REVIEW ARTICLE Year : 2023  |  Volume : 13  |  Issue : 3  |  Page : 104-111

Colon cancer and their targeting approaches through nanocarriers: A review

Richa Kumari1, Nitin Sharma1, Ritu Karwasra2, Kushagra Khanna3
1 Department of Pharmaceutics, ISF College of Pharmacy, Ferozepur GT Road, Moga, Punjab, 142001, India
2 Central Council for Research in Unani Medicine, Ministry of Ayush, Janakpuri, New Delhi, 110058, India
3 Faculty of Pharmaceutical Science, UCSI University, Kualalumpur, 56000, Malaysia

Date of Submission29-Nov-2022Date of Decision10-Dec-2022Date of Acceptance06-Jan-2023Date of Web Publication31-Mar-2023

Correspondence Address:
Nitin Sharma
Department of Pharmaceutics, ISF College of Pharmacy, Ferozepur GT Road, Moga, Punjab, 142001
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2221-1691.372283

Colon cancer is the fifth most common type of cancer in the world. Colon cancer develops when healthy cells in the lining of the colon or rectum alter and grow uncontrollably to form a mass known as a tumor. Despite major medical improvements, colon cancer is still one of the leading causes of cancer-related mortality globally. One of the main issues of chemotherapy is toxicity related to conventional medicines. The targeted delivery systems are considered the safest and most effective by increasing the concentration of a therapeutic substance at the tumor site while decreasing it at other organs. Therefore, these delivery systems required lower doses for high therapeutic value with minimum side effects. The current review focuses on targeting therapeutic substances at the desired site using nanocarriers. Additionally, the diagnostic applications of nanocarriers in colorectal cancer are also discussed.

Keywords: Colon cancer; Targeting approaches; Chemotherapies; Nanocarriers; Gold nanoparticles; Liposomes

How to cite this article:
Kumari R, Sharma N, Karwasra R, Khanna K. Colon cancer and their targeting approaches through nanocarriers: A review. Asian Pac J Trop Biomed 2023;13:104-11
How to cite this URL:
Kumari R, Sharma N, Karwasra R, Khanna K. Colon cancer and their targeting approaches through nanocarriers: A review. Asian Pac J Trop Biomed [serial online] 2023 [cited 2023 Apr 2];13:104-11. Available from: https://www.apjtb.org/text.asp?2023/13/3/104/372283   1. Introduction 

Colorectal cancer (CRC) ranks third in prevalence worldwide after breast and lung cancer. As per the literature, new cases of CRC reached upto 1880725 where colon and rectum cancer contributed 1148515 and 732210, respectively[1],[2]. Several risk factors, such as a sedentary lifestyle, the environment, obesity, old age, a diet high in meat and associated products, a lack of physical exercise, tobacco, alcohol drinking, and congestion can contribute to the development of CRC. In addition to these factors, a few novel studies also suggested the role of mitochondria biogenesis and clearance in the development of CRC. It is known that NO and H2O2 diffusion, mitochondrial oxidative damage, and mitochondrial dysfunction all contribute to the development of CRC[3],[4]. Symptoms of CRC include fat loss, blood in the feces, soreness, abdomen pain, changes in gut habits, abdominal weakness and increasing bloating, nausea, and vomiting[5].

Nanocarriers have a size range of less than 1000 nm acting as drug-delivery carriers for many therapeutic substances. The unique benefits of nanocarriers, such as biocompatibility, decreased toxicity, good stability, improved permeability, retention impact, and accurate targeting, make them suitable for the treatment of colon cancer. Currently, nanocarriers are considered a means of early detection and successful therapy for CRC. As the distribution of drug systems is for medicinal and diagnostic reasons, several nanocarriers have been produced and investigated to date. To treat patients selectively and minimize toxicity, such nanocarriers are connected to targeting moieties. Active targeting frequently includes the ligation of targeting moieties that are recognized through colon cancer tissues, such as folate, monoclonal antibodies, vascular endothelial growth factor, aptamers, and membrane penetrating peptides, whereas extravasation and increased permeability are considerable factors in passive targeting. Moreover, delivery systems based on nanotechnology have gradually started to use smart carriers in CRC by ensuring the maximum availability of anticancer drugs at cancer sites[6].

