Responsive nanosystems for targeted therapy of ulcerative colitis: Current practices and future perspectives

Abstract

The pharmacological approach to treating gastrointestinal diseases is suffering from various challenges. Among such gastrointestinal diseases, ulcerative colitis manifests inflammation at the colon site specifically. Patients suffering from ulcerative colitis notably exhibit thin mucus layers that offer increased permeability for the attacking pathogens. In the majority of ulcerative colitis patients, the conventional treatment options fail in controlling the symptoms of the disease leading to distressing effects on the quality of life. Such a scenario is due to the failure of conventional therapies to target the loaded moiety into specific diseased sites in the colon. Targeted carriers are needed to address this issue and enhance the drug effects. Conventional nanocarriers are mostly readily cleared and have nonspecific targeting. To accumulate the desired concentration of the therapeutic candidates at the inflamed area of the colon, smart nanomaterials with responsive nature have been explored recently that include pH responsive, reactive oxygen species responsive (ROS), enzyme responsive and thermo – responsive smart nanocarrier systems. The formulation of such responsive smart nanocarriers from nanotechnology scaffolds has resulted in the selective release of therapeutic drugs, avoiding systemic absorption and limiting the undesired delivery of targeting drugs into healthy tissues. Recent advancements in the field of responsive nanocarrier systems have resulted in the fabrication of multi-responsive systems i.e. dual responsive nanocarriers and derivitization that has increased the biological tissues and smart nanocarrier’s interaction. In addition, it has also led to efficient targeting and significant cellular uptake of the therapeutic moieties. Herein, we have highlighted the latest status of the responsive nanocarrier drug delivery system, its applications for on–demand delivery of drug candidates for ulcerative colitis, and the prospects are underpinned.

Keywords:

• Ulcerative colitis
• non – targeted therapy
• smart nanocarriers
• responsive system

1. Introduction

Ulcerative colitis is a recurrent and chronic inflammatory condition with debilitative effects on patients’ normal physiology (Mandlik et al. 2021). It affects the gastrointestinal tract by distributing in the distal portion of the colon. The incidence of the recurrent type ulcerative colitis is relatively high and thus to control the progression of the ailment, long-term and regular treatment is required (Kucharzik et al. 2020). Antibiotics, sulfasalazine, Probiotics, immunosuppressive agents, and salicylic acid derivatives are the common medications used for the treatment of UC currently (Ni et al. 2017). However, in the existing therapies for ulcerative colitis, there are several limitations and potentially worse side effects that limit their use in clinical settings. Accordingly, the therapeutic entities from natural sources such as polysaccharides, polyphenols, and flavonoids have shown somehow safer profiles with minimal side effects with progression inhibition of ulcerative colitis (Chen Z et al. 2021; Pang et al. 2022).

To proceed with the therapy outcomes for ulcerative colitis, recently nanotechnology-based approaches have been exploited that have shown bright prospects by boosting drug solubility, bioavailability, and pharmacokinetics (Zhang, Wang, et al. 2022). In addition, such nanoparticles were surface modified through the introduction of ligands in order to target specific sites of the colon surface and subsequently avoid off-target drug release, side effects and minimize toxicity (Chen L et al. 2021). In this context, hyaluronic acid-modified nanoparticles were evaluated that resulted in the release of loaded cargo following endocytosis and also targeted macrophages with the CD44 mediation during ulcerative colitis treatment (Liu P et al. 2021; Hlaing et al. 2022). It was also found that degradation, burst drug release, and early GIT uptake of the nanoparticles failed in ulcerative colitis therapy. A colonic intelligent response-based polysaccharide microparticulate system was developed and evaluated for pH sensitivity, colonic microbial activation, and time response and results showed a joint strategy for the smooth release of the drug in the colon (Zu et al. 2021). The Food and Drug Administration (FDA) has approved chitosan and alginates as natural and safe biopolymers and therefore are used extensively as delivery carriers for drugs in nanotechnology. The positive charge chitosan and negative charge alginates attract each other in solution and could be used for the fabrication of microparticles that could be targeted to the colon. To circumvent nanoparticles’ limitations of pre-mature clearance, they could be encapsulated in the microparticles for the oral delivery of cargo to target the colon (Ling et al. 2019). Such fabrication provides greater area and depot in terms of nanoparticles that could become stimulus-responsive after certain engineering processes. Such chemistry of nanoparticles within the microparticles for oral delivery integrates two particulate mechanisms (Naeem et al. 2020). Furthermore, these systems protect the nanoparticles from enzymatic degradation until it safely reaches the absorption site.

The targeting of ulcerative colitis tissue is achieved through various nanotechnology scaffolds that protect the nanosystems as well as loaded cargoes through encapsulation, and instability in the gastric transition is prevented along with eliminating the premature drug release. It also promotes the nanoparticle release profile during the course of therapy. Thus responsive oral delivery system from nanotechnology platform for ulcerative colitis treatment presents a promising approach in terms of specific localization and intestinal delivery (Wang et al. 2021). This review article aims to highlight the current status of ulcerative colitis targeted therapies using responsive nanosystems to overcome the main challenges/barriers associated with conventional targeted therapy as well as non-targeted therapies. The future directions for the safe and effective use of responsive nanosystems are also underpinned as a part of this review article.

2. Pathophysiology of ulcerative colitis

The gastrointestinal mucosa comes in contact with millions of antigens usually from the microbiome, the surrounding environment, and the ingested food (Fändriks 2017). The gut immune system is protected by a thick layer of mucin that lies above the epithelium being the most exposed layer of the GIT mucosa (Grondin et al. 2020). The mucin layer not only provides a partition between immune cells of the GIT and antigens but also exhibits antimicrobial potential (Donaldson et al. 2016). In the case of ulcerative colitis, mucin synthesis and secretion is impaired, and the resultant epithelial injury causes the pathogens to penetrate inside due to high permeability of the injured mucosa. This subsequently leads to the gut immune system stimulation by increased uptake of pathogens (antigens) (Cantero-Recasens et al. 2022; Wan and Zhang 2022). The colonocytes – epithelial cells of the colon are highly implicated in ulcerative colitis pathogenesis that’s why ulcerative colitis is confined mainly to the mucosal and sub-mucosal layers of the colon (Thomas et al. 2019). It is believed that PPARg – a nuclear receptor is abnormally expressed in case of ulcerative colitis that leads to the down-regulation of inflammation (Toumi et al. 2021). The overall scheme of ulcerative colitis pathophysiology is depicted in Figure 1.

