Potential Mechanism of Nanoparticles Targeting Cancer Metabolic Pathways: Novel Approaches for Cancer Treatment
Zia Ud Din*, Yasmeen Khan, Amn Zia, Nasira Anbreen and Rifasa Sultan
Department of Biosciences COMSATS University Islamabad, Pakistan
*Corresponding author: Zia Ud Din, Department of Biosciences COMSATS University Islamabad, Pakistan
Citation: Din ZU, Khan Y, Zia A, Anbreen N, Sultan R. (2023) Potential Mechanism of Nanoparticles Targeting Cancer Metabolic Pathways: Novel Approaches for Cancer Treatment. Adv Clin Med Res. 4(3):1-24.
Received: August 16, 2023 | Published: September 09, 2023
Copyright© 2023 by Din Zu. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cancer is the most prevalent disease worldwide that has respected no borders. Despite of the intensive research in the field of medical, no satisfactory cancer treatment strategy has been developed. Conventional cancer therapies have been facing multiple challenging factors that have made cancer difficult to treat. Poor drug delivery system, anticancer drug resistance and metastasis are the prime limitations in the conventional cancer therapies, posing serious effects on the health of the cancer patients. Nanotechnology is an exciting new field of study that has proven its significance in multiple areas including medicines. It has also provided potential views for cancer treatment, enabling more effective, target-specific treatment regimens with fewer adverse effects. Multiple nanotechnology-based cancer treatments are being studied and analyzed for which numerous varieties of nanoparticles are used. The current review highlights the novel approaches and current practices of nanomaterial-based cancer treatment strategies targeting multiple cancer metabolisms. Furthermore, it will spotlight the advantages of NPs- based treatments over conventional methods, challenges and future perspectives of nanotechnology-based cancer therapies.
Anticancer drugs; Nanoparticles; Drug delivery, Cancer metabolic pathways; Nanomedicines
Cancer is the most prevalent disease worldwide, has taken more than 10 million lives in the year 2020 . Cancer cells exhibit uncontrolled proliferation, transformation, and the capability to metastasize to distant organs, posing a threat to normal body cells . However, to fulfill its energy requirement for its unregulated proliferation and migration, tumor cells acquired energy and raw material through unusual metabolic pathways . The reason behind acquiring energy from unusual metabolic pathways is the more rigorous metabolism of cancer cells than normal cells . In cancer cells, various signaling pathways that promote carcinogenesis collectively control three prime metabolic pathways . However, lipids, glucose and protein metabolism are included in these metabolic pathways . The distinct metabolism in tumor cells indicates that changes in the metabolic process are crucial for tumor development . However, recent advancement in the area of medicine, conventional cancer treatments such as chemotherapy, have failed due to various factors connected with cancer. Normally tumor cells resist therapeutic drugs and other therapies such as chemotherapy . The current chemotherapeutic drugs not only destroy the tumor cells while also kill normal body cells. Therefore, the administration of these toxic drugs can lead to severe side effects and may sometimes become the cause of patient’s death . Some other limitations associated with free drug delivery system include reduced permeability and limited biocompatibility . The greatest disadvantages of the free drug delivery are the nonspecific targeting of cancerous sites. Similarly, in radiotherapy there is no cell specificity that leads to similar side effects in the cancer patients. Drugs resistance is another challenge where sometimes the anticancer drugs stop performing their function completely . Medical field are facing some other major challenges in the treatment of cancer like reoccurrence and metastasis of cancer cells. Some cancers cells escape the cancer treatment and reappear after being ready for metastasis . They uncontrollably grow again and form a tumor. This phenomenon is also termed relapse . Sometimes, the relapse occurs within days after treatment, whereas it can also take months or years to reoccur . In metastasis, it becomes difficult to treat cancer when the tumor spreads in the adjacent tissues and even in the entire body . Targeting cancer all over the body with drugs and other therapies becomes a challenge for doctors and patients . For instance, healthy tissues are also affected due to chemotherapy, so it's life-threatening to expose the whole body to chemotherapy . An overview of conventional methods of cancer treatments is summarized in (Figure 1). Keeping in view the challenges to cancer treatments, there is a dire need for treatments that are inexpensive, more precise, and have potential to overcome the challenges mentioned above . now a days nanoparticles are considered a therapeutic strategies for cancer treatment . It has grabbed the attention of cancer researchers due to its unique properties, which have been opening the gates to novel methods of cancer diagnosis, characterization, and treatment . This review will highlight the novel approach of nanoparticles to treat cancer, overcoming the limitations of the conventional cancer treatment methods, and the study of underlying mechanisms of NPs to target cancer metabolic pathways.