The applications of several nanocarriers in the treatment of CRC are summarized in the current review article. Several nanocarrierbased targeting approaches that have been extensively used in CRC are compiled here, including the passive and active targeting approaches. Several ligation moieties have been discovered so far which are overexpressed under CRC-associated pathophysiological conditions. The article highlights those ligands that could be used effectively in the case of active targeting.

  2. Colon cancer 

There are many reasons for colon cancer, including a sedentary lifestyle, food habits, and obesity. The probability of getting colon cancer is increased in obese people compared to those who are considered to be of normal weight because of the environment and obesity. Weight loss, red blood cells in the feces, pain, abdominal discomfort, stool pattern changes, appetite loss, worsening congestion, nausea, and vomiting are signs of CRC. Anemia or genital hemorrhage is a serious concern in older people (over 50 years of age)[5]. Cancer is a condition, where a subset of the cells in the body repeatedly divides especially invading nearby tissues. Standard cancer stem cells are caused by adenomatous polyposis coli gene mutations, and they proceed in increments to CRC[7]. The three main etiological and genetic instability pathways for CRC are the CpG island methylator phenotype, microsatellite instability, and chromosomal instability (CIN). The occurrence of CRC is mostly caused by the CIN route and is distinguished by frequent aneuploidy (abnormal chromosomal numbers) and a lack of heterozygosity. [Figure 1] demonstrates the pathophysiology of CRC at various stages of development and its many risk factors.

Figure 1: A diagram of the pathophysiology of colorectal cancer at various stages of development and its many risk factors.

Click here to view

  3. Targeting approaches 

There has been an increasing interest in the development of effective therapy techniques based on nanocarriers for CRC in the last forty years. The majority of anticancer medications have low efficacy and related adverse effects because they are unable to discriminate between healthy cells and malignant cells. Targeted drug delivery based on nanocarriers may be an option in this situation for increased efficacy and decreased negative effects via passive or active methods. For therapeutic and diagnostic purposes, a variety of nanocarriers, including polymeric micelles, liposomes, nanoparticles, quantum dots, and dendrimers, have been utilized[8]. Targeting through nanocarriers is possible in the following ways:

3.1. Passive targeting

Utilizing tumor-related pathophysiological alterations can enable the passive targeting of loaded therapeutic material to CRC cells. Due to the flawed design of tumor vasculature, enhanced permeability and additional retention of nanoparticles in cancer cells are feasible. In contrast to the conventional technique, the endothelial voids between blood arteries that are connected to cancerous tumors are said to be greater (100 nm to 2 m) than normal, allowing for improved permeability of size-specific drugloaded nanocarriers to the cancer cells. The fact that cancer tissues may have a compromised lymphatic system, which causes higher interstitial pressure at the centers of cancer cells than at their peripheries, is a reason for the passive targeting of nanocarriers. As a result, drug-loaded nanocarriers are kept in the interstitial region for a longer period and show better therapeutic value for the treatment of cancers[9].

Unlike traditional delivery techniques, nanocarriers have longer systemic circulation due to their avoidance of the reticular endothelial system, which further enhances the therapeutic effectiveness of the loaded anticancer drug. Because loaded nanocarriers are available for such a long time, certain cancer cells eventually pick them up. By coating or ligating nanocarriers with some hydrophilic chemicals, such as polyethylene glycol, opsonization (a technique for making stealth nanocarriers) can ensure the lengthy circulation of nanocarriers[10].

3.2. Active targeting

Active targeting of nanocarriers requires cancer cells to be recognized by the nanocarriers through molecular ligation. Therapeutic agents solely deposit at the cancer site by molecular recognition. Targeting molecules are often ligated on the surface of the nanocarrier for active targeting. The following formulations have been studied for the active targeting of the therapeutic substance in CRC[11].

3.2.1. Nanoparticles

Many nanoparticle combinations loaded with anticancer medicines have been taken into account during the past 50 years for the efficient therapy of CRC. The main goal of first-generation nanoparticles was to use physiological changes (enhanced penetration and retention effects supplied by the vascular and lymphatic drainage of CRC) occurring during the disease to combat the condition passively. Later, consideration was given to next-generation receptor-based active targeting with targeted delivery of drug-loaded nanoparticles into cancer cells alone. The numerous interactions (monoclonal antibodies, enzymes, and dendrimers) linked to the nanoparticle occurs for cancer cell activity identification and served as a guide for the movement of the nanoparticles. The study conducted by Fay et al. demonstrates that the conatumumab (AMG 655)-coated nanoparticles are more absorbed by the colorectal HCT116 cancer cell. They show that camptothecin, an encapsulated therapeutic substance, was delivered specifically to HCT116 cancer cells to induce apoptosis[12]. Hydrogel-based chitosan/alginate nanoparticles were prepared in a similar work by Abdelghany et al., for the encapsulation of meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate. The prepared nanoparticles were coated with antibodies that target death receptor 5 for selective uptake by the HCT116 cells during the 16 h incubation[13].

