Examples of GSH-stimuli responsive theranostics.
Abstract
Since the prehistorical period, cancer has been a pervasive affliction in the human body, representing one of the most formidable challenges to human health and well-being. Its insidious presence in the human body commands the highest mortality rate among those who succumb to its grasp. Epigenetic factors often play a critical role as the primary caretakers orchestrating the transformation from an innocuous, rudimentary stage to the formidable and often fatal metastasis phase. In the battle against this lethal illness, the concept of theranostics was embraced in the early twenty-first century, combining both treatment and diagnostic techniques. This prompt data on treatment methods could pave the way for the advancement of tailored medicine, potentially curbing medication misuse as well. The use of fluorescence as a partially invasive method has been adapted for diagnostic purposes in the field of intelligent medicine. Within this approach, the overexpression of unique elements (ROS, thiols, enzymes, proteins, etc.) within cancer cells facilitates the cleavage of the theranostic agent, resulting in the immediate release of drugs exclusively in cancer cells. This approach rapidly offers temporal data on the activation of therapies and their effects at the subcellular level in animal models, as demonstrated through in situ biopsies.
Keywords
- endogenous stimulators
- theranostics
- prodrug
- fluorescence
- cancer
1. Introduction
Cancer represents a potentially life-threatening condition within human society, with its various types categorized based on their origin and location [1]. Alterations in the genes responsible for cellular signaling, particularly the malfunctioning of protein kinases, can lead to the growth of cancer [2]. The unveiling of the human genome sequence has spurred the development of novel treatment protocols for this ailment.
In 2004, the U.S. Food and Drug Administration (FDA) promoted the exploration of innovative products for cancer treatment, specifically emphasizing personalized medicine to mitigate drug misuse and encourage targeted therapy. The pharmaceutical industry views the “Trojan horse” approach, in conjunction with therapeutic and diagnostic tools, as a potential solution for precise treatment. The term “theranostic” was initially coined by John Funkhouser, the Chief Executive Officer of PharmaNetics, in 1998, and has since become a widely searched keyword in cancer research.
Parallel advancements in chemistry, biotechnology, nanotechnology, pharmacy, medicine, and imaging have led to the continual development and assessment of theranostic nanomedicine and its clinical significance in recent years [3]. Engineered nanoparticles and devices have been crafted to meet the current demands for personalized treatment. Research in the realm of theranostic tools for cancer treatment has resulted in the development of various anticancer drugs and carriers, such as polymers, liposomes, and diverse nanoparticles.
In the initial stages of theranostic nanomedicine development before 2005, therapeutic and diagnostic tools were incorporated into polymer vehicles that passively entered the target site due to the enhanced permeability and retention (EPR) effect. Subsequently, theranostic nanomedicines were devised with specific ligands capable of targeting particular cancer types based on their genetic signatures or the expression of specific proteins in tumor cells. This approach capitalizes inherent variance between normal and cancer cells to enhance cancer cell-specific uptake. The technologies behind targeted theranostic nanocarriers have exhibited desirable improved properties at the treatment site, localizing specifically to affected areas, providing targeted therapeutic release, and enabling noninvasive monitoring with diagnostic tools [4].
While targeted therapy has demonstrated effective therapeutic efficacy, various imaging modalities, including magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound, fluorescence, and computed tomography, have shed light on the underlying disease mechanisms and facilitated assessment in pre-and post-treatment stages [5, 6, 7, 8, 9].
Newly developed materials, including upconversion nanoparticles, graphene-based nanodevices, and other theranostic prodrugs, have been introduced as innovative solutions to address various forms of sporadically mutated cancer. Contrarily, the primary obstacle lies in surpassing the limitations of imaging for seamless
Considerable efforts have been dedicated to the creation of theranostic tools, although most of these tools rely on nanoparticle technology. Regrettably, none of the existing nanoparticles are capable of offering real-time insights into the process of drug release and its activation. Currently, advanced techniques, such as small molecular optical-modulated theranostics, appear to be resolving this issue and instilling confidence in tailoring suitable treatments for individual patients. These newer methodologies, particularly those involving ROS-activatable systems, enzymes, and similar agents, facilitate the precise delivery of therapeutic agents to specific tumor regions [11]. In this approach, chemotherapeutic agents are linked to a tumor-guiding group
2. Cancer formation and their properties
Cancer is characterized by the fundamental anomaly of unregulated cell growth across various cell types. This irregularity is manifested through the modification of normal cellular signaling pathways, invasion into healthy cells and tissues, and eventual dissemination throughout the body, often in the form of metastasis.