Figure 1. Pathophysiology of Ulcerative colitis.

The innate immune response is mainly activated by certain antigens such as T cells and antigen-presenting cells that also activate the adaptive immune system and eventually stimulate the inflammatory cascades (Ordás 2012). In ulcerative colitis, apart from pre – mentioned initiators the sensitivity and activation of mature dendritic also take part in the induction of inflammation as well (Tatiya-Aphiradee et al. 2018). Furthermore, the expression of these mature dendritic cells leads to the activation of a lot of Toll – like receptors that in turn provide recognition pattern to pathogens for the multiple transcription factor signal activation which finally starts various inflammatory cascades (Lee and Kim 2007). In turn, the triggered inflammatory cascades results in proinflammatory cytokine production particularly interleukins and tumor necrosis factor alpha that transduce message across the intracellular proteins notably Janus kinases that in response potentiate the activation of lymphocytes and proliferation (Danese et al. 2016; D’Amico et al. 2022). These findings suggest that such intracellular proteins and proinflammatory cytokines in the currently available treatments of ulcerative colitis act as suitable targets. In ulcerative colitis, there is also an imbalance between regulatory and effector T – cells that lead to dysregulation of the adaptive immune system (Xu X-R et al. 2014). Among the effector cells, the T – helper 2 cells in the colon activate natural killer T cells that upon stimulation trigger the secretion of various cytokines i.e. interleukin − 13, which results in the apoptosis induction within epithelial cells and hence leads to tight junction disturbances (Heller et al. 2008). The inflamed mucosa also attracts circulating leukocytes that mimic the inflammatory responses and such effect is mostly carried out by cytokines, which in the vascular endothelium trigger the adhesion molecule expression and thus promote the extravasations and adhesion of leukocytes into the tissues (Claesson-Welsh et al. 2021).

3. Current therapeutic approach for UC and limitations

Due to uncertainties about the etiology of the disease, it currently has limited therapeutic success. Therapeutic approaches, therefore, aim to achieve and sustain remission from inflammatory episodes. Anti-inflammatory medications such as 5-aminosalicylates (5-ASAs) e.g. mesalamine and corticosteroids, immuno-suppressants such as 6-mercaptopurine, azathioprine, methotrexate, and tacrolimus, and biologic anti- TNF (tumor necrosis factor) agents i.e. infliximab, golimumab, and adalimumab are some of the commonly prescribed medications (Yang et al. 2020). Several recently developed medications are also awaiting marketing approval, such as natalizumab, a leukocyte inhibitor, and several pro-inflammatory cytokines inhibitors such as interleukin 12 and 23 (IL-12 and IL-23) (Neurath 2017; Pagnini et al. 2019).

The treatment approach changes considerably with the type and progression of UC. There are three main types of UC namely, Mild-Moderate, Moderate-Severe, and Acute severe UC. Clinically, mild-moderate UC is defined as having four to six bowel movements per day with mild-moderate rectal bleeding, without constitutional symptoms like fever and tachycardia, and without laboratory abnormalities like anemia or elevated inflammatory markers (Kayal and Shah 2019). Mesalamines are the first-line treatment for mild-to-moderate UC remission induction. Sulfasalazine is a suitable substitute for mesalamine in patients with severe arthritic symptoms, though it is frequently poorly tolerated due to side effects like headache, nausea, diarrhea, and rash (Ko et al. 2019). The other moderate-severe type of UC is characterized by daily 4 to 6 bowel movements and moderate to severe rectal bleeding without any constitutional symptoms (Sc and Lj 1955). In addition to the small-molecule Janus kinase (JAK) inhibitor tofacitinib, biologics are frequently employed to treat this moderate-sever type of UC. The acute-severe UC requires hospitalization as it is a life-threatening condition. This type of UC is characterized by symptoms tachycardia (>90 bpm), fever (>37.8 °C), decreased hemoglobin (around 10.5 gm/dL), and/or raised erythrocyte sedimentation rate (ESR >30 mm/h) and at least six bloody bowel movements per day. Cyclosporine, Steroids and infliximab are currently accepted medical treatments for people with this type of UC who are being treated in a hospital (Lynch et al. 2013). A general schematic diagram for the most commonly used drugs class based on severity of the disease is given in Figure 2.

Figure 2. Schematic diagram for the commonly used classes of drugs based on severity of the UC.

Although these medications can reduce inflammation to some extent, 30 to 50% of patients still experience little to no improvement. In addition, long-term administration increases the likelihood of relapse and multiple adverse effects (Table 1), thus limiting further clinical applications (Mohan et al. 2019). Therefore, there is an urgent need to develop new treatment strategies to enhance targeting and reduce side effects. Decreasing drug-related side effects, effectively targeting drugs to the colonic region of the GIT, and increasing the drug concentration at the particular site are major challenges in treating UC. The main therapeutic benefits of using nanocarriers based drug delivery for the treatment of colonic diseases include: high drug concentration in the colonic inflamed tissues, which results in better therapeutic effects; a reduction in drug-related side effects due to a decreased systemic absorption of active agents; need of smaller drug dose to achieve the desired therapeutic outcome because higher local concentration is achieved; and a significantly increased patient compliance.

Table 1. Examples of the major drugs used for ulcerative colitis with their limitations.

