. In line with this, biodegradable hydrogels have been developed from PDLLA-PEG-PDLLA to deliver cisplatin and 5-fluorouracil. The hydrogels provided the prolonged release of cargo, and stimulated apoptosis, while suppressing proliferation of cancer cells. On the other hand, the adverse impacts were reduced, and the in vivo experiment highlighted the reduction of growth in metastatic tumors [108].

Compared to systemic therapy, local therapy has been suggested to be more effective in cancer therapy [109,110,111]. The local intraperitoneal chemotherapy allows to preserve high levels of drug at peritoneal cavity for a prolonged period of time, and this can also decrease side effects [112, 113]. In line with this, hydrogels have been developed from polyethylene-glycol-modified bovine serum albumin (PEG-BSA). Then, red blood cell membrane biomimetic nanostructures containing paclitaxel were loaded into the hydrogels. The nanostructures had a size of 133 nm with a negative zeta potential. Moreover, their drug encapsulation and loading were 85% and 22%, respectively. These injectable hydrogels provided prolonged drug release with a cumulative release of paclitaxel of 30% after six days. In addition to being biocompatible and biodegradable, these hydrogels showed high anticancer activity and impaired tumorigenesis in vivo [114]. Regarding the high importance of intraperitoneal delivery of drugs in GC therapy, a similar strategy has also been used for the delivery of cisplatin. A biodegradable hydrogel has been developed from crosslinking of hyaluronic acid with adipic dihydrazide and aldehyde that can mediate in-situ gelation in peritoneum, and it released cisplatin for 4 days. This delivery system reduced the weight of peritoneal nodules [115]. It appears that the development of hydrogels from hyaluronic acid is beneficial in improving the sustained release of cargo. For instance, hyaluronic acid-based hydrogels can release cisplatin for 2 days [116]. Hybrid networks can be also developed, such as a network of gelatin microsphere-alginate hydrogel, which can provide prolonged release of 5-fluorouracil as cargo in GC therapy [117]. Hydrogels should be developed from sources and compounds to improve their erosion capacity. Notably, the development of hydrogels from poly(organophosphazene) (PPZ) containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 improves the erosion ability of the hydrogels, and they can deliver docetaxel in GC therapy [118]. As a result, hydrogels can provide co-delivery of drugs (paclitaxel and doxorubicin) [119] and mediate prolonged release of chemotherapy drugs [120]. Nanoparticles can be loaded in gelatin hydrogels to exert anti-tumor activity upon local implantation [121].

Liver cancer (hepatocellular carcinoma)

Liver cancer is the fifth leading cause of death in the USA, and its incidence rate has gradually increased [122]. Up to 80–90% of all liver cancers are hepatocellular carcinoma (HCC), and cholangiocarcinoma is responsible for the 10–15% of liver cancer cases [123]. Hepatoblastoma and HCC can affect both children and adolescents, responsible for 67–80% and 20–33% of cases, respectively [124]. Despite advances in the treatment of HCC and the development of new strategies for the diagnosis of this disease, it is still one of the leading causes of death. Regardless of the diagnosis, liver cancer cells can develop therapy resistance, urging scientists to develop new strategies for its treatment. Although chemotherapy is the main tool for liver cancer therapy, systemic chemotherapy shows poor efficacy, and it is associated with side effects. Hydrogels can provide new insights for the effective treatment of cancer through local chemotherapy [125]. The hydrogels utilized for the treatment liver cancer have been synthesized from different compounds including hyaluronic acid and tyramine [126], poloxamer 407 and alginate [127], PEG and gelatin [128], PCLA [129], cellulose [130], curdlan derivatives [131], k-carrageenan [132], PVA/CNCs [133] and PNIPAm-co-Polyacrylamide [134]. Each of these hydrogels demonstrates its own benefits, and they can be used for drug delivery, sustained release of cargo, and overall, improving the fight against tumors.