Essentially, modifications in epigenetics profoundly influence the expression of genes, which serves as the inception of cancer [12]. Gene mutations are greatly impacted by changes in DNA, including modifications like DNA methylation and hydroxymethylation, as well as alterations in histone acetylation, histone methylation, and variations in small noncoding RNAs. Consequently, these changes give rise to unregulated cell division, ultimately resulting in the expansion of tumor cell population which originate from a single clone. Frequently, cancer-causing substances, including arsenic and its derivatives, asbestos, benzo(a)pyrene, polyaromatic, dimethylnitrosamine, nickel compounds, and others harm the DNA, leading to gene mutations. These altered genes foster the invasion of tumors and diminish the function of tumor suppressor genes [13]. Apart from the cancer-causing agents, tumor growth stimulants are also triggered during the initial phase of cancer prognosis through the activation of protein kinase C induced by phorbol ester [14]. Furthermore, epigenetic suppression entails an overabundance of methylation on the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT), resulting in the deactivation of MGMT for DNA repair, a process frequently observed in cancerogenesis. Within cancer cells, micro-RNAs, a type of noncoding RNA comprising around twenty bases, bind to messenger RNAs, leading to their degradation or the inhibition of translation. This process significantly influences the growth and spread of numerous cancer types [15].
The unrestricted proliferation of cancer cells leads to numerous alterations in cellular communication, the cell cycle, cell adhesion, and the extracellular matrix. Typically, the growth pattern of normal cells is tightly regulated, with density-dependent inhibition restricting further cell growth, overseen by cell growth regulators. However, during the progression of cancer cells, the phenotype of extracellular growth factor receptors changes, and the density-dependent inhibition process becomes ineffective. Occasionally, cancer generates fresh growth factors to promote unregulated growth, a process known as autocrine growth stimulation, making it independent of the usual growth factors that regulate the growth of normal cells [16]. Consequently, cellular growth signaling varies in cancer cells, where the intracellular signaling pathway is disrupted by the deactivation of growth factor receptors or other critical proteins, such as Ras proteins or protein kinases [17].
The adhesion between cells and their attachment to the matrix is notably weaker in cancer cells. Within these cells, the primary adhesion function of E-cadherin in cell-matrix interactions is compromised, resulting in decreased activity. Receptors responsible for cell-cell attachment are downregulated, while those associated with cell motility are upregulated. Additionally, this process stimulates the activation or overexpression of surface metalloproteases, leading to the degradation of the extracellular matrix. This degradation facilitates the movement of cells with mesenchymal traits, which is crucial for metastasis. Also, increased secretion of collagenase has enhanced the capacity of carcinomas to break down and penetrate basal laminae, facilitating the invasion of underlying connective tissue. Moreover, the heightened expression of vascular endothelial growth factor receptors fosters the creation of fresh blood vessels.
Importantly, within tumor cells, the process of apoptosis, which typically serves as a tightly controlled mechanism for cell death in the development and sustenance of a normal cell population in mature organisms, is also disrupted. Anomalies in the apoptosis process are also a prominent characteristic of carcinogenesis. In certain types of cancer, the natural intrinsic apoptosis pathway is hindered by regulators like X-linked inhibitor of apoptosis protein (XIAP) and the B-cell lymphoma 2 family of proteins [18]. Similarly, the proteins FLIPL and FLIPS also impede alternative extrinsic pathways [19].
Numerous notable distinctions between cancer and normal cells contribute to their accelerated growth rates and enhanced migratory capabilities.