Conventional Drugs for UC	Limitations	References
Aminosalicylates	High daily dosing, pancreatitis, interstitial nephritis,	(Sutherland and MacDonald 2006; Feagan and MacDonald 2012)
Azathioprine	leukopenia, pancreatitis, hepatopathy, increased infection tendancy, elevated chances of skin cancer other than melanoma, lymphoma, cancer of the urogenital tract	(Timmer et al. 2016)
Infliximab	Increased infection tendency, reactivation of TB, joint pain, rash, risk of melanoma	(Rutgeerts et al. 2005)
Adalimumab	Increased infection tendency, reactivation of TB, joint pain, rash, risk of melanoma	(Sandborn et al. 2012)
Golimumab	Increased infection tendency, reactivation of TB, joint pain, rash, risk of melanoma	(Sandborn et al. 2014a; Sandborn et al. 2014b)
Vedolizumab	respiratory infections	(Feagan et al. 2013)
Tofacitinib	Increase infection tendancy, embolism and thrombosis risks,	(Sandborn et al. 2017)
Cyclosporine	kidney and liver dysfunction, leukopenia, headache, hirsutism	(Lichtiger et al. 1994)

4. Barriers/challenges in successful therapy of ulcerative colitis

In the successful treatment of ulcerative colitis, there are various barriers that should be considered during the therapy and drug delivery that are mainly due to physiological and pharmaceutical factors. The drug delivery system must overcome all obstacles in the stomach and small intestine to reach the colon in the proper form. Major factors to be considered for successful therapy of UC are listed below:

4.1. Gastrointestinal (GI) motility and pH

Transit time in colon and intestine is one major challenge from physiological point of view. In this regard 21 healthy volunteers were evaluated for transit time and results showed an average transit time of 53 hours. As compared to other parts of gastrointestinal tract the colonic passage time was 40 hours (Sardo et al. 2019). Moreover, to hit ileocecal junction, duration of 3 – 4 hours is required for the administered dosage form (Sarvar et al. 2016). After an oral drug administration, the passage of bowl and gastric emptying as well pose a profound effect on the drug delivery. Here the matter of issue when the administered drug enters the stomach and before reaching the duodenum the time spent by it in the stomach (Caster et al. 2019). Furthermore, after administration of the drug, the process of gastric emptying varies with variation in the stomach phases. Particle size of the drug after reaching the colon plays an important role and decides the drug transit time i.e. small particles traverse colon faster than large particles and time taken ranges from 5/10 minutes up to two hours (Gauri et al. 2011). It shows that a drug delivery system targeted to colon should spent sometime in the stomach and so the release of drug at a far place from the colon will manifest an efficient delivery system. A small transit time is shown by diarrhea patients while larger by constipation patients (Deng et al. 2019). Drugs with delayed release (enteric coatings) kinetics and its association with the gastric pH is an important factor during drug delivery. A through look into the pH window of GIT shows that, in a healthy individual the stomach pH ranges from 1.5 − 3.5, while this acidic pH converts into basic pH down the duodenum (pH 6) reaches to 7.4 in small intestine and eventually drops to nearly 5.5 in the colon (Gaohua et al. 2021). Of note, colonic pH is considered as one major factor during the design of colonic delivery system because it is involved in the release of drug from the dosage form. In this regard, polymers are used to target the drug to a specific location and also to protect it from the harsh gastric environment (Verma et al. 2012).

4.2. Gastrointestinal enzymes and microflora

The metabolism process in the body is accelerated by certain intestinal enzymes that are secreted by certain microbial flora in the gastrointestinal tract. Such microbial floras also help in the eradication of several gastrointestinal disorders such as irritable bowel disease and thus have a significant impact on health (Garbern et al. 2011). The growth of existing microbial flora is controlled by the gastrointestinal contents and peristaltic movements. The terminal area of ileum is rich in microbial flora and thus it enrich the colon as well (Peng C-L et al. 2010). The drug from dosage form is released into the colon through the action of certain enzymes i.e. azoreductase, glycosidase etc. that is released by microbial flora into the colon. Moreover, gut flora have the ability to hydrolyze the certain polysaccharides, thus delivery polymers of this nature can be hydrolyzed by floral enzymes that will deliver the drug cargo efficiently (Nicholls et al. 2013). Therefore, selection of the polymers/other components liable to microbial degradation should be considered for proper release of the loaded contents in the right targeted site of the GI.

4.3. Mucus layer of the GI

Highly glycosylated material known as mucin is the mucus layer of the GI that works as a pseudo physical barrier for some large molecular drugs and that must be overcome by orally administered drugs (Xiao and Merlin 2012). Mucin is a hydrogel type mixture consisting of lipids, bacteria, proteins (including antibodies), carbohydrates, and inorganic salts. Mucin fibers, which make up the dense network of mucus and contain highly glycosylated, negatively charged segments, are the foundation of mucus’ barrier qualities. Additionally, mucins have regularly distributed hydrophobic domains that have a strong affinity for attaching hydrophobic particles. Whether a medication can enter and be absorbed by epithelial cells depends on how well a carrier interacts with mucus (Yang et al. 2014). Orally administered nanosystems could encounter any of the three different fates i.e. remaining bound to chyme, transiting rapidly through the GI tract and being quickly eliminated through the feces; binding to loosely adherent mucus, remaining bound until the mucus is cleared; or penetrating the mucus, remaining bound to firmly adherent mucus or entering the intestinal epithelium. In spite of the fact that mucus does not serve as an obstruction to the oral transport of many small and large molecular drugs, encapsulating these medicines within nanocarriers may increase their oral bioavailability (Lundquist and Artursson 2016).

