Flexible Aptamer-based Nucleolin-targeting Cancer Treatment Modalities: A Focus on Immunotherapy, Radiotherapy, and Phototherapy

AUTHORS

Pouya Safarzadeh Kozani 1 , 2 , Pooria Safarzadeh Kozani 3 , Fatemeh Rahbarizadeh 3 , *

1 Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran

2 Student Research Committee, Medical Biotechnology Research Center, School of Nursing, Midwifery, and Paramedicine, Guilan University of Medical Sciences, Rasht, Iran

3 Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

How to Cite: Safarzadeh Kozani P , Safarzadeh Kozani P, Rahbarizadeh F. Flexible Aptamer-based Nucleolin-targeting Cancer Treatment Modalities: A Focus on Immunotherapy, Radiotherapy, and Phototherapy, Trends in Med Sci. Online ahead of Print ; In Press(In Press):e113991. doi: 10.5812/tms.113991.

ARTICLE INFORMATION

Trends in Medical Sciences: In Press (In Press); e113991
Published Online: April 12, 2021
Article Type: Review Article
Received: February 22, 2021
Revised: March 23, 2021
Accepted: April 1, 2021
Uncorrected Proof scheduled for 1 (3)
Crossmark
Crossmark
CHECKING
READ FULL TEXT

Abstract

Cancer radiotherapy and phototherapy are well-recognized as alternative approaches for chemotherapy-resistant malignancies. Additionally, recently cancer immunotherapy is introduced as a potential therapeutic option for cancer treatment, which has had its ups and downs despite the reported heart-warming outcomes. Nevertheless, it is proved that nanotechnology-facilitated approaches might facilitate the success of these modalities. The nucleolin-targeting aptamer, AS1411, is one of the various aptamers utilized for reducing nanocarriers carrying radiosensitizers and photosensitizers. Recently, the potential applicability of this aptamer has been investigated in cancer immunotherapy. In this review, we, firstly, discussed how aptamer-mediated nucleolin targeting nanoplatforms might ameliorate the side effects of cancer radiotherapy, phototherapy, and immunotherapy, and, secondly, how it improved the outcomes of these therapeutic approaches.

1. Context

Aptamers are small and specific DNA- or RNA-based single-stranded oligonucleotides that harbor the capability to fold into three-dimensional (3D) structures and binding to particular targets such as proteins, surface antigens, etc. They have demonstrated high therapeutic applicability due to their binding affinity towards malignancy-related antigens overexpressed in various types of hematological malignancies or solid cancers such as breast, lung, and colon cancer.

Cell surface biomarkers that are involved in various biological processes and pathways such as signal transduction, cell-cell interactions, cell adhesion, cell migration, and communication between the intra- and extracellular environments are crucial elements for various types of targeted cancer therapies, including aptamer-based cancer therapy. In most of the malignancies, there is a relation between the abnormal expression of cell surface biomarkers and tumorigenesis (1), and a high proportion of cancer-targeting drugs, such as therapeutic antibodies and small molecule inhibitors, have been developed to target biomarkers of these cells (2). As a result, increased attention has been paid to these cell surface biomarkers for cancer treatment. Recently, several cell surface biomarker-targeting aptamers have been introduced through the development of both protein- or cell-based SELEX technologies. The role of several of these aptamers in the diagnosis or treatment of hematological malignancies, as well as lung, liver, breast, ovarian, brain, colorectal, and pancreatic cancers, is investigated (3-8).

Nucleolin is a protein engaged in various cellular functions, including DNA metabolism and RNA regulatory processes like transcription, translation, and ribosome assembly. It is predominantly located in the nucleolus alongside being present in the cytoplasm and the cell membrane (9). The dysregulation of nucleolin expression leads to the accumulation of nucleolin mRNAs and proteins. In addition, its cell surface overexpression, in comparison with normal cells, is a hallmark of various cancers.