3. Anticancer drugs and delivery
During the sixteenth-century, the pioneering physician Paracelsus was among the first to utilize medicine and minerals in the treatment of cancer. Up until 2020, the FDA had approved approximately 89 medications intended for the treatment of cancer [20]. These medications are categorized as alkylating agents, antimetabolites, anthracyclines, plant alkaloids, microtubule inhibitors or modulators, topoisomerase inhibitors, chromosome binding agents, and other antitumor treatments. These drugs exhibited anticancer effects by causing DNA fragmentation, inhibiting topoisomerase activity, and inducing apoptosis through different mechanistic pathways. In more than 90% of instances, chemotherapy is prescribed with the primary goal of providing palliative care, aiming to either stabilize the disease or enhance the patient’s quality of life. Regrettably, the limited rate of drug accumulation within cancer cells is insufficient to manage the rapid growth of tumors effectively. Therefore, combination therapy might be more effective in controlling the swift and proliferative cancer growth. Nonetheless, the intrinsic heterogeneous characteristics and hypoxic conditions significantly disrupt the effectiveness of anticancer drugs in chemotherapy. Even during advanced stages, various factors such as multidrug resistance, changes in drug activation mechanisms, detoxification, activation of cellular efflux, and delayed apoptosis further diminish the anticancer efficacy of chemotherapy [21]. The idea of drug delivery emerges as a means to expand the therapeutic window, which is presently limited. In general, micro/macro encapsulated particles, polymer-bound micro drug delivery systems, and prodrug-linked low molecular weight drug delivery systems are frequently utilized. Ligand-receptor interaction-based targeted delivery system is the key strategy behind the effective transport of chemotherapeutics agents to the cancerous region. Generally, integrin-binding RGD peptide, folic acid, monoclonal antibody, glycoside, D-biotin, and similar substances are commonly employed for targeting different forms of cancer [22, 23]. Several thousand publications concerning drug delivery systems illustrate their internalization through either receptor-ligand interaction within the endocytosis pathway or passively through the concept of the enhanced permeable retention (EPR) effect. These endeavors are essential from the standpoint of patient care, reducing drug misuse, and minimizing mortality.
4. Theranostics and importance of self-immolative linker
The ongoing management of cancer in the modern era motivates the development of inventive protocols for delivering anticancer drugs, aiming to enhance the therapeutic window. In light of this, the concept of theranostics emerges in the current century. Theranostics represents a pioneering cornerstone in nanomedicine, possessing both diagnostic and therapeutic capacities that work simultaneously and complementarily. It offers the capability to provide immediate insights into real-time drug activation, distribution, and the scope of therapeutic interventions. Typically, magnetic particles, mesoporous silica, carbon, and polymer nanoparticles are used to create theranostic systems. The emergence of small molecular theranostic prodrugs in nanomedicine, which incorporate fluorophores as optical markers, has gained traction for monitoring the process of drug delivery and release. This is due to their capacity to activate fluorescence signals simultaneously with drug release. In this design approach, commonly, the reporter fluorophore and chemotherapeutic agents need to be activated simultaneously and detached from the carrier. To achieve this, one or two covalent bonds must be broken specifically within the cancerous region. The aim is to prevent the premature release of the drug into the bloodstream or normal cells. The active form of the drugs will only be attained upon encountering specific entities that are notably abundant within the cancer cells. The most sophisticated approach involves designing a theranostic prodrug that ensures seamless breakage of the chemical bond precisely at the tumor site. Figure 1 illustrates the framework for the potential activation of both the reporter and the drug. In each instance, there exists an activation or breaking point, which triggers the cleavage process. Subsequently, the self-immolative linker undergoes fragmentation through a distinct decomposition process that enables the formation of both the reporter fluorophore and the drug, allowing them to attain their active states. In the Type 1 approach, cleavage happens at the center of the linker, leading to the production of both the active drug and fluorophore through self-immolation. In the Type 2 approach, the triggering unit in the tumor-specific region activates a coordinated pathway to generate both the fluorophore and drug
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F1.png)
Figure 1.
The design strategy of various self-immolative theranostics.
4.1 Glutathione-activated theragnostic
Glutathione (GSH) is a tripeptide composed of glutamic acid, cysteine, and glycine. Functioning alongside its oxidized form glutathione disulfide (GSSG), it serves to uphold cellular redox balance. Primarily generated in the cytosol, it predominantly remains there, safeguarding against oxidative stress by counteracting reactive oxygen species (ROS). Moreover, glutathione (GSH) plays a pivotal part in numerous cellular activities, including cell differentiation, proliferation, and apoptosis.