3.2.2. Liposomes

The liposomes consist of phospholipids derived from either plant or animal sources and can be unilamellar or multilamellar tiny artificial spherical vesicles[14]. The size of the liposomes varies from 20 nm to 1000 nm, and they have a spherical hydrophobic phospholipid bilayer structure around an aqueous core domain[15]. As a non-toxic molecule that can encapsulate both hydrophilic and hydrophobic therapeutic substances, liposomes provide better protection to the encapsulated therapeutic substance from environmental degradation throughout the systemic circulation[16],[17]. In drug delivery systems, liposomes are frequently utilized as a carrier for a variety of anticancer substances[18]. However, liposomes are limited with numerous drawbacks, such as poor encapsulation efficiency, poor solubility, brief half-life, and rapid burst drug release[19],[20],[21].

To enhance the drug’s effectiveness and safety, a research was performed to prepare 5-fluorouracil-loaded liposomes and they were actively targeted to CRC by the ligation with folic acid. The cytotoxicity of formulations on the HT-29, Caco-2, CT26, HeLa, and MCF cell lines was evaluated using the MTT assay after 48 h. When compared to the free medication and control groups, an in-vivo investigation found that folate-ligated liposomes effectively inhibited tumor growth[22]. To encapsulate 5-fluorouracil, Mansoori et al., developed hyaluronic acid-modified liposomes and tested them against a colorectal cell line (HT29) that expresses CD44 and a hepatoma cell line that does not express CD44. Hyaluronic aciddecorated liposomes were found to be 114.77 nm in size on average. Based on the expression of CD44, the MTT experiment indicated time-dependent specific cancer cell death. The results demonstrated that produced liposomes have improved anticancer activity by active targeting[23].

3.2.3. Dendrimers

Organic and hyperbranched macromolecules, known as dendrimers with a size of 1 to over 10 nm, have a shape like a tree[16],[17]. With a high drug encapsulation rate, dendrimers are different drug delivery technology. Because of their special characteristics including consistent size and dispersion, extensive branching, a known molar mass, and chemical makeup, dendrimers are an appealing carrier for drug delivery applications[24],[25],[26]. The monomers that make up the dendrimer’s core have two or more extra groups that can connect to other moieties[27]. Dendrimers are often created using one of two methods: Convergent strategies versus divergent methods[28].

Dendrimers are widely used in cancer medication delivery and cancer cell detection due to their precise size and branching patterns. In a recent study, Myc et al., used polyamidoamine dendrimers with methotrexate by the ligation of folic acid as a targeting agent[29]. The outcomes of tests on both cytotoxicity and specificity indicated that dendrimer conjugates significantly improved anticancer activity. In a related study, Alibolandi et al. developed a polyamidoamine dendrimer for site-specific targeting of HT29 and C26 CRC cells that were loaded with camptothecin and connected with S1411 antinucleolin aptamers. Additionally, the system was tested on mice with C26 tumors, and the outcomes of the investigation showed improved therapeutic efficacy[30]. More recently, Sun et al., reported a generic method for creating nano assemblies from phospholipids and hydrophilic and hydrophobic dendrimers[31].

3.2.4. Gold nanoparticles

Due to their distinct optical, physical, and electrical features, gold nanoparticles (AuNPs) are most frequently employed as a preferred material in various disciplines[16],[17],[32]. Based on their size, shape, and physical characteristics, the AuNPs may be divided into Au nanospheres, Au nanorods, Au nanocages, and Au nanoshells, with diameters ranging from 2 to 100 nm[33],[34]. The special properties of AuNPs for drug delivery techniques include inertness, biocompatibility, large surface area, excellent stability, and low toxicity[35]. AuNPs’ enormous potential in diagnostics for the detection of biomarkers and imaging in existing cancer treatments is one of their primary developing applications[36],[37]. Due to the ease with which gold can bind functionalizing or targeting ligands, localized surface plasmon resonance of AuNPs has been extensively explored in a variety of applications ranging from biomolecular sensing to therapeutic interventions[38].