Surgery is one of the options in the treatment of HCC. In addition to the surgical hemorrhage, the relapse rate of HCC is also high. Hydrogels have been shown to overcome such challenges in the treatment of HCC and reduce its recurrence. In this regard, nanoparticle-embedded hydrogels have been suggested. A block copolymer containing PEG and polyglutamic acid has been utilized for the encapsulation of monoclonal antibodies, generating self-assembled micelles. However, such nanostructures suffer from poor stability, and therefore, magnesium calcium carbonate nanostructures encapsulating monoclonal antibodies were developed through a chemical precipitation strategy to improve stability. Finally, the hydrogels synthesized from fibrinogen and thrombin were combined with previously synthesized nanostructures. These hydrogels not only diminish surgical hemorrhage but also prevent cancer recurrence through inducing dendritic cell maturation and activation of T cells to impair tumorigenesis [135].

In addition to proliferation, metastasis and recurrence, another issue in HCC is the angiogenesis, which is the generation of new vessels from the pre-existing ones to increase the nutrition entrance into the tumor site and mediate their spread. HCC could recruit tumor-associated macrophages (TAMs) in revascularization and enhance tumorigenesis. In this regard, hydrogels have been developed from the co-assembly of PCN-Len nanoparticles and oxidized dextran, and then, the nanomodulators of TAMs-reprogramming polyTLR7/8a, known as (p(Man-IMDQ) nanoparticles, were embedded into the hydrogels. Each part has a function in the cancer therapy. PCL-Len nanoparticles can target the tyrosine kinases in vascular endothelial cells to impair VEGFR. Then, (p(Man-IMDQ) nanoparticles mediate the re-education of M2 polarized macrophages into M1 macrophages through mannose-binding receptors and diminish VEGF secretion by suppressing the invasion and growth of vascular endothelial cells. The in vivo experiment showed that single administration of such hydrogels can reduce tumor microvessel density and increase vascular network maturation [136].

In addition to the delivery of chemotherapy drugs, hydrogels have been used to deliver bioactive natural compounds with anticancer activity. Curcumin is a bioactive compound of Curcumin longa, and in addition to its antioxidant activity, this compound has shown high potential in cancer therapy and overcoming chemoresistance. The delivery of curcumin by hydrogels can potentiate its anticancer activity. The hydrogels were developed from glycyrrhetinic acid-modified curcumin supramolecular pro-gelators showing desirable water solubility. The formation of supramolecular gels is due to the disulphide bond reaction mediated by glutathione. The hydrogels can release curcumin in a prolonged manner, and due to the upregulation of GA on the surface of liver cancer cells, they show high internalization in tumor cells and impair tumorigenesis [137]. In addition, the hydrogels developed from PDLLA-PEG-PDLLA can be loaded with paclitaxel nanostructures to impair liver metastasis [138]. Therefore, hydrogels are promising candidates for the suppression of lymph node metastasis [139] and delivery of chemotherapy drugs [140] in cancer therapy.

Pancreatic cancer

Pancreatic cancer (PC) is one of the leading causes of death worldwide [141]. Although PC is accountable for 3% of all cancer cases, PC is responsible for 7% of all cancer deaths [122, 142]. The on-time diagnosis of PC is still challenging, and it is mainly diagnosed in advanced stages. Moreover, only 10% to 20% of patients are eligible for the surgical resection [143]. The aggressive nature of PC can result in drug resistance [144, 145]. Gemcitabine is commonly used for the treatment of PC; however, the tumor cells can develop resistance to therapy. Regarding this, hydrogels have been utilized for the prolonged release of gemcitabine in PC therapy. The hydrogels have been prepared from oxidized-carboxymethylcellulose (OCMC) and CMCS via a dopamine-functionalized method to mediate prolonged release of gemcitabine for impairing growth, increasing apoptosis and the treatment of PC [146]. In another experiment, PEG cross-linked HA hydrogels comprised of PEGylated TRAIL have been prepared. HA was conjugated to the 4-arm PEG(10 k)-amine as cross-linker using another cross-linker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, and then PEG-TRAIL was loaded within the hydrogels. The yield for the preparation of hydrogels at a 100:1 ratio was more than 88%, and they were moderately stiff. These hydrogels released PEG-TRAIL in a period of 14 days in vitro, while it lasted 7 days in vivo. They demonstrated high anticancer activity through PEG-TRAIL mediated apoptosis [147]. Since TRAIL is beneficial for increasing apoptosis in PC cells, another study focused on the development of albumin-crosslinked PEG hydrogels through a thiol-maleimide reaction. These hydrogels are comprised of the thiolated human serum albumin and 4-arm PEG20k-maleimide. The gelation time of such hydrogel is adjustable, and it is in the range of 15 s to 5 min. This hydrogel demonstrated a hard interaction with the TRAIL protein, showing favorable release profiles for increasing therapeutic potential. Such hydrogels are beneficial for the injectable, prolonged release of antitumor compounds [148]. Solid tumor treatment can be accelerated by the application of intratumoral radiotherapy. Recently, hydrogels have been applied to potentiate PC radiation therapy. Notably, hydrogels can mediate intratumoral radiotherapy. In this way, thermosensitive micellar nanoparticles were synthesized from an elastin-like polypeptide (ELP), and their labeling was performed by radionuclide (131)I to generate in situ hydrogel. The presence of body heat induces the ELP micelles to change into insoluble form. The high energy β-emissions of (131)I increase depot stability through mediating crosslinks within the ELP depot over 24 h. These ELP depots demonstrated 52% and 70% accumulation in prostate and pancreatic tumors, respectively [149]. However, the studies regarding the hydrogel application in PC therapy are poor in terms of the variety of the applied drugs, the impact on the underlying molecular pathways in cancer, and the lack of attention to overcoming chemoresistance. Figure 2 highlights the development of hydrogels for the treatment of GI tumors.