The concentration of GSH in cancer cells is significantly higher than that found in normal cells, with intracellular GSH levels (1–10 mM) approximately 1000 times greater than those in the extracellular compartment (2–20 μM). This heightened GSH concentration renders neoplastic tissues more resistant to chemotherapy [24]. Additionally, increased GSH levels in certain tumor cells are commonly linked to elevated GSH-related enzyme activity, such as γ-glutamylcysteine ligase (GCL) and γ-glutamyl-transpeptidase (GGT), along with an upregulation of GSH-transporting export pumps [25]. Undoubtedly, GSH can serve as a significant trigger for the targeted delivery of chemotherapy to the tumor microenvironment.
Within the small molecular theranostic approach, both the fluorophore and drug are linked through a spacer containing a susceptible “–S–S–” linker, which can be broken down by cellular glutathione (GSH). In addition to this responsive bis-thiol (–S–S–) linker, a cancer-targeting ligand has been integrated to enhance the selective release of therapeutics in specific cancer cells. As depicted in Figure 2, the doxorubicin linked with folate (
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F2.png)
Figure 2.
Theranostic prodrug
Another theranostic prodrug
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F3.png)
Figure 3.
GSH-mediated activation of theranostics
Theranostics | Drugs | Target ligand | Abs./emission (λabs/ λem) nm | Ref. | ||
---|---|---|---|---|---|---|
CPT | RGD (Arg-Gly-Asp) integrin | 430/535 | U87 | — | [28] | |
Gemcitabin | D-biotin | 700 (TP) /450 | A549 | — | [29] | |
Gemcitabine | Folate | 630/700 | KB | KB cell mice | [30] | |
(PEG-PL) | CPT | EPR effect | 465/665 | BCap-37 | BCap-37 tumor xenograft mod | [31] |
Gemcitabin | D-biotin | 700/720 | A549 | — | [32] | |
HJ-inhibitor | D-biotin | 430/540 | HepG2 | — | [33] | |
chlorambucil | — | 430/540 | HeLa | — | [34] | |
SN-38 | PVA-biotin | 510/550 | HeLa | — | [35] |
Table 1.
While GSH-triggered theranostics have primarily been examined, concerns about stability in blood plasma persist due to the considerable presence of thiol entities in the blood.
4.2 Hydrogen peroxide mediated theranostics
Hydrogen peroxide is a widely recognized reactive oxygen species formed from superoxide in mitochondria. It plays a critical role in cell signaling, proliferation, and maintaining redox balance. However, it is continuously produced in cancer cells (at a rate of 0.5 nmol per 1 × 104 cells per hour) [36]. The cancer cells utilize hydrogen peroxide as a mechanism to acquire nutrients from neighboring fibroblasts through stromal induction of autophagy and mitophagy. Moreover, it leads to DNA damage, cellular metabolism, and inflammation by activating NFκB [37]. Consequently, endogenous H2O2 can serve as an excellent stimulant for the cancer cell-specific activation of theranostic prodrugs. The theranostic prodrug
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F4.png)
Figure 4.
H2O2 mediated SN-38 activation.
Utilizing ROS-mediated theranostic, particularly the activation of prodrugs induced by H2O2 could represent a futuristic strategy to enhance the therapeutic potential of anticancer drugs.
4.3 Hydrogen sulfide stimuli-responsive theranostic
Hydrogen sulfide, a gasotransmitter, plays a crucial role in neurotransmission. Enzymes like cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) are overexpressed in certain cancer cells to generate endogenous H2S [41]. This compound aids in cellular bioenergetics, supporting tumor growth and proliferation, and also facilitates angiogenesis and vasorelaxation, contributing to the blood supply and nutrient provision for the tumor [42, 43]. Other than colon cancer, Bhuniya et al. noted that cervical cancer cells (HeLa cells), breast cancer cells (MDA-MB-231 cells), and prostate cancer cells (DU145 cells) generate a larger amount of H2S in the mitochondria compared to normal cells [44]. The same research group later employed a distinctive strategy to specifically decrease the mitochondrial inner membrane potential (Ψ) in cancer cells by releasing the 2,4-dinitrophenol protonophore (Figure 5, prodrug
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F5.png)
Figure 5.