Figure 1: Conventional Methods of treating cancer.
Application of Nanoparticles in Cancer Therapy
In medical field nanoparticles with size ranging between 1-100 nm are used  . These NPs are used in therapeutic drugs synthesis, designing devices and manufacturing . NPs differ from conventional macromolecules due to their distinct optical, magnetic, and electrical characteristic that manifest at nanoscale . Super magnetic behavior, High surface-to-volume ratio, improved electrical conductivity, and unique fluorescence properties are the typical characteristics of the nanoparticles . In the field of medical, nanoparticles are being applied for drug transportation with controlled release . Increased permeability and enhanced biocompatibility are also the prominent features of the nanoparticles . These unique properties of nanoparticles make them potential for use in cancer therapeutics . Nanoparticles has the potential to increase the specificity of the drugs in targeted therapy because of its high surface to volume ratio property, therefore improves the efficiency of the nanoparticles-based treatment although minimizing its toxicity to normal cells . Photodynamic therapy (PDT) and Photo thermal therapy (PTT) are the two mechanism of treatment associated with optical interference . Photodynamic treatment (PDT) produces cytotoxic reactive oxygen species as well as singlet oxygen., leading to cell death . In PPT based treatment, materials with maximum photo thermal transforming properties are used that have the ability to elevate the temperature of the cancerous location ultimately leading to necrosis. These methods are considered advanced cancer treatment methods with impressive application and materials utilized for these therapies are under intensive investigation . Some nanoparticles can also be used in PDT and PTT cancer treatment methods due to its distinct fluorescence properties . The unique and distinct properties of nanoparticles enable them to be used for cancer diagnosis and treatment . Because of their excellent targeting accuracy, small size, controlled release, and ability to avoid the immune response, super paramagnetic iron oxide particles (SPIONs) have the potential to treat hyperthermia . To eliminate cancer, targeting tumorous sites is some conventional therapies . It is now conceivable for these carriers to enter malignant locations and release therapeutic drugs by combining the enhanced permeability and retention effect (EPR) with active targeting techniques like as modified nanoparticles (NPs) or dendrimers . In addition, biomaterials antibodies which aim at targeting overexpressed specific antigens found on cancer cell surfaces are extensively used . After the process of endocytosis, encapsulated drugs are released and exert cytotoxic effect or nuclear materials triggers cell apoptosis, depends on the encapsulated drugs . Progress has been achieved in the delivery of nucleic acid nanoparticle-based drug delivery systems (DDS) targeting transporters, utilizing platforms such as exosome, liposomes, dendrimers and polymeric nanoparticles are extensively explored and researched in cancer therapy . Targeted cancer therapy aims at targeting specific cancer metabolic pathways and proteins involved in the cancer progression .
Advantages of NPs-based cancer treatment over conventional treatment methods
The prime advantage of the nanoparticles is the targeted administration directly to the metabolic pathways of cancer  . Intensive research and progress has been made for targeted drug delivery in cancers. It is accomplished by either active or passive targeting . Active targeting comprises the attachment of nanoparticles to antibodies, peptides, aptamers, and other small molecules, whereas passive targeting involves better retention time and permeability . Targeted nanoparticles-based drug delivery helps minimizing harms to healthy cells, prevent drug degradation, increases half-life, drug loading capacity and solubility . NPs-based cancer treatment provides maintenance of better specificity, compatibility with biological systems, reduce toxicity, longer duration of effectiveness, regulated medication release, and better drug carrying capacity, overcoming the limitations in the conventional chemical methods of cancer treatment . When drugs are encapsulated with NPs, anticancer therapies are less likely to be resistant to target cell resistance, i.e. the anticancer drug Metformin coupled with NPs is more effective than using Met alone to treat cancer .
Moreover, target-specific NPs can also be used to regulate the genes involved in the regulation of metastasis and have potential to inhibit them . Intravesical delivery of mucoadhesives NPs along with Lysine Demthylase 6A (KDM6A-mRNA) could inhibit the metastasis of the bladder cancer . Despite the intensive research for cancer therapies using nanoparticles, only a limited number of nano-drugs has been created successfully and are in clinical use. These nanoparticles can be typically classified into multiple categories shown in (Figure 2) .
Figure 2: A range of nanomaterials finds application in the field of cancer treatment. a Nanoparticles. b Solid lipid nanoparticles. c. Liposomes d. Nanostructured lipid carriers. e Nanoemulsions. f Graphene. g Dendrimers. h Metallic nanoparticles. PEG, poly (ethylene glycol) .