Stimuli-responsive hydrogels in the treatment of gastrointestinal tumors

Stimuli-responsive hydrogels respond to the endogenous or exogenous stimuli by changing their physical and chemical features. Such changes can occur in response to pH, temperature, light, magnetic or electric fields, and specific biochemicals. Overall, there are several kinds of stimuli-responsive hydrogels with potential applications in cancer therapy. The pH-sensitive hydrogels are able to respond to alterations in pH levels that are efficient for the drug delivery in TME. The temperature-sensitive hydrogels undergo a volume-phase transition in response to temperature changes that can be utilized for responding to body heat or external temperature stimuli. The light-responsive hydrogels can alter their structure or release the cargo in response to specific light wavelengths with spatio-temporal precision. The magnetic-sensitive hydrogels contain magnetic particles that can react to magnetic fields, thereby releasing cargo. The redox-sensitive hydrogels respond to the alterations in the levels of glutathione in healthy and cancerous tissues. Moreover, there are enzyme-responsive hydrogels capable of responding to the enzymes in TME, including matrix metalloproteinase. More information regarding stimuli-responsive hydrogels can be found in these reviews [150,151,152,153].

Stimuli-responsive hydrogels in colorectal cancer

The stimuli-responsive of nanomaterials are a novel class in which they respond to the specific stimulus in the TME to release the cargo. Currently, the TME has a number of distinct features compared to the normal tissues, including alterations in pH, redox status, temperature and enzymes. Therefore, the development of stimuli-responsive hydrogels can provide new insights in the treatment of cancer. The most common kind of hydrogels that have been used for CRC therapy is thermosensitive hydrogels. This kind of hydrogel can be synthesized from conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) to deliver 5-fluouracil. This thermosensitive hydrogel can impair proliferation and metastasis, while it induces apoptosis in CRC cells [154]. Thermosensitive hydrogels release the drug in demand, and they can also be used for the delivery of other chemotherapy drugs including doxorubicin [155]. Other compounds for the synthesis of thermosensitive hydrogels are poloxamers P407 and P188 as well as alginate that can deliver 5-fluorouracil. This injectable hydrogel demonstrates a free-flowing form in ambient temperature, while having a SOL–GEL transition at 26.0 °C ± 0.6 °C, providing an in situ non-flowing gel at the physiological temperature. This thermosensitive hydrogel showed an elastic behavior and responded to shear-thinning fluid. The presence of alginate delays the release of cargo, and the drug undergoes release mainly by diffusion [156]. Thermosensitive hydrogels can also be synthesized from methyl-cellulose to deliver oxaliplatin as a chemotherapy drug. Along with high biocompatibility and thermosensitive feature, these hydrogels were able to provide prolonged release of cargo, and they stimulated apoptosis through inhibition of the PI3K/Akt axis [157]. Other kinds of nanoparticles can be loaded into thermosensitive hydrogels to increase their potential in cancer therapy. Biodegradable thermosensitive hydrogels have been synthesized from chitosan, and 5-fluorouracil-embedded micellar nanoparticles and cisplatin were loaded in the hydrogels. These hydrogels can disrupt the proliferation and invasion of CRC cells, while improving the survival time of animal model. Moreover, hydrogels can impair the metastasis of CRC cells to liver and lung [158]. As a result, the thermosensitive hydrogels are a promising approach in CRC therapy [159, 160]. However, other kinds of hydrogels, especially pH-sensitive hydrogels, can also be developed for CRC treatment.