Endogenous H2S-mediated protonophore activation.
Utilizing endogenous H2S for theranostic activation in different cancer types is a distinctive strategy. It eliminates the need for a cancer-specific ligand, simplifying the synthesis of theranostic prodrugs, and making the process more straightforward and highly valuable for cancer treatment.
4.4 pH-dependent theranostics activation
The characteristic feature of cancer is an extracellular acidic environment. This arises from the production of lactic acid through anaerobic glycolysis and increased activity of the pentose pathway, resulting in the generation of carbonic acid within cancer cells. While the extracellular pHe in normal cells typically remains at 7.4, the extracellular pHe in cancer cells, on the other hand, ranges between 6.3 and 7.1. Therefore, the hydronium ion (H3O+) may serve as a potential trigger for the activation of chemotherapeutics from their theranostic prodrug systems. Zhang et al. introduced a theranostic compound called Mal-hyd-Dox, which utilized an integrin-specific Gly-Arg-Gly-Asp-Ser (GRDS)-oligopeptide as a cancer cell-specific ligand [49]. Dox was linked to the compound
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F6.png)
Figure 6.
pH-responsive paramagnetic theranostic
Later Wang et al. incorporated PEGylated biotin as a targeting ligand to improve the selectivity for precise anticancer activity in biotin receptor-positive human colorectal cancer cell lines (HT-29 and LS180 cells) [52]. The theranostic prodrug
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F7.png)
Figure 7.
pH-responsive PEGylated biotin theranostic
In general, these strategies revolve concept of prodrugs, wherein established commercial drugs are repurposed as part of a novel formulation system following chemical alterations in anticancer medications. Occasionally, these modifications can impact the drug’s metabolic properties. Kamkaew et al. devised a novel pH-triggered photodynamic therapy approach using theranostic
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F8.png)
Figure 8.
pH driven photodynamic therapeutic NIR theranostic
While the acid labile activation of theranostics demonstrated promising outcomes, a substantial portion of the payload may be released in the extracellular matrix due to its acidic nature. Consequently, this conventional strategy might not suffice as a robust approach.
4.5 β-Galactosidase stimulated theranostics
β-galactosidase exhibits notable potency as a cancer biomarker in specific cancer subtypes, including colon cancers, lung cancers, liver cancers, and ovarian cancers [54]. Bhuniya and colleagues observed that a coumarin-conjugated theranostic
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F9.png)
Figure 9.
β-Galactosidase activated cancer theranostics.
Recently identified as a cancer biomarker, β-galactosidase is poised to find diverse applications in activating theranostic agents for targeted cancer treatments. However, till now, a limited number of theranostics have been reported. Most of the theranostics cases introduce anticancer agents with reporter fluorophore through a covalent linker, which may perturb the chemotherapeutic activity of the parent drugs, and sometimes alter metabolic ingredients which introduce unwanted toxicity. Additionally, it is crucial to focus on the design approach and gather thorough pharmacokinetic data on theranostic prodrugs. It is even more advantageous to consider a novel strategy centered around theranostics to circumvent reliance on currently available drugs.
4.6 Theranostics for tumor hypoxia
Unrestrained proliferation of blood vessels leads to the restriction of blood supply in the tumor area, creating a harsh hypoxic microenvironment. This condition is exacerbated by the anaerobic glycolysis in tumor tissues, triggering hypoxia through an excessive expression of hypoxia-inducible factor (HIF1α) [58]. Consequently, the HIF1α suppressor, prolyl hydroxylase, fails to regulate the expression of HIF1α. The hypoxic tumor is located at a significant distance from the closest bloodstream (≥150 μm) (Figure 10), thereby preventing the diffusion of oxygen to the cancer cells, resulting in a decreased partial oxygen pressure in this zone (pO2 ≤ 20 mmHg). Consequently, hypoxia diffuses heterogeneously within the solid tumor, leading to the development of metastatic tumor masses.