4.4. P-glycoprotein efflux system

P-glycoprotein (P-gp) is an ATP-dependent drug efflux system at the apical surface of cells and works as an efflux membrane carrier (Johnstone et al. 2000). Lipophilic substrates that cross the lipid bilayer membrane into the lumen might get removed by P-gp and returned to the external medium before they can enter the cytoplasm. Examples of hydrophobic substrates include anticancer drugs, immuno-suppressants, steroidal drugs, calcium channel blockers, beta receptor blockers and glycosidic caridiac drugs. Small intestinal epithelial cells produce p-gp at significant levels, indicating the significance of this protein in reducing the oral bioavailability of certain drugs (Gavhane and Yadav 2012). Lymphocytes, the luminal epithelium of the colon, and other barrier-functioning tissues all show P-gp that must be considered before designing a carrier system for treating UC (Cortada et al. 2009).

4.5. Comorbid gastrointestinal conditions

In addition, the disease conditions such as constipation, diarrhea, irritable bowel disease etc. alter the colonic drug delivery system and should be considered during therapy and desing of nanosystem (Kadiyam and Muzib 2015). In the context of disorders as barriers, irritable bowel disorders causes thickening of the mucosa that leads to reduction in the surface area and subsequently low absorption of the lipophillic drugs. In addition, diarrhea leads to reduced drug retention time and less absorption (Kotla et al. 2014). Therefor, these factors should be kept in mind when selecting a nanosystem for specific patient.

4.6. Pharmaceutical factors

Weakly absorbed substances, like peptides, are more frequently absorbed in colon because the colon provides a longer retention time for them. Drug delivery to the colon can be accomplished using the same drug molecules that are used to treat GIT diseases. In the context of pharmaceutical factors, the colonic stay of drugs affects the drug absorption and thus for the low absorbed drugs colon provide more stay time and hence high absorption (Singh N and Khanna 2012). Therefore, such parameters should be considered for the delivery systems targeting colon. Drugs’ nature and intended use can be employed as carrier screening criteria. Other variables at play include the active functional groups in the drug, the chemistry of the medicine, stability factors, and other variables like the partition coefficient of the drug.

5. Conventional nanocarriers targeting ulcerative colitis

Among conventional nanocarriers systems targeting ulcerative colitis, the therapeutic agents or nanosystem could be efficiently protected from the acidic pH environment of the GIT by using nanogel and thus release the payloads when the carrier reaches the intestine (Bertoni et al. 2020). An extracellular matrix based hydrogel was fabricated and targeted to ulcerative colitis to avoid surgical procedure. Results showed a marked change in the phenotype of macrophage leading to a rapid replacement of barriers in the way of colonic mucosa. The prepared nanosystem was adhesive to the colonic tissue that resulted in an accelerated healing outcome (Keane et al. 2017). Similarly, another study showed the promising potential against ulcerative colitis by decreasing the expression of proinflammatory cytokines (Sun et al. 2021). To overcome barriers in the oral route of administration, siRNA loaded metal – organic – framework encapsulated in the sodium alginate hydrogel as a hybrid delivery system was targeted to ulcerative colitis. Results showed efficient delivery of the loaded cargo into the colon without degradation in the stomach and ensured targeted colon delivery (Gao et al. 2022).

Liposome is a nanoscafold that encapsulate both hydrophobic and water soluble drug candidates and provide the opportunity of surface modification as well that helps in targeting the inflamed colon (Singh AK et al. 2019). Solid – lipid nanoparticles provide a stable platform that offer more extended drug release and better protection due to slow disruption of the used matrix in these dosage units (Lee et al. 2020). Furthermore, self-micro emulsifying delivery system is used for hydrophobic drugs targeting into gastrointestinal disease conditions (Alsaad et al. 2020). In term of surface modification, curcumin loaded folate modified self micro emulsifying liposome were designed and targeted to ulcerative colitis that showed effective therapeutic outcome for the natural curcumin from the nanocarrier system (Zhang et al. 2012). Taking benefit of the anti-inflammatory properties of Oxymatrine – a Chinese medicinal herb, it was loaded into liposome for targeted delivery to ulcerative colitis. Due to the anti-inflammatory potential of Nitric oxide, it was also loaded to the same liposomal system and biodistribution studies investigated higher accumulation and retention time for the loaded drug entities. Results from ulcerative colitis mice model showed significant down – regulation of proinflammatory cytokines and decrease in macrophages’ infiltration, suggesting the anti – colitis potential of oxymatrine and nitric oxide loaded liposomes (Tang et al. 2020).

The role of polymeric nanoparticles for drug delivery is widely explored in recent years; however it bears certain serious hurdles such as synthesis scale up and toxicity. Such issues are somehow resolved by using polymers from natural sources (Yang Mei et al. 2020). For instance, nanoparticles from ginger and Lyceum barbarum have shown excellent anti-inflammatory effects by delivering siRNA (Zhang et al. 2017; Zu et al. 2020). Moreover, mesalamine loaded apple polysaccharide silver nanoparticles were developed for the effective treatment of ulcerative colitis. Results from acetic acid induced ulcerative colitis rat model showed effective therapeutic outcomes at higher doses of the drug loaded nanocarrier system as compared to low doses showing the efficacy of the afore mentioned nanosystem (Kaur et al. 2020). Similarly, Phragmites rhizoma polysaccharide selenium nanoparticles were developed and loaded with Azathioprine for targeting ulcerative colitis lesions. In-vivo results showed significant down regulation of the inflammatory cytokines at colonic and serum level that resulted in the clinical symptoms alleviations of the ulcerative colitis as well as healing of the lesions (Cui et al. 2022).

Still, these traditional nanocarriers are incapable of transporting and releasing medicines at the proper concentration at the desired site in response to internal or external stimulation. Consequently, conventional nanocarriers are not intelligent and they must be modified or functionalized to become intelligent and smart. The intelligent nanosystems should avoid the immune system’s clearance, accumulate in designated locations and release the loaded cargo at the desired concentration at the target site in response to internal or external stimulation. Moreover, they should be able to co-deliver drugs and other substances, like imaging agents, genetic components etc. Depending on the types and uses of nanocarriers, there are measures to convert conventional nanocarriers into intelligent ones (Hossen et al. 2019). Various features of the conventional and smart nanosystems are compared and contrasted in Table 2.