Stimuli-responsive hydrogels in gastric cancer

The development of stimuli-responsive hydrogels can also offer help with the fight against GC. The majority of studies have focused on thermosensitive hydrogels in GC therapy. The thermosensitive hydrogels can be developed from poly(organophosphazene) (PPZ) to deliver docetaxel. These hydrogels can decrease tumor growth, improve the survival rate of animal models, and impair peritoneal metastasis in GC [161]. Previously, it was mentioned that Plu-CLA hydrogels can be developed for CRC therapy, and this has also been followed in the treatment of GC. The thermosensitive hydrogels based on Plu-CLA can deliver docetaxel, decreasing survival of GC cells. Moreover, these thermosensitive hydrogels stimulate apoptosis and decrease the number of peritoneal metastatic nodules [162]. The thermosensitive hydrogels are able to encapsulate gabbogic acid-loaded and iRGD-functionalized nanoparticles to exert anticancer activity [163]. The reason for functionalization with iRGD is to increase attachment to integrin receptors for increasing internalization by GC cells.

Stimuli-responsive hydrogels in liver cancer

Similar to other tumor types, stimuli-responsive hydrogels are also beneficial in the treatment of liver tumor. The most common type of hydrogels used for the treatment of liver cancer are thermosensitive hydrogels that can be prepared from PELG-PEG-PEGL to provide prolonged release of paclitaxel, and along with biocompatibility, they can suppress tumor xenograft [164]. In addition to paclitaxel, other kinds of chemotherapy drugs, such as doxorubicin, can be delivered by thermosensitive gels in cancer therapy [165]. One important potential is the co-delivery of chemotherapy drug and natural products in tumor suppression. Notably, thermosensitive Pluronic F127 hydrogels were utilized for the delivery of resveratrol microspheres and cisplatin to accelerate apoptosis and cell cycle arrest. In vivo experiments demonstrated the potential of hydrogels in reducing ascite number, decreasing proliferation, angiogenesis, and improving the survival rate of mice by increasing the potential of intraperitoneal chemotherapy [166]. Notably, the dual responsive hydrogels have been used in liver cancer therapy. The pH- and thermosensitive hydrogels can be developed from N-isopropyl acrylamide (NIPAm) and acrylamide (AAm) as comonomers. These hydrogels are known as PNIPAm-co-PAAm HG and they can deliver curcumin. The release of drug was performed in response to pH and temperature, and drug loading efficacy was 65%. The release of drug was performed at pH 5.5 and 40 °C and despite possessing favorable biocompatibility, they can reduce viability of tumor cells [167]. The hydrogels possessing self-healing and pH-sensitive features are of importance in cancer drug delivery. The changes in the TME (competition for proliferation and metabolism) can decrease the pH levels and put it at a mildly acidic level. Therefore, the pH-responsive hydrogels can release the drugs at the TME. Such hydrogels can be developed from N-carboxyethyl chitosan (CEC) through Michael reaction and dibenzaldehyde-terminated poly(ethylene glycol) (PEGDA). Doxorubicin was loaded in hydrogels for delivery, and the hydrogels possessed self-healing properties because of the dynamic covalent Schiff-base linkage between amine groups from CEC and benzaldehyde groups from PEGDA. In addition to biocompatibility and pH-sensitive release of drug, the hydrogels can impair the HCC [168]. Most studies have focused on the single drug delivery by hydrogels in cancer therapy. In order to accelerate loading bioactive compounds into hydrogel structures, porous hydrogels are suggested that can be developed from pNIPAM particles and deliver 5-fluorouracil and metformin. These hydrogels provide prolonged release of cargo in response to temperature, and due to encapsulation, they support the drug against resolving [169]. One of the challenges in the treatment of liver cancer is the presence of drug resistance. The upregulation of P-glycoprotein (P-gp) as a drug transporter on the surface of cancer cells can mediate drug efflux to decrease accumulation of drugs within the cells and mediate chemoresistance. To overcome such an issue, thermosensitive hydrogels have been developed from Pluronic PF127 and then modified with TPGS to suppress tumor growth and disrupt the resistance in P-gp-upregulating cancer cells [170]. Taking everything together, current studies highlight the importance of hydrogels in liver cancer therapy, and the thermosensitive hydrogels are more beneficial in this case due to responding to temperature. However, more attention should be paid to self-healing, thermosensitive hydrogels. The limitations have been mentioned in the conclusion of this paper.