It has emerged as an attractive drug delivery system for the treatment of a variety of diseases due to its advantages in facile synthesis, vast surface area, flexible surface chemistry, and easy functionalization. It is possible to make a useful delivery system that releases its payload in response to an external signal[39]. Xie et al. conducted a study to describe an efficient method for using multiple Sialyl Lewis X antibodies-conjugated polyamidoamine dendrimers for specific binding with colon cancer (HT29) cells. The findings demonstrated that the compound increased HT29 cell capture in a concentration-dependent manner, with a maximum capture efficiency of 77.88%[40].

3.2.5. Quantum dots

Semiconductor particles having optical and electrical properties that are nanometer-sized, when excited, become luminous at wavelengths ranging from visible to infrared. This characteristic makes these particles particularly useful for imaging and diagnostic purposes in a range of diseases, including CRC. Numerous studies have been conducted on quantum dots, which are steered by ligands absorbed by CRC cells, and which suggest their potential utility as CRC diagnostic tools. Quantum dots designed to attach to vascular endothelial growth factor receptor 2 have been created by Carbary-Ganz et al. According to the outcomes of immunofluorescence and immunohistochemistry, the generated quantum dots were preferentially deposited on colon cancer in mice[41]. Quantum dots conjugated with bevacizumab were created by Gazouli et al. for molecular imaging in CRC. The findings of this study also demonstrated a straightforward, practical, and non-invasive method for detecting excessive vascular endothelial growth factor receptor expression in CRC cells[42]. In addition to their use in diagnostics, quantum dots have demonstrated their ability as therapeutic drug carriers in CRC. In a recently completed study, Eudragit RS 100 was used to create curcumin-loaded quantum dots. Researchers discovered that the produced formulation exhibits higher bacterial and CRC cell inhibition. Despite the paucity of research in this field, it has been concluded that ligation-based targeting of drugloaded quantum dots may provide a useful alternative to diagnostic application in the management of CRC[43]. Targeted nanoparticles can be encapsulated with various anticancer medications, as shown in [Table 1].

Table 1: The use of several nanocarriers targeting methods in colorectal cancer.

Click here to view

3.2.6. Carbon nanotubes

Carbon nanotubes are gaining the attention of researchers for the last two decades. They are considered a good choice for the delivery of an anticancer therapeutic substance to the site of action because of their strong hydrophobicity. Additionally, several targeting moieties can be coupled with the delivery system for the effective identification of tumor cells. Depending on the number of layers, these nanostructures can be single-walled, double-walled, or multiwalled when produced from rolled-up graphite sheets. Important characteristics of carbon nanotubes include their light weight, tiny size, superior strength, and great conductivity[52],[53].

Wang et al. demonstrated that a greater aspect ratio of thin multiwalled nanotubes is the comparatively better choice because they accumulate more near the cancer cells. They compared narrow multiwalled nanotubes (9.2 nm average diameter) and broader multiwalled carbon nanotubes (39.5 nm average diameter) and concluded that narrow multiwalled nanotubes showed better therapeutic value with selective targeting[54]. In another study, Arora et al. demonstrated the enhanced anticancer properties of docetaxel when conjugated with multi-walled carbon nanotubes[55].

  4. Nanocarrier toxicity and future perspectives 

Nanocarriers are extensively being used in the diagnosis, treatment, and prevention of cancer. However, because of their small size and their distinctive properties, it confers safety-related issues. Many studies revealed that the accumulation of nanocarriers in different cells and tissues may lead to major health hazards. Ma-Hock et al, demonstrated that inhalation of a liquid aerosol of CdS/Cd(OH)2 core-shell quantum dots causes respiratory toxicity in male Wistar rats[56]. Another study conducted by Kim et al. confirmed that the silver nanoparticles altered the level of cholesterol and alkaline phosphatase which may be due to liver toxicity. They hypothesized that the release and accumulation of metal ions from silver nanoparticles may be responsible for these harmful consequences. Additionally, they demonstrated that NPs given intravenously or intraperitoneally tend to cause mild liver toxicity[57]. Size-specific clearance from the kidney has been followed by the nanocarriers. Large particles may be retained in the kidney for a longer time and may cause nephrotoxicity. Coccini et al. demonstrated that cadmiumcontaining silica nanoparticles caused nephrotoxicity and fibrosis in rats with increased expression of interleukin 6 and transforming growth factor beta 1. It was concluded that nephrotoxicity was developed due to the retention of nanoparticles in the kidney[58]. The studies also demonstrated the easy passes of nanocarriers to the brain by passive diffusion or by receptor-mediated endocytosis which may further increase nanocarrier-related brain toxicity. With the alignment of this hypothesis, researchers demonstrated hemorrhage and changes in the level of neurotransmitters in the brains of mice after intranasal administration of titanium dioxide nanoparticles[59].