Table 2. Salient features of the conventional and smart nanosystems.

Characteristics	Conventional nanosystems	Smart nanosystems
Effects on healthy organs/ tissues	Pronounced effects	Less effects
Bioavailability	Low	high
Specificity	Relatively nonspecific	Specific
Therapeutic efficacy	Lower	high
Toxicity and side effects	High	low
Required dose	High	less

6. Smart nanosystem targeting ulcerative colitis

Strategies to convert traditional nanocarriers to smart ones rely on their intended use. The nanocarriers must pass through various physiological barriers, including reticulo-endothelial system (RES) of the liver and spleen. PEGylation- first reported by Davies and Abuchowsky (Abuchowski et al. 1977), is one way to avoid such clearance of the nanocarriers. However, PEGylation also decreases drug uptake by cells (Moghimi et al. 2001; Moghimi and Szebeni 2003). Additionally, nanocarriers can be decorated with certain ligands that could specifically distinguish diseased cells from healthy ones. The physiochemical variations of the diseased tissues and overexpression of certain components can be exploited for such purposes. Smart nanocarriers target such overexpressed receptors or proteins and ligands attach to their receptors making the system able to deliver the loaded drug to desired sites. Stimulating the nanocarrier system to release the drug in the desired target site is also a problem. Grafting chemical bonds or functional groups to nanocarriers makes them sensitive to internal and external stimuli. For synergistic and theranostic effects, co-delivery of drugs and other agents can also be exploited using smart delivery systems (Yan et al. 2022).

In nanocarriers based drug delivery systems, smart polymers based nanosystems have shown extensive applications particularly in colonic drug delivery (Singh D et al. 2015). Among these smart polymers, two types are widely explored including cationic and anionic pH sensitive smart polymers. Example of anionic pH sensitive smart polymer includes; poly(N,N-dimethylaminoethyl methacrylamide and the later one includes; chitosan, poly(lysine) and poly ethylenemie (Zhou and Chen 2015). Many studies have shown the use of smart nanosystem for the colon specific drug delivery. The use of such smart nanosystems have shown efficacy in various GIT disorders including ulcerative colitis (Salvi and Pawar 2019). It is one of the versatile advantages of the drug delivery from smart nanosystem that it offers reduced particle size, which targets a specified location and thus boosts bioavaibility. Reduction in the particle size also minimizes the delivery dose for the drugs and subsequently leads to reduction in the systemic side effects (Cherukuri et al. 2012). In addition, the conventional mood of drug delivery lacks the potential to absolutely deliver the desired drug concentration to the target site with accuracy; however, smart nanosystems ensure the target specific delivery of the payloads with minimal toxicity and better therapeutic outcomes (E Leucuta 2012). The delivery of drugs from different nano-platforms for treating UC is diagrammatically illustrated in Figure 3.

Figure 3. Illustration of smart nanosystems and their potential benefits for colon specific drug delivery.

6.1. Microbially triggered smart nanosystems for UC

Microorganisms known as the gut microbiota live in harmony with the host in the gut and secrete a number of enzymes that are involved in the metabolism of carbohydrates and reductive compounds (Peng et al. 2021). In the colon – stimuli – responsive systems, microbially triggered system are those that release the loaded contents when the system is degraded by the microflora causing release of the drug in to the intestinal environment and thus deliver at specific site (Dev et al. 2011). Of note, the smart polymers are not degraded at the gastric environment and early intestinal levels since less quantity of the flora is present at these areas. In this regard, metronidazole loaded azo aromatase based capsule were targeted to colon for treating colitis and the desired effect was achieved through degradation of polymer by floral enzymes at colon level (Hita et al. 1997). The enzymes from microbial flora involved in such mechanisms include; nitroreductase, arabinosidase, galactosidase, dehydroxylase, xylosidase (Sharif et al. 2017). In another study, dextran sulfate sodium induced colitis mice was evaluated by administration of a tripeptide loaded hydrogel. Results showed a lowest delivery concentration for the tripeptide as compared to free solution, however provided similar therapeutic efficacy with minimal side effects (Soni et al. 2015). A guar gum based 5 fluorouracil loaded system was delivered to the colon and resulted in an efficient release of the drug after exposure to the microbial flora indicating the enzyme responsive potential and subsequent use of the guar gum for UC targeting (Kumar et al. 2017).

Similarly, in vitro results from chitosan modified lipid nanoparticles showed esterase responsive property along with significant release of the drug that showed colon targeting effects. The invivo distribution results showed high retention of the drug in colitis bearing mice model as compared to free dexamethasone. This enzyme responsive smart nano system showed prominent anti ulcerative colitis effect (Chen S-q et al. 2020). To specifically deliver the payloads, curcumin loaded nanomicelles were fabricated in order to evaluate the enhanced mucoadhesion of the fabricated system and the azoreductase based drug release. The prepared nanosystem significantly released the drug based on azoreductase sensitive particles dissociation. The designed smart nano system based complex also mitigated ulcerative colitis symptoms through acceleration of colitis repair (Zhang, Li, et al. 2022b). In the field of oral gene therapy, nucleic acid drugs exhibit anti inflammatory potential by healing ulcers and thus manifest suitable opportunity for the ulcerative colitis. In a study, miR − 320 loaded alginate based polymeric nanocapsules were prepared and targeted to colon. Results from invivo imaging showed that the designed nanosystem reached the colon after 2 hours and released miR − 320 at colonic mucosa after degradation of alginates by enzymes (Li et al. 2022). To overcome the anatomical and physiological barrier in the colonic drug delivery, Li et, al. designed curcumin – cyclodextrin complex loaded chitosan and alginate based nanoparticles and targeted to ulcerative colitis bearing mice. Invitro studies’ results showed that the drug release exhibited enzyme responsive characteristics i.e. α – amylase responsive release while invivo results showed reshaping of the microbial flora, rapid uptake of macrophages, strong biodistribution at colonic level and therapeutic efficacy that all resulted in healing of ulcerative colitis (Li S et al. 2021).