Stimuli-responsive hydrogels in pancreatic cancer

The development of stimuli-responsive hydrogels is important in the treatment of PC due to their dense TME, requiring site-specific delivery systems to maximize the accumulation and internalization of drugs in PC cells. Paclitaxel-embedded liposomal gels are beneficial in the treatment of PC. The thermosensitive hydrogels demonstrate favorable sol-to-gel transition temperatures, and they can improve the drug stability [171]. A method for the preparation of such thermosensitive hydrogels is their development from PVLA-PEG-PVLA, and then paclitaxel- and gemcitabine-loaded liposomes functionalized with PR-b (targeting integrin α₅β₁) were loaded into hydrogels. These hydrogels can mediate prolonged delivery of cargo, and they can suppress the growth of PC [172]. Notably, pH- and enzyme-sensitive hydrogels have been also developed for the treatment of PC. These self-healing hydrogels have been developed from PLys- b-(PHIS- co-PBLG)-PLys- b-(PHIS- co-PBLG)- b-PLys that have been combined with the aqueous solution of gemcitabine. After injection at the tumor site, they are transformed into hydrogels, and their degradation occurs after being close to PC due to their pH-sensitive nature, improving their site-specific feature. The in vivo experiment showed that the efficacy of such hydrogels with embedding only 40% of the drug is similar to the peritumoral injection of 100% of the free drug [173]. Figure 3 demonstrates the application of stimuli-responsive hydrogels in GI cancer therapy.

Hydrogels in the phototherapy of gastrointestinal tumors

Colorectal cancer phototherapy by hydrogels

Regarding the progresses in the field of nanobiotechnology, there has been a significant focus on the application of new methods, including immunotherapy, photothermal (PTT), and photodynamic (PDT) therapy, and their combination in tumor elimination [174,175,176]. PDT and PTT are becoming novel strategies in cancer therapy because of their non-invasive features, high specificity, and poor adverse impacts [177]. Indocyanine green (ICG) has been utilized as a photothermal compound, and through changing light into the singlet oxygen, it can cure tumor [178]. However, this agent has poor photostability [179]. According to this, ICG-embedded pH-sensitive bortezomib supramolecular hydrogels have been synthesized to improve photostability of ICG and increase the potential of PTT and PDT as well as their combination with chemotherapy [180]. In another work, the hydrogels have been developed from sonosensitizer protoporphyrin IX (PpIX)-conjugated manganese oxide (MnO₂) nanoparticles and a glutathione (GSH) inhibitor. In this way, the MnO₂ nanostructures can increase oxygen levels to reduce hypoxia and promote ROS generation through the action of sonodynamic therapy. Then, GSH depletion can suppress GSH synthesis, increasing the potential of sonodynamic therapy in CRC therapy [181]. The combination of immunotherapy and phototherapy for the treatment of CRC should be followed in the upcoming studies. Moreover, EGFR-conjugated fucoidan/alginate-embedded hydrogels have been demonstrated to stimulate the EGFR/Akt axis in increasing apoptosis, and they also enhance mtROS levels to induce mitochondrial dysfunction and enhance protein aggregates. Moreover, such hydrogels can mediate cell cycle arrest and increase ROS levels to mediate cell death in CRC cells [182].