Metabolic Pathways Involved in the Progression of Cancer
Oncogenes activation and tumor suppressors’ loss have the key role in the promotion of reprogramming of the metabolism of cells in cancer . This alteration leads to enhancement in the uptake of nutrients that are required to supply energy to pathways of biosynthesis . Solid tumors experience lack of nutrients . To overcome this limitation metabolic flexibility is adapted by the cancer cells that help in sustainability of growth and survival . Adjustment of metabolic pathways is assumed as the one of the major hallmarks of the cancer . Hence it has been the focused area of cancer research over the last decade. When nutrients are in abundance, more nutrients are exquisite by cancer signaling pathways to facilitate the assimilation of carbon into various macromolecules including proteins, nucleic acids and lipids . These cellular activities facilitate the growth and multiplication of cells . In oncogenic pathways, glucose and glutamine metabolism are reprogrammed consistently by mutations . The mutations are evident in Tumor Protein 53, Myc proteins, the Ras-assosiated oncogenes, along with the signaling pathways involving PI3 kinase (PI3K) and the upstream kinase liver kinase B1- Activated protein kinase (LKB1-AMP) kinase (AMPK), among others as shown in (Figure 3) [58,59]. Oncogenic Ras is implicated in the activation of both the glucose uptake via enhanced activity of Glucose transporter 1(GLUT1) and uptake of glucose uptake with the help of anabolic pathways . Ras also has its key role in the regulation of glutamine metabolism where it directs glutamine carbon into such pathways that support cell survival and growth . Enhanced MYC expression is involved in the exhibition of multiple metabolic effects  including enhanced glycolysis  enhanced glutamine catabolism , enhanced mitochondrial biogenesis and enhanced metabolism of glutamine, culminating in assimilation of biomass . The convergence of multiple pathways on glutamine and glucose indicates an abundance of these nutrients, which then enter the central metabolism . Glutamine also provides its two nitrogen atoms for the synthesis of nucleotides, hexosamines and amino acids essential for growth . In a nutshell, studies cancer studies reveal that cancer cells bear much more complicated metabolic requirements and multiple pathways complement production of biomass dependent on glutamine and glucose . Some of major pathways are discussed here to elaborate how they contribute to cell proliferation and growth.
Although the blood pressure inside the tumors is low, lymphatic deficiency and leaky blood vessels come into play and make the blood serum protein reachable to cancer cells . Ras- driven tumors experience maximum number of macropinocytosis which facilitate them to uptake extracellular proteins (ECPs) Fig 2b . It is also has been observed that in case of nutrient starvation by blocking of mTORC1 signaling pathway forces tumor cells exhibit dependency on extracellular macromolecules rather than amino acids . In an experiment, Phosphatase and tensin homolog (PTEN-deficient prostate cancer cell lines and K-Ras driven pancreatic tumors were studied which revealed that AMPK activation and suppression of mTORC1 in a state of glucose and amino acid deprivation tumor proliferation is facilitated by clearing cellular debris . Cell Biomass is developed facilitated by amino acids from cell debris . Moreover, pancreatic ductal adenocarcinoma (PDAC) has the ability to incorporate collagen I and IV via glucose and glutamine starvation . PDAC cells degrade the encapsulated collagens taken up by lysosomes for the provision of proline . Proline enters the tricarboxylic acid cycle via extracellular signal-regulated kinase 1/2 pathways, which results in ATP generation and, ultimately, cell viability . In vitro Studies reveals that albumin is the main source of nutrients for cancer cell survival . An in vivo study exhibited that PDAC cells have the ability to ingest albumin and utilize amino acids generated from albumin in other metabolic pathways whereas this property does not belong to normal cells  Tumors cells can also utilize extracellular lipids for cell proliferation and survival in a state of hypoxia or nutrient limitation . For the reproduction of membrane and proliferation cancer cells need extracellular lipids and fatty acids . Non-essential fatty acids are produced by tumor cells in normal condition in which oxygen is readily available . On the other hand, Ras-driven cancers or hypoxic depend on the scavenging fatty acids from tumor microenvironment . Ras-driven cancer cells have the ability to internalize lipids with one fatty acid tail to fulfill the requirement of lipid . Cancer cells have a decrease in lipid droplet content during periods of famine. Prostate cancer cells lacking PTEN rely on lipids derived from cellular waste . Invasive breast tumor in co-culture with obese adipocytes, exhibit increased proliferation and migration . When fatty acids from adipocytes are transferred to invasive breast cancer cells, it activates adipose triglyceride lipase (AGTL) - induced lipolysis and fatty acid oxidation in mitochondria .