Despite the enhanced therapeutic values, nanocarriers may also cause several cellular and organ toxicity. Therefore, a potential toxicity concern by using clinical approaches should be undertaken while preparing the nanocarriers for a certain disease or disorder. The clinical toxicological effects of nanocarriers should be fully understood. The exposure kinetics and clearance study should be well planned during the scale-up manufacturing and even the packaging of nanocarriers carrying the chemotherapeutic substances. Further, the retention and possible impact on particular cells and tissues should be studied clinically. These controlled sets of data may be useful to minimize the occurrence of nanotoxicity with improved anticancer activity.

  5. Conclusion 

For customized oncology that encompasses cancer detection, diagnosis, and treatment, nanotechnology has emerged as a key tool. Nanocarriers play a crucial role in cancer treatment by reducing the drawbacks of traditional chemotherapy. A new technique of targeting chemotherapeutic substances at the cancer site is possible by nanocarriers. Decorated nanocarriers may be an effective tool for the selective targeting of therapeutics and herbal anticancer substances in the treatment of CRC. In the near future, extensive clinical testing and mass manufacture of nanoformulations will be necessary for clinical application.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors are highly thankful to ISF College of Pharmacy, Moga for providing the necessary facilities for the review work.

Funding

The authors received no extramural funding for the study.

Authors’ contributions

NS conceived the idea and guided the content of the article. RK and RKW collected and compiled the data. NS and KK gave the final edits to the manuscript. NS and RK equally participated in all activities before the approval of the final manuscript.

 