AS1411 is a nucleolin-targeting aptamer known as the most investigated aptamer in the field of cancer research, which highlights its strong potential and safety profile for clinical utilization. The first phase I study of AS1411 was initiated in September 2003 at the University of Louisville’s James Graham Brown Cancer Center (Louisville, KY). This study was performed on patients with different advanced solid tumors who had progressive metastatic disease when enrolled in the trial. It worth noting that the disease of all patients was incurable with available therapeutic options. They reported promising results for renal cell carcinoma and non-small cell lung cancer patients with objective responses, long-term disease stabilization, and no serious systemic toxicity. Moreover, in late 2007, the first phase II trial (NCT00512083) begun at several institutions to treat patients with relapsed or refractory acute myeloid leukemia (R/R AML) (10). The trial was completed in April 2009; however, no report of this trial has been posted on clinicaltrial.gov or publicly published yet. Furthermore, there is also another phase I clinical trial (code: NCT00881244) that has investigated the safety index and clinical efficacy of AS1411 in 30 participants with advanced solid tumors. Despite being completed in 2007, to this day, no report has been published regarding the outcomes of the mentioned trial.

Various linking methods, such as covalent and non-covalent linking, can be exploited to attach different cargoes to AS1411, which paves the way for linking a wide range of drug conjugates to this aptamer (10). Aptamer-drug conjugation (ApDC) is a straightforward and practical approach of conjugating aptamer sequences directly to therapeutic agents. This could lead to the preferential internalization of the conjugated drugs by tumor cells rather than by healthy cells, which in turn mediates, achieving enhanced therapeutic efficacy and reduced treatment-related side effects. Furthermore, nanoparticles (NPs) are exciting vehicles for aptamer-mediated delivery of different types of cargoes, including drugs, as they can increase both the drug half-life and the payload capacity of aptamer-based drug delivery systems. Alongside characteristics like biocompatibility for clinical applications, drug loading capacity, and uniform size and shape for enhanced biodistribution, NPs pose different additional physical and chemical characteristics based on the material used in their structure. Such characteristics can be exploited to improve biodistribution, stability, and targeting affinity of aptamers. For instance, metal materials offer extraordinary photothermal and magnetic performance, and copolymers and liposomes are both nature-friendly and biodegradable. Consequently, using NPs provides an exceptional delivery system that is beneficial for the development of controlled-cargo release systems. In this review, we highlighted how the nucleolin targeting aptamer, AS1411, can be utilized for improving the outcomes of cancer radio- and photothermal therapy and immunotherapy.

2. Novel AS1411-Equipped Delivery Nanosystems for Cancer Treatment

2.1. Delivery of Radiosensitizers

Radiation therapy (RT) is a localized cancer treatment that is based on using high-energy radiation beams focused on the tumor. It is one of the most common and primary options available for cancer treatment benefiting more than half of the cancer patients (11). However, it has negative consequences, such as damaging healthy tissues while attacking cancer cells, which linger on as a factor limiting the broader success of this primary cancer treatment approach (12). To this date, different strategies have been proposed to overcome these limitations. Strategies like inhibiting specific pathways that mediate radioresistance in tumor cells (e.g., NF-κB and MAPK) or attacking the tumor vasculature to augment tumor sensitivity to ionizing radiation (13). Here, we briefly discussed the advantages of nucleolin aptamer-mediated approaches to overcome the unfavorable events of RT. Radiosensitizers are an effective strategy for the enhancement of RT efficacy and safety. High atomic number materials, including gold nanoparticles (GNPs), are among the most popular radiosensitizers, which have drawn major attention to themselves lately. Radiosensitizers improve radiation effects after the collision of radiation beams at the tumor site (14, 15). The small size of these nanoparticles makes them ideal candidates for reticuloendothelial system escape and sufficient accumulation in tumor cells (16, 17). They harbor a high level of renal clearance and are capable of minimizing side effects due to their appropriate excretion (16). Additionally, the decoration of GNPs with different types of cappings, such as bovine serum albumin (BSA), leads to their enhanced internalization by tumor cells alongside rendering them more stable and biocompatible and results in their uniform size (18-24). It worth mentioning that smart targeting of these GNPs to tumor sites by conjugating them to antibodies or aptamers and their uptake and internalization by tumor cells (not by healthy ones) is a factor of paramount importance. Therefore, smart targeting might come as a second strategy for improving the efficacy of RT. Conjugating BSA and gold nanoclusters (GNCs) to the AS1411 aptamer (Apt-GNCs) to obtain AS1411-functionalized BSA-GNCs can lead to a more specific tumor targeting strategy while increasing the internalization of gold nanoclusters by tumor cells (25, 26).