6.2. Osmotically controlled smart nanosystems for UC

Osmotic controlled drug delivery system is another scaffold that targets colonic disorders including ulcerative colitis with efficient systemic absorption and consist of five to six push – pull unit within a single osmotic unit enclosed in a hard gelatin capsule (Arévalo-Pérez et al. 2020). The system consist of a drug layer and an osmotic push layer that collectively form a bilayer that is covered by a semi permeable membrane consist of an orifice in drug layer (Akbarzadeh et al. 2019). The osmotic push compartment is swelled after the absorption of water into the system and form a gel. The drug gel mass is expelled outside through orifice (Ogueri and Shamblin 2022). In the context of ulcerative colitis therapy, the delivery system is designed in such a way that a few hours of post gastric delay the drug delivery is avoided in the small intestine (Aslan et al. 2013). Furthermore, when the delivery system reaches the colon, a constant drug release rate is achieved after delivering the drug cargo for almost 24 hours within the colitis site (Awad et al. 2022). Calcium phosphate (CaP), a naturally pH-sensitive substance, was used to construct siRNA-loaded CaP/PLGA nanoparticles (Frede et al. 2016), which had a high affinity for nucleic acids but dissolved in the low pH environment inside the lysosome after endocytosis. The release of nucleic acids into the cytosol was aided by an increase in osmotic pressure. CaP/PLGA NPs loaded with TNF-, keratinocyte chemoattractant, or IP-10 siRNA were efficiently taken up by gut epithelial cells, resulting in a significant decrease in target gene expression in colonic biopsies and mesenteric lymph nodes of colonic inflammation mice model. The system resulted in significant relief of the colitis symptoms in mice model.

6.3. pH responsive smart nanosystems for UC

The pH of empty stomach gets rise after the ingestion of meal and rises in the descending parts of the GIT eventually reaches to a pH 7 at the colon level (Vinarov et al. 2021). Smart nanosystems sense these changes in the pH and accordingly release the loaded cargo at the colon pH. Because of their susceptibility to digestion while passing through the GI system, liposomes are not preferred for oral drug delivery. Coating liposomes with polymers is one way to protect them during transit, but there has been very little research into specifically targeting the colonic area (Barea et al. 2012). Methacrylic acid (Eudragit L − 100) and ethyl acrylate (Eudragit S − 100) are the two pH responsive polymers used in colonic drug delivery (Hua 2014). During the treatment of ulcerative colitis, such polymers get protonated or deprotonated depending on pH changes and thus behave accordingly to swell or contract resulting in the retention or release of the loaded contents (Nagpal et al. 2010). In a study, liposome-in-microsphere (LIM) containing drug-loaded liposomes within pH responsive Eudragit S100 microspheres were developed. The liposomes were loaded with model drug 5-ASA and coated with chitosan to protect them from clumping in subsequent encapsulation in microspheres and to enhance tailored release features. LIMs inhibited drug release in simulated stomach and small intestine conditions, with subsequent drug release happening in large intestine conditions, according to in vitro drug release studies. As a result, the nanosystem showed the ability for oral colonic drug administration (Barea et al. 2012). In another research study, drug release from liposomes based on Eudragit S100 was lower in solution that simulated the stomach pH conditions i.e. 1.4 and 6.3 of small intestine thus showed pH responsive drug release (Barea et al. 2010).

Polymers used in the pH responsive nanoparticles includes anionic polymers and acrylate that at high pH gets swell and at low pH pose insolubility property (Liu L et al. 2017). Such pH sensitivity behavior enables them to deliver the loaded cargoes at higher pH of the colon and protect the payloads from degradation by harsh acidic environment (Gugulothu et al. 2014). In this regard, a PLGA and Eudragit S − 100 co – polymer was used as a pH sensitive system loaded with budesonide and was fabricated into nanoparticles. The resultant system showed pH dependent release and at a pH of 7.4, sustained release kinetics was shown by the prepared system (Makhlof et al. 2009). In another study, prednisolone was loaded into mesoporous silica nano particles based on ε – polylysine. Invitro results from the study showed pH responsive drug release from the smart nanosystem such as; no drug release at pH 5 of small intestine, 1.9 of stomach and high drug release at pH 7 of colon (Nguyen et al. 2017).

To explore the core shell nano particles in ulcerative colitis, curcumin nanocrystals were prepared and loaded to chitosan – alginate based nanoparticles that were targeted to ulcerative colitis. Biodistribution and drug release studies showed that the resultant nanoparticles showed higher distribution at colon as compared to stomach and small intestine, wherease the drug release was high at higher pH and lower at reduced pH thus presenting it a suitable ulcerative colitis therapy (Oshi et al. 2020). Similarly, 5 amino salicylic acid core shell nanoparticulate system was fabricated and targeted to ulcerative colitis. Results from invitro studies showed enhanced stability of the fabricated core shell system, avoided the drug release at upper gastro intestinal tract and sustained drug release at colon (Wang N et al. 2022). Cyclosporine A is an immunosuppressant agent that has limited use in ulcerative colitis due to systemic side effects. To overcome this issue and increase the therapeutic efficacy, cyclosporine A loaded alginate micro particles coated with Eudragit S100 was prepared and targeted to colon for the treatment of ulcerative colitis (Table 3). The resultant complex smart polymer based delivery system upon exposure to simulated gastric condition showed no release, no absorption and thus avoided side effects while upon exposure to simulated colon condition showed disintegration of the microparticles with sustained release behaviors for 24 hours (Oshi et al. 2021). In a recent study, sulfasalazine loaded pectin – PEG – methacrylic acid grafted hydrogel was prepared and evaluated in ulcerative colitis model. Free radical polymerization was used for the grafting of smart polymers. Invitro studies confirmed the degradation of used smart polymer by microbial flora and the drug release was maximal at pH 7.4 of the colon (Abbasi et al. 2019). Over all, despite of the marked results observed from pH responsive delivery systems targeting ulcerative colitis, the intra – individual as well as inter – individual differences in pH is a major concern here and the luminal pH changes due to disease conditions should also be considered.