  References 
1.Meng F, Yun Z, Yan G, Wang G, Lin C. Engineering of anticancer drugs entrapped polymeric nanoparticles for the treatment of colorectal cancer therapy. Process Biochem 2021; 111: 36-42.  
    2.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-249. doi: 10.3322/caac.21660.  
    3.Chodari L, Dilsiz Aytemir M, Vahedi P, Alipour M, Vahed SZ, Khatibi SM, et al. Targeting mitochondrial biogenesis with polyphenol compounds. Oxid Med Cell Longev 2021; 2021. doi: 10.1155/2021/4946711.  
    4.Sanchez-Pino MJ, Moreno P, Navarro A. Mitochondrial dysfunction in human colorectal cancer progression. Front Biosci 2007; 12: 1190-1199.  
    5.Dekker E, Tanis PJ, Vleugels JL, Kasi PM, Wallace MB. Risk factors. Lancet 2019; 394: 1467-1480.  
    6.Eftekhari A, Ahmadian E, Salatin S, Sharifi S, Dizaj SM, Khalilov R, et al. Current analytical approaches in diagnosis of melanoma. Trends Analyt Chem 2019; 116: 122-135.  
    7.Izukawa S, Mushiake H, Watanabe T, Ishiguro T, Segami K, Fukushima T. Characteristics of tumor thrombosis in the inferior mesenteric vein from colorectal cancer: A report of three cases and review of the literature. Int J Surg Case Rep 2023; 102. doi: 10.1016/j.ijscr.2022.107840.  
    8.Rudzinski WE, Palacios A, Ahmed A, Lane MA, Aminabhavi TM. Targeted delivery of small interfering RNA to colon cancer cells using chitosan and PEGylated chitosan nanoparticles. Carbohydr Polym 2016; 147: 323-332.  
    9.Shah MR, Imran M, Ullah S. Metal nanoparticles for drug delivery and diagnostic applications. The Netherland: Elsevier; 2019.  
    10.Attia MF, Anton N, Wallyn J, Omran Z, Vandamme TF. An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites. J Pharm Pharmacol 2019; 71(8): 1185-1198.  
    11.Biffi S, Voltan R, Bortot B, Zauli G, Secchiero P. Actively targeted nanocarriers for drug delivery to cancer cells. Expert Opin Drug Deliv 2019; 16(5): 481-496.  
    12.Fay F, McLaughlin KM, Small DM, Fennell DA, Johnston PG, Longley DB, et al. Conatumumab (AMG 655) coated nanoparticles for targeted pro-apoptotic drug delivery. Biomaterials 2011; 32(33): 8645-8653.  
    13.Abdelghany SM, Schmid D, Deacon J, Jaworski J, Fay F, McLaughlin KM, et al. Enhanced antitumor activity of the photosensitizer mesotetra (N-methyl-4-pyridyl) porphine tetra tosylate through encapsulation in antibody-targeted chitosan/alginate nanoparticles. Biomacromolecules 2013; 14: 302-310.  
    14.Sang R, Stratton B, Engel A, Deng W. Liposome technologies towards colorectal cancer therapeutics. Acta Biomater 2021; 127: 24-40.  
    15.Banerjee K, Banerjee S, Mandal M. Enhanced chemotherapeutic efficacy of apigenin liposomes in colorectal cancer based on flavone-membrane interactions. J Colloid Interface Sci 2017; 491: 98-110.  
    16.Rani V, Venkatesan J, Prabhu A. Liposomes-A promising strategy for drug delivery in anticancer applications. J Drug Deliv Sci Technol 2022; 76. doi: 10.1016/j.jddst.2022.103739.  
    17.Fan Y, Yuan S, Huo M, Chaudhuri AS, Zhao M, Wu Z, et al. Spatial controlled multistage nanocarriers through hybridization of dendrimers and gelatin nanoparticles for deep penetration and therapy into tumor tissue. Nanomedicine 2017; 13(4): 1399-1410.  
    18.Shamshiri MK, Jaafari MR, Badiee A. Preparation of liposomes containing IFN-gamma and their potentials in cancer immunotherapy: In vitro and in vivo studies in a colon cancer mouse model. Life Sci 2021; 264: 118605. doi: 10.1016/j.lfs.2020.118605.  
    19.Sen K, Banerjee S, Mandal M. Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer. Colloids Surf B Biointerfaces 2019; 180: 9-22.  
    20.Krajewska JB, Bartoszek A, Fichna J. New trends in liposome-based drug delivery in colorectal cancer. Mini Rev Med Chem 2019; 19(1): 3-11.  
    21.Tiwari A, Gajbhiye V, Jain A, Verma A, Shaikh A, Salve R, et al. Hyaluronic acid functionalized liposomes embedded in biodegradable beads for duo drugs delivery to oxaliplatin-resistant colon cancer. J Drug Deliv Sci Technol 2022; 77. doi: 10.1016/j.jddst.2022.103891.  