Ghahremani et al. (25, 26), in a study on the radiosensitizing effects of the AS1411 aptamer-modified GNCs as tumor-specific radiosensitizers for improving the efficacy of megavoltage RT and enhancing the tumoral uptake of GNCs, reported that the Apt-GNCs could attach to nucleolin and were internalized by the target cancer cells. This mechanism led to the accumulation of a significant number of Apt–GNCs in the tumor cells. Moreover, the interaction of radiation beams with intracellular Apt–GNCs not only increased the damage to cancer cells, but also improved radiation therapy efficacy (25, 26). GNCs have been in the center of attention for their radiosensitizing properties (16, 17). This property of GNCs is due to the arrangement of the gold atoms. The atomic arrangement of GNC elevates the probability of radiation interaction with gold atoms. Moreover, because of having tiny size mediates, they pose fast renal clearance, which has made them materials with great levels of biocompatibility. This phenomenon can prevent the unwanted accumulation of these materials in healthy organs, which may evade their trapping in the reticuloendothelial system (25, 26).

Some studies have also investigated the utilization of the AS1411 aptamer for improving the outcomes of RT in glioma (27). They have reported that silver nanoparticles (AgNPs) functionalized with the AS1411 aptamer could selectively target C6 glioma cells with high specificity (27). Also, according to the results, the tumor cell internalization and the tumor mass penetrance of these AgNPs were satisfactory (27). Moreover, comparing the mentioned NPs with PEGylated AgNPs indicated that the AS1411-functionalized NPs could exhibit superior radiosensitizing effects and induced higher rates of apoptosis in tumor cells (27). However, it is well proved that PEGylation can enhance the solubility, stability, and circulation life of NPs (28). Additionally, in a recent study by Mehrnia et al. (29), the radiosensitization effects of AS1411-functionalized GNPs have been investigated on various breast cancer cell lines. They reported that functionalization of gold NPs with the AS1411 aptamer was associated with increased cellular uptake in the MCF-7 and MDA-MB-231 cancer cell lines and the mammospheres of MCF-7 cells (29). This mechanism can enhance radiation-induced apoptosis in these cancer cells in vitro, which paves the way for more similar studies and preclinical research regarding this effect. Finally, these investigations propose that the AS1411 aptamer-GNCs conjugates can improve the outcomes of tumor radiotherapy by elevating the targeting power of RT and attenuating the unwanted damages to healthy tissues (25, 26).