Pancreatic cancer phototherapy by hydrogels

In the recent years, phototherapy has emerged as a potential therapeutic strategy for PC [183,184,185]. Hydrogels can increase phototherapy-mediated PC ablation. In this regard, a thermosensitive liposomal hydrogel was developed for the delivery of gemcitabine and NIR-II photothermal compound, known as DPP-BTz. The injectable hydrogels demonstrated a flowing solution at room temperature, while they demonstrated cross-linked gel structure at the physiological temperature. Exposure to 1064 nm laser irradiation can mediate heat to degrade the thermosensitive liposomes for releasing gemcitabine in the elimination of PC cells, highlighting the importance of phototherapy and chemotherapy combination [186].

Hydrogels in the immunotherapy of gastrointestinal tumors

Colorectal cancer immunotherapy by hydrogels

In the recent years, nanoparticles have been introduced as novel therapeutics for the regulation of tumors and improving cancer immunotherapy. The activation of alternative molecular pathways and other genomic changes in cancer can mediate immune evasion and the low response of patients to immunotherapy. Therefore, nanoparticles have been utilized for the delivery of immunomodulators and reversing the immune evasion in human cancers [10]. Increasing evidences have shown the application of hydrogels for the regulation of immune responses in CRC therapy. Regarding this, thermosensitive hydrogels have been developed based on the self-assembly of PDLLA-PEG-PDLLA to generate PLEL micelles and then loading R848 and oxaliplatin to develop PLDL hydrogels. The in vivo injection of these hydrogels leads to the in situ vaccination of tumor cells through the regulation of TAAs, CRT and HMGB1 to finally induce dendritic cell maturation. Then, dendritic cells mediate proliferation and activation of cytotoxic T lymphocytes in the lymph nodes to increase chemo-immunotherapy [187].

The immune checkpoint inhibitors have been widely utilized in the treatment of cancer, demonstrating better efficacy compared to small molecules and antibodies [188]. In addition, the anti-PD-L1 antibodies have been combined with other therapies, including radiotherapy and chemotherapy, to enhance their potential [189]. The introduction of nanomaterials can improve the efficacy of this therapy [190, 191]. In this regard, sodium alginate hydrogels have been synthesized that are comprised of elesclomol-Cu and galactose, inducing cuproptosis and reducing PD-L1 levels in cancer immunotherapy. The immobilization of elesclomol into a sodium alginate saccharide chain through the coordination with bivalent copper ions (Cu^2 +), followed by the incorporation of galactose, can lead to the fabrication of hydrogels. The implantation of these hydrogels into the cancer site can lead to the crosslinking with Ca²⁺ in the generation of hydrogels. Such hydrogels mediate DLAT oligomerization and cuproptosis in CRC, and despite PD-L1 upregulation by radiotherapy, these hydrogels suppress PD-L1 to release ES-Cu and galactome, increasing the efficacy of immunotherapy and radiotherapy in CRC suppression [192]. Therefore, the immune checkpoint inhibition by hydrogels can accelerate immunotherapy [193].

Gastric cancer immunotherapy by hydrogels

In the recent years, immunotherapy has been introduced as a novel therapeutics for GC. Several factors are responsible for the immune evasion in GC, including IL-1β-associated NNT acetylation [194] and PD-1 [195]. Therefore, hydrogels have been introduced for the immunotherapy of GC. The immunosuppressive TME in GC can be mediated by tumor-associated macrophages (TMAs) that the M2 polarized macrophages have carcinogenic function. In this way, injectable hydrogels have been developed for the delivery of polyphyllin II (PP2) and resiquimod (R848) in localized immunotherapy of GC. The synthesis of hydrogels was based on the Schiff base reactions between aldehyde-functionalized polyethylene glycol and the amino group of polylysine. These hydrogels increase M1 polarization of macrophages and promote the generation of TNF-α and IL-6. Furthermore, they upregulate iNOS/CD206 ratio in TAMs, increase infiltration of CD⁸⁺ T cells in GC therapy, and reverse immunosuppressive TME [196].