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F10.png)
Figure 10.
Schematic representation of hypoxic tumor formation.
The diminished oxygen pressure during hypoxia significantly impacts the effectiveness of current anticancer treatments. In the context of radiotherapy, the inadequate generation of reactive oxygen species in hypoxic areas often leads to radiation resistance, thereby impeding the creation of lethal damage to DNA in cancer cells. Furthermore, the hypoxia-induced HIF-1α/β factor and free oxygen radicals may stimulate the production of angiogenesis factors, counteracting the damage intended to be inflicted by radiation therapy. Likewise, the efficiency of chemotherapeutic agents is generally compromised in hypoxic tumor regions. These agents may face obstacles in reaching the hypoxic tumor area. Moreover, elevated extracellular acidosis in hypoxia plays a pivotal role in impeding the cellular uptake of chemotherapeutic agents like anthracycline analogs and others. Attaining the intended therapeutic outcomes within the hypoxic region becomes unfeasible due to the combination of reduced oxygen levels and increased distance from the nearest blood capillary. This situation represents an unfavorable prognostic and predictive factor, as it contributes to various aspects such as chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism, and genomic instability. In all challenging circumstances, different reductase enzymes are upregulated during hypoxia, effectively reducing aromatic azo (∙N∙N∙), nitro (∙NO2), and quinone moieties. Based on this inherent conversion, several theranostics have been created, wherein the cleavage of the azo bond (∙N∙N∙) or reduction of the nitro group (∙NO2) to amine (∙NH2) facilitates the self-immolative discharge of active therapeutic components into the low-oxygen area of the solid tumor. Recent advancements in hypoxia-responsive theranostics have been consolidated in Table 2.
Theranostics | Activating group | Active drug | Imaging modality | Ref. | ||
---|---|---|---|---|---|---|
∙NO2 | SN-38 | Green FL | HeLa, A549 | HeLa cells xenograft mouse model | [59] | |
∙N∙N∙ | SN-38 | Green FL | HeLa | 4 T1-cells inoculated xenograft murine mouse model | [60] | |
∙NO2 | Gemcitabine | Green FL | MGC-803 cells | MCF-7-cell-inoculated xenograft mice | [61] | |
∙NO2 | SN-38 | Green FL | HeLa | – | [62] | |
∙N∙N∙ | melphalan analog | NIR FL | HeLa | 4 T1 Tumor-bearing xenograft mouse | [63] | |
∙NH2OH | KDAC inhibitor Pano | – | HCT116 cells | OE21 xenografts | [64] | |
∙NO2 | 3,4-difluorobenzylidene curcumin | Green FL | MDA-MB-231 | MDA-MB-231 xenografts | [65] |
Table 2.
Information about various hypoxia-induced theranostic activation system.
While diverse strategic theranostics have been documented, none have yet progressed to the clinical trial stage. Further efforts are required to develop hypoxia-sensitive theranostics that may enhance clinical benefits and address existing healthcare challenges.
4.7 Light-activated theranostics
To date, we have discussed numerous endogenous stimuli-responsive theranostics that actively deliver chemotherapeutic agents to various cell types/cancers based on the presence of specific stimulants. It is important to note that these stimulants are also present in normal cells but in relatively lower quantities, thus ensuring that the therapeutic agents are selectively released solely in the tumor region cannot be guaranteed. External stimulants, such as light, have been utilized to trigger the release of therapeutics, a process commonly referred to as “photo caging,” where drugs are shielded or “caged.” UV or laser irradiation facilitates the controlled release of therapeutics in a spatially and temporally precise manner. Some critical examples of the photo trigger theranostic in a consulate form are provided in Table 3.
Theranostics | Active ingredients | Ref. | ||
---|---|---|---|---|
OPV-Luminol | Luminol & ROS | HeLa | HeLa cell tumor mice model | [66] |
10/11 | SN-38/CA-4 | MCF-7 | — | [67] |
CMP-NCL-CA4 (1–5) | combretastatin A-4, Pc-(L-CA4) | Colon 26 cells | SC colon 26 tumors | [68] |
CMP-L-Rh | Combretastatin A-4 | Colon 26 cells | SC colon 26 tumors mice model | [69] |
1(Biotin-tagged-ONB-CC) | chlorambucil | MDA-MB-231 cells | — | [70] |
CA-074 Inhibitors | MDA-MB-231/MCF-10A | — | [71] |
Table 3.