Table 3. Examples of major studies conducted for treating UC with smart nanosystems.

Therapeutic agent	Nanoformulation	Characteristics	References
Clodronate	Cationic Polymethacrylate NPs	Decreased myeloperoxidase activity in TNBS- and OXA-induced-colitis compared to free clodronate	(Niebel et al. 2012)
5-ASA	Pectin coated Chitosan hydroxide hybrid beads	Protection of NPs in upper GIT and sustained release of the drugs at pH 7.4	(Ribeiro et al. 2014)
TNFα- siRNA	Polymeric NPs complexed with DOTAP	ROS responsive, enhanced mucosal transport by and DOTAP. Decreased TNFα level	(Wilson et al. 2010)
Tacrolimus	PLGA NPs encapsulated in Eudragit P4135F microspheres	Protected the drug at acidic pH	(Lamprecht et al. 2004)
Budesonide	PLGA/Eudragit nanospheres	Sustained release of the drug at colonic pH with improved therapeutic effects against TNBS-induced colitis	(Makhlof et al. 2009)
	ethyl cellulose/ Eudragit S100 nanofibers	Sustained release of budesonide at pH of 7.4	(Xu Q et al. 2013)
Curcumin	Eudragit S100/PLGA NPs	Decreased neutrophils infiltration in colitis Model, LPS-activated macrophages.	(Beloqui et al. 2014)
	PEG-Azo-PLGA, and catechol-modified TPGS micelles	Enzyme responsive, Decreased colitis symptoms and augmented colitis repair in mice colitis model	(Zhang, Li, et al. 2022)
Cyclosporine	Eudragit S100 nanospheres coated with PLGA	Sustained release of the drug at pH 7.4	(Naeem et al. 2018)
Dexamethasone	Eudragit S100 microcrystals coated with alginate and Chitosan	pH dependant release of the drug in colonic region and alleviated the inflammation symptoms in colitis model	(Oshi et al. 2018)
Indomethacin	Pectin cross-linked microspheres	Increased colon-specific delivery and pH dependant release	(Lee et al. 2004)
Mesalazine	Silica gel beads containing calcium and pectin	Controlled release of the drug at simulated upper GI conditions and higher release in the simulated colonic fluid	(Günter et al. 2018)
	eudragit-S100 coated pH sensitive liposome for co-delivery of Mesalzine and curcumin	pH dependant release of the drugs and mitigated the UC stress in pig model	(Aib et al. 2022)
Quercetin	Chitosan microparticle	reduced colitis upon oral administration in rabbit colitis model	(Helmy et al. 2020)
Resveratrol	PLGA NPs conjugated with Folic acid	Reduced colitis in rat colitis model upon oral administration	(Naserifar et al. 2020)
Ginger	NPs derived from Ginger	increased the anti- inflammatory cytokines and decreased the concertations of pro-inflammatory cytokines	(Zhang M et al. 2016)
Methotrexate	Nanovesicles derived from grapefruite	Induced anti-inflammatory properties against colitis animal model	(Wang B et al. 2014)
Rhein	Rhein loaded Cyclodextrin host guest supramolecular system	ROS responsive macrophages targeted, on-demand release of the drug and effectively alleviated inflammation	(Tan et al. 2022)
	chitosan and fucoidan natural Polysaccharide nanoparticles	Dual ROS and pH responsive, significantly reduced inflammation in DSS-induced colitis mice model	(Qi et al. 2022)
Celecoxib	bilirubin conjugated glycol chitosan nanoparticles	Dual PepT1 and CD44 receptor targeting, attenuated bodyweight loss, alleviated colon histological damage in mice model	(Chen R et al. 2023)
Artesunate	Chitosan coated PLGA nanoemulsion	pH responsive release of the drug at colonic region, relieved clinical symptoms of UC in mice model	(Tao et al. 2022)

6.3.1. Reactive oxygen species (ROS) and redox- responsive smart nanosystems for UC

In the treatment of ulcerative colitis, reactive oxygen species responsive delivery systems have shown promising potentials (Talaei et al. 2013). The imbalance in the production of reactive oxygen species and decrease response of the immune system is referred as oxidative stress that is mainly observed with inflammatory conditions and an over production of reactive oxygen species is observed in ulcerative colitis (Birben et al. 2012; Piechota-Polanczyk and Fichna 2014). The redox – responsive nanosystem takes the advantage of the pathological condition of ulcerative colitis and thus exhibit a profound potential for the therapy of ulcerative colitis. In this regard, TNF – α siRNA loaded thioketal nanoparticles were fabricated for oral administration and targeting of ulcerative colitis. The aim of using thioketal was as a carrier and degradation in response to the reactive oxygen species. Results from murine ulcerative colitis model showed the degradation of the polymer at ulcerative colitis site due to high contents of the reactive oxygen species and efficient delivery of siRNA to protect the mice from ulcerative colitis (Wilson et al. 2010). Similarly, nanoparticles loaded with nitroxide radicals having an amphiphilic block co – polymer was targeted to ulcerative colitis bearing mice and results showed high accumulation of the nitroxide radicals at inflammation site. Mechanistically, the used radicals significantly scavenged reactive oxygen species concluding that nitroxide radicals could be effective therapeutic alternative for ulcerative colitis (Vong et al. 2012). In relationship between reactive oxygen species and ulcerative colitis, luteolin being anti – Inflammatory and ROS scavenging natural flavonoid, was loaded in tocopherol polyethylene glycol succinate – b – poly(β – thioester) copolymer based nanoparticles and targeted to inflamed colon of murine model. Results showed healing of the inflammatory mucosa and resolving inflammation through the suppression of reactive oxygen species and upregulation of anti – inflammatory factors (Tan et al. 2022).