Liver cancer immunotherapy by hydrogels

One of the most challenging issues in the immunotherapy of liver cancer is the presence of immune evasion. The researchers have revealed a number of mechanisms involved in the immune evasion including PRDM1/BLIMP1 [197], HERC2 [198], HKDC1 [199] and TP53/mTORC1 [200]. However, such advancements have not been sufficient to overcome immune evasion in cancer patients. Therefore, novel strategies should be used with the possibility of clinical translation, and hydrogels are among them. The abnormal expression of ABHD5 is observed in HCC, and it can mediate PD-L1 to induce immunosuppression. An experiment has focused on the delivery of ABHD5 using the host–guest interaction with branched polyethyleneimine-g-poly (ethylene glycol), poly (ethylene oxide) and poly (propylene oxide) block copolymers and α-CD (PPA/CD) for the prolonged release of cargo. These hydrogels possess high stability and elevate the gene transfection efficiency for increasing apoptosis in the HCC cells [201]. Navoximod, an Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor, is able to enhance the herpes simplex virus type 1 (HSV-1) replication and HSV-1-induced oncolysis in cancer. Therefore, it is ideal for combination with HSV-1-mediated virotherapy. Both HSV-1 and Navoximod have been loaded in the injectable and biocompatible hydrogels known as V-Navo@gel to treat HCC. Such hydrogels provided a local delivery to increase the replication of virus (increasing anticancer immune responses) and were able to distribute in the tumor site upon one injection. These hydrogels improved the disease-free survival of mice and prevented cancer relapse. The mechanism of IDO1 upregulation is that virus induces Senser to mediate nuclear translocation of IRF₁. Then, secretion of IFNα/β occurs, which mediates the STAT1-STAT2 complex to increase IDO1 levels in inhibition of virus replication. Therefore, its inhibition by hydrogels can increase virus-mediated anticancer immune responses [202]. Hydrogels can be harnessed for improving the cell death-accelerated cancer immunotherapy. Notably, chitosan hydrochloride and oxidized dextran (CH-OD) were used to develop injectable hydrogels for the delivery of sulfasalazine. Such hydrogels stimulate ferroptosis with immunogenic activity. Moreover, these hydrogels can induce M1 polarization of macrophages and enhance maturation of dendritic cells to accelerate immunotherapy. These hydrogels also demonstrate synergistic impact with PD-1 immunotherapy to regress up to 50% of ascites and mediate long-term immune memory [203].

Pancreatic cancer immunotherapy by hydrogels

Immunotherapy has emerged as a potent strategy in the elimination of PC. Regarding the fact that various factors and mechanisms, including CD155/TIGIT [204], autophagy-induced MHC-I degradation [205] and FAK-inhibited antigen processing [206], participate in immune evasion in PC, it would be difficult to target all of these factors to disrupt immune evasion. Therefore, current treatments have been directed towards potentiating the immunotherapy of PC using novel strategies, and hydrogels are among them. TME remodelling by hydrogels has been suggested to be beneficial in cancer immunotherapy. The injectable hydrogels were prepared from chitosan and then IRF5/CCL5-siRNA-embedded nanostructures were loaded into the hydrogels to mediate immune niche reprogramming. Such hydrogels can increase IRF5 levels and reduce CCL5 secretion to promote M1 polarization of macrophages, increasing T-cell mediated responses in PC immunotherapy [207]. The hydrogels can function as vaccines in PC immunotherapy. The CD103⁺ CD11b⁻ cDC1-activated hydrogel microsphere vaccine was prepared for the PC ablation. For this purpose, Cas9 plasmid and CD40L were loaded into liposomes and CaCO₃ nanostructures, respectively, and at the next step, their combination with FLT3L cytokines and HA was performed to generate a hydrogel microsphere vaccine. These hydrogels can increase cDC1-induced antigen cross-presentation and CD⁸⁺ T-cell induction to trigger PC transformation from “cold” to “hot” tumor. Moreover, such hydrogels increase systemic immunity and suppress distant metastasis that are valuable in improving the survival of animal models [25]. Notably, hydrogel-mediated immunotherapy can prevent PC recurrence after surgical resection [208]. Figure 4 highlights the application of hydrogels in the phototherapy and immunotherapy of GI tumors.