    22.Handali S, Moghimipour E, Rezaei M, Ramezani Z, Kouchak M, Amini M, et al. A novel 5-Fluorouracil targeted delivery to colon cancer using folic acid conjugated liposomes. Biomed Pharmacother 2018; 108: 1259-1273.  
    23.Mansoori B, Mohammadi A, Abedi‐Gaballu F, Abbaspour S, Ghasabi M, Yekta R, et al. Hyaluronic acid‐decorated liposomal nanoparticles for targeted delivery of 5‐fluorouracil into HT‐29 colorectal cancer cells. J Cell Physiol 2020; 235(10): 6817-6830.  
    24.Contin M, Garcia C, Dobrecky C, Lucangioli S, D’Accorso N. Advances in drug delivery, gene delivery and therapeutic agents based on dendritic materials. Future Med Chem 2019; 11(14): 1791-1810.  
    25.Sheikh A, Md S, Kesharwani P. RGD engineered dendrimer nanotherapeutic as an emerging targeted approach in cancer therapy. J Control Release 2021; 340: 221-242.  
    26.Hani U, Honnavalli YK, Begum MY, Yasmin S, Osmani RA, Ansari MY. Colorectal cancer: A comprehensive review based on the novel drug delivery systems approach and its management. J Drug Deliv Sci Technol 2021; 63. doi: 10.1016/j.jddst.2021.102532.  
    27.Ge P, Niu B, Wu Y, Xu W, Li M, Sun H, et al. Enhanced cancer therapy of celastrol in vitro and in vivo by smart dendrimers delivery with specificity and biosafety. Chem Eng J 2020; 383. doi: 10.1016/j.cej.2019.123228.  
    28.Carvalho MR, Reis RL, Oliveira JM. Dendrimer nanoparticles for colorectal cancer applications J Mater Chem B 2020; 8(6): 1128-1138.  
    29.Myc A, Kukowska-Latallo J, Cao P, Swanson B, Battista J, Dunham T, et al. Targeting the efficacy of a dendrimer-based nanotherapeutic in heterogeneous xenograft tumors in vivo. Anticancer Drugs 2010; 21(2): 186-192.  
    30.Alibolandi M, Taghdisi SM, Ramezani P, Shamili FH, Farzad SA, Abnous K, et al. Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo. Int J Pharm 2017; 519(1-2): 352-364.  
    31.Sun Q, Ma X, Zhang B, Zhou Z, Jin E, Shen Y, et al. Fabrication of dendrimer-releasing lipidic nanoassembly for cancer drug delivery. Biomater Sci 2016; 4(6): 958-969.  
    32.Lee CS, Kim H, Yu J, Yu SH, Ban S, Oh S, et al. Doxorubicin-loaded oligonucleotide conjugated gold nanoparticles: A promising in vivo drug delivery system for colorectal cancer therapy. Eur J Med Chem 2017; 142: 416-423.  
    33.Anadozie SO, Adewale OB, Fadaka AO, Afolabi OB, Roux S. Synthesis of gold nanoparticles using extract of Carica papaya fruit: Evaluation of its antioxidant properties and effect on colorectal and breast cancer cells. Biocatal Agric Biotechnol 2022; 42. doi: 10.1016/j.bcab.2022.102348.  
    34.Amina SJ, Iqbal M, Faisal A, Shoaib Z, Niazi MB, Ahmad NM, et al. Synthesis of diosgenin conjugated gold nanoparticles using algal extract of Dictyosphaerium sp. and in-vitro application of their antiproliferative activities. Mater Today Commun 2021; 27. doi: 10.1016/j.mtcomm.2021.102360.  
    35.Khiavi MA, Safary A, Aghanejad A, Barar J, Rasta SH, Golchin A, et al. Enzyme-conjugated gold nanoparticles for combined enzyme and photothermal therapy of colon cancer cells. Colloids Surf A Physicochem Eng Asp 2019; 572: 333-344.  
    36.Kim S, Han J, Park JS, Kim JH, Lee ES, Cha BS, et al. DNA barcodebased detection of exosomal microRNAs using nucleic acid lateral flow assays for the diagnosis of colorectal cancer. Talanta 2022; 242. doi: 10.1016/j.talanta.2022.123306.  
    37.Huang Z, Lin Q, Ye X, Yang B, Zhang R, Chen H, et al. Terminal deoxynucleotidyl transferase based signal amplification for enzymelinked aptamer-sorbent assay of colorectal cancer exosomes. Talanta 2020; 218. doi: 10.1016/j.talanta.2020.121089.  
    38.Bai X, Wang Y, Song Z, Feng Y, Chen Y, Zhang D, et al. The basic properties of gold nanoparticles and their applications in tumor diagnosis and treatment. Int J Mol Sci 2020; 21(7): 2480.  
    39.Saha K, Agasti SS, Kim C, Li X, Rotello VM. Gold nanoparticles in chemical and biological sensing. Chem Rev 2012; 112(5): 2739-2779.  
    40.Xie J, Wang J, Chen H, Shen W, Sinko PJ, Dong H, et al. Multivalent conjugation of antibody to dendrimers for the enhanced capture and regulation on colon cancer cells. Sci Rep 2015; 5. doi: 10.1038/srep09445.  