Budesonide encapsulated nanoparticles based on self – assembled polyether micelles were designed to effectively target ulcerative colitis. The purpose of using smart polymer was its oxidation potential at ulcerative colitis site due to increased ROS concentration. Results of this study showed that the fabricated delivery system significantly repaired the intestinal barriers and the colonic damaged tissues were healed effectively (Zhao et al. 2022). Similarly, Haiting et, al. fabricated pH and ROS dual responsive curcumin loaded chitosan – alginate based hydrogel for targeting ulcerative colitis. Their results showed significant suppression of the high reactive oxygen species level at colon level and also protected the degradation of complex delivery system from the harsh gastric acidic environment. The mechanism behind the anti – inflammatory effect of the drug loaded smart drug delivery system in animal model was targeting TLR4-MAPK/NF-κB signaling pathway (Xu H et al. 2022). In the context of dual smart delivery system i.e. both pH and ROS responsive delivery system another study investigated acid resistant – ROS responsive hyper branched self assembling polythioether micelle targeting ulcerative colitis. Findings of the study showed that the thioester bonds were significantly oxidized into sulfone groups that in response to accumulated high reactive oxygen species enhanced the hydrophilicity and ultimately mimicked the encapsulated drug release. Furthermore, the self assembling micellar structure helped in bypassing the acidic gastric environment without leaking the drug candidate (Shi et al. 2020). Prominent research studies conducted for treating UC via the application of smart nanosystems are summarized in Table 3.

6.3.2. Thermo- responsive smart nanosystems for UC

The thermo- responsive drug delivery platform has been frequently applied for liposomes, causing drug release at 42 °C and resulting in maximum drug concentration at the desired site. Certain lipids and polymers have abrupt and discontinuous shifts in physical properties with temperature fluctuations (Lee and Thompson 2017). This drug delivery method is also applicable to hydrogels. In this regard mesalazine was delivered to the ulcerative colitis by loading it into the pectin cross linked chitosan based thermo – responsive hydrogel. Results of this study showed sustained release kinetics for the loaded drug due to cross linkage between chitosan and pectin. The release pattern of drug at targeted site and drug loading to the smart nanocarrier was in desirable range (Ding et al. 2017). In another research study thermo responsive smart carrier was used for targeting ulcerative colitis and to delivery mesalamine or budesonide. The nanocarrier system was administered through rectal route to the mice that was initially in liquid form and upon exposure to body temperature it was converted into a viscous gel (Sinha et al. 2015). The hypothetical mechanism is depicted in Figure 4. All these findings suggest that the stimuli responsive smart drug delivery system is an efficient way for targeting the ulcerative colitis and it give an opportunity for the therapeutic candidates to be used for other gastro intestinal disorders using such stimulus responsive delivery system.

Figure 4. Ulcerative colitis targeted by thermo responsive nanocarrier system via rectal route.

7. Conclusion and future perspectives

The current therapeutic agents used for the treatment of ulcerative colitis are suffering from chronic systemic exposure and immunosuppression. In such circumstances, nanotechnology platform offers an effective and safe approach targeting ulcerative colitis. Up till now, various conventional nanocarriers have been investigated however; the use of smart nanocarrier system has opened new avenues in the field of bowel diseases through providing more retention time at inflamed site, responsiveness toward various physiological conditions and reduction in frequency of administration. Furthermore, such smart nanocarrier system has resulted in the efficient accumulation of therapeutic candidates at inflamed site and protection of healthy tissues from concerned side effects. In addition, responsive smart nanocarrier delivery system results in delivery of loaded cargoes at specified site of the colon at desired pH, high contents of the reactive oxygen species and presence of specific enzymes. All these factors enables the drug delivery system to release the payloads at target site without disrupted by the harsh gastric environment of the stomach.

Although such responsive smart nano delivery system could improved patient’s quality of life by boosting the therapeutic efficacy, but so far no conclusion and factual data regarding the level of nano carrier adverse effects have been brought up that needs nanotoxicology studies in the human gastrointestinal tract and animal models. The responsive nanocarrier system have been explored for surface interactions, multiple materials and different sizes however; with enhanced understanding of the human gastrointestinal tract, the applications of such responsive nano system needs further expansion. Moreover, ulcerative colitis is an inflammatory condition and in such cases the immune cells and functions dramatically alters, so macrophages being major immune system regulators are polarized to pro – inflammatory state leading to dysfunctioning of the system. Thus, using responsive smart nanocarriers to switch the phenotypes of the immune cells need further investigations in ulcerative colitis. Among stimuli responsive nanocarrier system, excluding pH responsive system, there are certain obstacles in the way of other responsive systems that include the enzyme rich and harsh acidic environment of the upper gastro intestinal tract where the drug undergoes instability issues, so it should be focused in the future for successful ulcerative colitis therapy. Also the premature release of drugs leads to less delivery of therapeutic agents to the target colon site and also causes side effects needs future investigations. The use of dual-responsive nanosystem have shown effective outcomes in the treatment of ulcerative colitis however it needs clinical translation to ensure and confirm its status of pre – metabolism and long term safety within the systemic circulation. In summary, to mitigate the drugs concern problems in the future, work should be carried out to design multifunctional delivery systems that respond to various stimuli at a time and overcome the multiple barriers in a single unit so then it could be easily transformed from bench top to the clinical settings for the effective therapy of ulcerative colitis.

Authors’ contributions

Min Chen: writing initial draft and revision of the manuscript; Huanrong Lan: initial draft and revised the manuscript; Ketao Jin: Conception and design of the study; Yun Chen: revision and finalization of the manuscript.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by Zhejiang Provincial Science and Technology Projects (grants no. LGF22H160017 to MC, LGD19H160001 to KTJ, and LGF22H160046 to HRL), National Natural Science Foundation of China (grant no. 82104445 to HRL), and Jinhua Municipal Science and Technology Projects (grants no.2021-3-040 to KTJ, and 2021-3-046 to HRL).