Information on photo-triggered theranostics.
The utilization of photo-triggered activation of anticancer drugs represents a unique and innovative strategy. By employing this approach, it becomes possible to activate the therapeutic agent with a higher degree of precision specifically at the intended target tumor site.
4.8 Recent cutting-edge strategies in cancer theranostics
The forefront of medical advancement includes the innovative idea of self-immolative theranostics, in which the therapeutic substance undergoes a controlled chemical reaction, causing its self-degradation under certain circumstances. This characteristic is frequently harnessed to prompt the release of the therapeutic payload precisely at the disease site, thereby improving its effectiveness and reducing unintended effects elsewhere. In the previously mentioned approaches, the primary focus is on delivering chemotherapeutic agents to cancer cells or tumors. However, these strategies have not yet been assessed for their effectiveness against multidrug-resistant cancers/metastasis cancer. It’s crucial to note that multidrug-resistant cancer remains one of the most lethal forms of cancer, with the highest mortality rates. With a focus on addressing multidrug-resistant cancer, Kim et al. strategically engineered prodrug
![](http://cdnintech.com/media/chapter/89593/1721887748-1289628492/media/F11.png)
Figure 11.
Example of recently reported cutting-edge cancer theranosic.
By reprogramming mitochondrial metabolism, the cancer esterase-activated prodrug
An additional theranostic prodrug, labeled as
Another formidable aspect is tumor recurrence, wherein 90% of anticancer medications fall short of providing the anticipated therapeutic effectiveness, resulting in increased mortality rates [75]. Ironically, recurrence is frequently triggered by chemotherapy as a result of the accumulation of nuclear genomic mutations throughout the treatment regimen. Antineoplastic agents that induce nuclear-DNA damage, such as alkylating agents, are prevalent chemical mutagens and have been associated with tumor recurrence. To address this ongoing challenge in cancer treatment, ciprofloxacin-conjugated
Hypoxia poses another challenge in overcoming multidrug resistance in tumors. Kim et al. introduced theranostic
In this discussion, there is a notable focus on addressing multidrug resistance in cancer therapy through diverse and sophisticated strategic approaches. These methods include the activation of reactive oxygen species (ROS) and the incorporation of multidrug components. This approach integrates both the therapeutic and diagnostic components, aiming to overcome resistance mechanisms exhibited by cancer cells against multiple drugs. Through a combination of various therapeutic modalities and diagnostic techniques, this approach seeks to enhance treatment efficacy while providing insights into the resistance mechanisms at play, thereby enabling personalized and more effective cancer therapy.
5. Conclusions and prospective outlook
In conclusion, the development and exploration of stimuli-responsive theranostics (GSH, H2O2, H2S, pH, β-galactosidase, hypoxia) have brought significant advancements to the field of cancer treatment and diagnostic capabilities. The numerous strategies and methodologies discussed herein reflect the tremendous potential of these emerging technologies. As researchers continue to delve into the intricacies of various stimuli-responsive platforms, there remains a wealth of opportunities and potential for further exploration and development in this domain. Currently, optically modulated theranostics remain primarily of academic interest. Advancing these to clinical trial phases requires generating additional data through high-throughput assays, comprehensively exploring mechanisms, and collecting pharmacokinetic and pharmacodynamic information.
Looking ahead, the prospective outlook for stimuli-responsive theranostics is exceedingly promising. Continued research and development in this area hold the key to addressing the existing limitations and challenges associated with traditional cancer treatment modalities. By leveraging the dynamic nature of these responsive systems, it is conceivable that refined and highly targeted therapeutic interventions can be achieved, thereby maximizing efficacy while minimizing off-target effects and potential toxicity. With a comprehensive understanding of the underlying mechanisms and a focused effort toward the development of novel and optimized therapeutic strategies, stimuli-responsive theranostics are poised to play a pivotal role in the future of personalized and precision medicine.
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