    41.Carbary-Ganz JL, Barton JK, Utzinger U. Quantum dots targeted to vascular endothelial growth factor receptor 2 as a contrast agent for the detection of colorectal cancer. J Biomed Opt 2014; 19(8). doi: 10.1117/1.JBO.19.8.086003.  
    42.Gazouli M, Bouziotis P, Lyberopoulou A, Ikonomopoulos J, Papalois A, Anagnou NP, et al. Quantum dots-bevacizumab complexes for in vivo imaging of tumors. In Vivo 2014; 28(6): 1091-1095.  
    43.Tabrez S, Jabir NR, Adhami VM, Khan MI, Moulay M, Kamal MA, et al. Nanoencapsulated dietary polyphenols for cancer prevention and treatment: successes and challenges. Nanomedicine 2020; 15(11): 1147-1162.  
    44.Yu Z, Li X, Duan J, Yang XD. Targeted treatment of colon cancer with aptamer-guided albumin nanoparticles loaded with docetaxel. Int J Nanomed 2020; 15: 6737.  
    45.McCarron PA, Marouf WM, Quinn DJ, Fay F, Burden RE, Olwill SA, et al. Antibody targeting of camptothecin-loaded PLGA nanoparticles to tumor cells. Bioconjug Chem 2008; 19(8): 1561-1569.  
    46.Jain A, Jain SK, Ganesh N, Barve J, Beg AM. Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomedicine 2010; 6(1): 179-190.  
    47.Jain A, Jain SK. In vitro and cell uptake studies for targeting of ligand anchored nanoparticles for colon tumors. Eur J Pharm Sci 2008; 35(5): 404-416.  
    48.Sharma M, Malik R, Verma A, Dwivedi P, Banoth GS, Pandey N, et al. Folic acid conjugated guar gum nanoparticles for targeting methotrexate to colon cancer. J Biomed Nanotech 2013; 9(1): 96-106.  
    49.Safwat MA, Soliman GM, Sayed D, Attia MA. Gold nanoparticles enhance 5-fluorouracil anticancer efficacy against colorectal cancer cells. Int J Pharm 2016; 513(1-2): 648-658.  
    50.Emami F, Banstola A, Vatanara A, Lee S, Kim JO, Jeong JH, et al. Doxorubicin and anti-PD-L1 antibody conjugated gold nanoparticles for colorectal cancer photochemotherapy. Mol Pharm 2019; 16(3): 1184-1199.  
    51.Hashemkhani M, Demirci G, Bayir A, Muti A, Sennaroglu A, Hadi LM, et al. Cetuximab-Ag2S quantum dots for fluorescence imaging and highly effective combination of ALA-based photodynamic/chemo-therapy of colorectal cancer cells. Nanoscale 2021; 13(35): 14879-14899.  
    52.Ahmadian E, Janas D, Eftekhari A, Zare N. Application of carbon nanotubes in sensing/monitoring of pancreas and liver cancer. Chemosphere 2022; 302. doi: 10.1016/j.chemosphere.2022.134826.  
    53.Sheikhpour M, Golbabaie A, Kasaeian A. Carbon nanotubes: A review of novel strategies for cancer diagnosis and treatment. Mater Sci Eng C 2017; 76: 1289-1304.  
    54.Wang JT, Fabbro C, Venturelli E, Ménard-Moyon C, Chaloin O, Da Ros T, et al. The relationship between the diameter of chemically-functionalized multi-walled carbon nanotubes and their organ biodistribution profiles in vivo. Biomaterials 2014; 35(35): 9517-9528.  
    55.Arora S, Kumar R, Kaur H, Rayat CS, Kaur I, Arora SK, et al. Translocation and toxicity of docetaxel multi-walled carbon nanotube conjugates in mammalian breast cancer cells. J Biomed Nanotechnol 2014; 10(12): 3601-3609.  
    56.Ma-Hock L, Brill S, Wohlleben W, Farias PM, Chaves CR, Tenório DP, et al. Short term inhalation toxicity of a liquid aerosol of CdS/Cd(OH)2 core shell quantum dots in male Wistar rats. Toxicol Lett 2012; 208(2): 115-124.  
    57.Kim YS, Song MY, Park JD, Song KS, Ryu HR, Chung YH, et al. Subchronic oral toxicity of silver nanoparticles. Part Fibre Toxicol 2010; 7. doi: 10.1186/1743-8977-7-20.  
    58.Coccini T, Barni S, Mustarelli P, Locatelli C, Roda E. One-month persistence of inflammation and alteration of fibrotic marker and cytoskeletal proteins in rat kidney after Cd-doped silica nanoparticle instillation. Toxicol Lett 2015; 232(2): 449-457.  
    59.Ze Y, Zheng L, Zhao X, Gui S, Sang X, Su J, et al. Molecular mechanism of titanium dioxide nanoparticles-induced oxidative injury in the brain of mice. Chemosphere 2013; 92(9): 1183-1189.  
    

Publisher’s note The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

  [Figure 1]
 
 
  [Table 1]