Recent studies have revealed the role of acetate and enzymes involved in acetate metabolizing in cancer cells . Infusion of 13C-glucose and 13C-acetate into mice with orthotropic glioblastomas exhibited that both substrates could be oxidized . But, in the blood stream the tumors oxidized at higher rate than did the healthy brain tissues in the surrounding . In metastatic brain tumors acetate oxidation was observed that proposed that this pathway is a general feature of tumor in the brain [89,90]. Also in gliomas and brain metastases extensive acetate oxidation was revealed when similar mixture of 13C-glucose and 13C-acetate was infused in the human patients [91,92]. To explore the importance of tumor cells prolifiration, a mouse model of Acyl-CoA Synthetase Short Chain 2 of deficiency was used [93,94]. These ACSS2-deficient embryonic fibroblasts are not able to utilize exogenous acetate for histone acetylation and lipogenesis . Moreover, ACSS2 knockout in two models of hepatocellular carcinoma reduces the burden of tumor [93,96]. Selective ACSS2 inhibitors development proposed the idea that modulating acetate metabolism may lead to strong therapeutic approach in some forms of cancer [97-99]. Keeping in view the significance of above mentioned metabolic pathways of cancer, some key points of metabolism in these pathways can be targeted with the help of Nanoparticles to find out potential therapeutic approaches of cancer. In this review, application of NPs is explored in different forms of cancer with an objective to find out a successful treatment of cancer.
Application of JX06 Nanoparticles for Targeting Cancer Metabolism
Diabetes is an illness associated with the appearance of endometrial cancer (EC) incidence and its poor detection . But for EC patients with diabetes, there is no effective treatment available . In an experimental study, JX06 nanoparticles were applied for targeting cancer metabolism by inhibiting 3-Phosphoinositide-dependent kinase 1 in combination with Metformin for EC patients with diabetes disease. To find out novel therapeutic targets, Ishikawa cell lines were cultured with high glucose (IshikawaHG) [102,103]. The condition of IshikawaHG resembles much like hyperglycemia in EC cancer with diabetes (EC+/dia+) . It exhibited glucose metabolic reprogramming in IshikawaHG as an increased glycolysis level and oxidative phosphorylation reduction was observed. With the development of IshikawaHG cell lines, exposure to high-glucose culture promoted the convergence of cancer metabolism to glycolysis of EC from oxidative phosphorylation. Moreover, the identified enzyme behind the promotion glycolysis of IshikawaHG was pyruvate dehydrogenase kinase 1 (PDK1). Furthermore, a novel PDK1 inhibitor, JX06 NPs, in combination with the diabetic drug Metformin (Met), greatly inhibits the IshikawaHG proliferation, although Met faces resistance in IshikawaHG cell lines. For encapsulation of JX06, a biodegradable polymer that is sensitive to reduction  was utilized to develop nanoparticles (JX06-NPs) for the delivery of the drug. The in vitro experiment revealed that JX06 Nanoparticles have a significant inhibitory effect on patient- derived EC cells (PDC) and the IshikawaHG cell lines than the simple use of JX06. In addition, it was also found that JX06-NPs have the capacity to accumulate in the tumor proliferation of mice having endometrial cancer with diabetes (miceEC+/dia+) as a result of intravenous injection. The results also showed that JX06-NPs in combination with Met have the power to significantly inhibit the tumor growth of EC in mice with diabetes. The mass spectrometry- based on proteomic screening  revealed the 3.3 times higher expression of the key enzyme in glycolysis, PDK1. In the state of knockdown of PDK1 using shRNA, significant inhibition of proliferation, glycolysis, invasion, and AKT/GSK3𝛽/𝛽-catenin signaling pathway of IshikawaHG was observed. The schematic representation of downregulation of PDK1 is shown in (Figure 3) . It confirmed that PDK1 could have a significant role in the malignancy of the EC cells activated by high glucose. Inhibition activity of JX06  was 2.5 times greater than Met only on IshikawaHG cell lines. Also, the apoptotic rate was higher on Ishikawa HG cell lines induced by JX06 based nanoparticles with combined Met . The mechanism of inhibition is purposed to be associated with inhibition of the glycol sis pathway and oxidative phosphorylation. Mouse models have been established that exhibited promising results. To sum up, the study revealed that JX06-NPs, when used in combination with Met, have the ability to target the plasticity of cancer metabolism, which resulted in the significant inhibition of the proliferation of endometrial cancer. Hence, it put forwards a novel adjuvant-based therapy for EC patients with diabetes. The experiment suggests that Met, in combination with JX06-NPs, exhibits anticancer effects, and adjuvant treatment for patients EC+/dia+ can give promising results for future clinical practices. By combining Met with JX06-NPs, outstanding anticancer effects can be achieved. Despite the successful results of in vitro trials, there are challenges in the application of JX06 NPs need to be addressed and resolved .