2.2. Delivery of Photosensitizers

Photodynamic therapy (PTD) is a light-activated therapeutic modality utilized for the treatment of various malignancies. It is one of the most promising and non-invasive methods for treating malignant or premalignant tissues. In this method, radiation of a photoactive drug, such as a photosensitizer, with suitable wavelengths of light leads to the production of highly cytotoxic reactive oxygen species (ROS), which in turn causes fatal damages to cancerous cells (30, 31). However, the quantum yields and the systemic biodistribution of ROS are overshadowed by the hydrophobicity of the existing photosensitizers, which harbor limited solubility in aqueous solutions (30, 32). Moreover, pure photosensitizers have also demonstrated limited selectivity towards cancer cells, causing nonspecific photodamage to the cells of normal tissue (30). New strategies like NP-based platforms for the delivery of photosensitizers have been contemplated to address such limitations. This new approach has several advantages such as maintaining the activity and stability of photosensitizers in aqueous solutions (30). Also, the NPs themselves can be further functionalized with various types of targeting moieties for cancer-specific PDTs (30). Furthermore, various porphyrin derivatives used as photosensitizers, such as N-methylmesoporphyrin IX (NMM), tend to have low fluorescence intensity aqueous solutions (30). Such porphyrin derivatives can achieve a remarkable fluorescence enhancement if linked to G-quadruplex DNA, such as the AS1411 aptamer (30). They can also be applied as efficient photosensitizers for targeted cancer cell imaging and PDT (30).

As one of the first attempts in this regard, Shieh et al. conjugated six 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrins (TMPyP4) to the AS1411 aptamer and demonstrated that this aptamer could redirect the porphyrin derivatives to the MCF7 breast cancer cells overexpressing nucleolin (33). Additionally, they reported that damages made to these cells after photodynamic therapy were significantly higher than those made to M10 normal epithelium cells (33). A fact that highlights the effects of the AS1411 aptamer selectively redirecting the photosensitizers towards the tumor cells (33). Furthermore, other researchers have conjugated AS1411-functionalized fluorescent GNPs to the porphyrin derivative N-methylmesoporphyrin IX (NMM) (34). They reported that the mentioned porphyrin derivative conjugated to AS1411-redirected NPs can be utilized as an efficient and specific photosensitizer for increasing the sensitivity of various tumor cell lines to PDT (34). In addition, Zhu et al. demonstrated that chemical photodynamic therapy nanosystems can be exploited as useful and controlling synergistic tactics for fighting against brain tumors as well as various brain diseases related to the central nervous system (35). They applied Ruthenium (II) polypyridyl complexes such as [Ru(bpy)2(tip)]2+ (RBT) in their AS1411-functionalized nanocarriers, which not only can produce reactive oxygen species (ROS) in target tumor cells under laser irradiation, but also can induce apoptotic cell death that in turn improves the results of PDT in gliomas cells (35). Some researchers have combined more intricate co-delivery systems, which are composed of a therapeutic oligonucleotide like a DNAzyme and a photosensitizer. In this regard, Jin et al. (36) developed an upconversion nanoplatform composed of repetitive survivin DNAzyme and the AS1411 aptamer fabricated in a long single-stranded DNA (ssDNA) by rolling circle amplification (RCA) and, eventually, adsorbed on the upconversion nanoparticles (UCNPs) by electrostatic attraction.

The enhanced photosensitizer (TMPyP4) and DNAzyme loading capacity of the upconversion nanoplatforms are due to the multivalence of the ssDNA; thus allowing for an enhanced PDT by DNAzyme-mediated gene silencing of survivin. The PDT effects of this platform were triggered by near-infrared (NIR) right after the internalization of the nanoplatforms into cancer cells resulting in the generation of ROS and their subsequent cytotoxic effects (36). Additionally, survivin DNAzyme could potentially enhance the efficiency of PDT by inhibiting the gene expression of surviving, which conclusively demonstrated the efficacy of the upconversion photodynamic nanoplatforms for combinatorial cancer therapy (36). Some nanosystems functionalized with the AS1411 aptamer for the delivery of radiosensitizers and photosensitizers are presented in Table 1.

Table 1. A summary of AS1411-Functionalized Radiosensitizer and Photosensitizer Delivery Nanosystems Used in Radiation and Photodynamic Therapy
Type OF TherapyDescriptionComponentsRadiosensitizer/PhotosensitizerAnimal Models or/and Cell Line(s)Investigated Cancer Type(s)In Vivo/in VitroReference
Radiation therapyVia gold nanoparticlesBSA-capped GNPsGoldBALB/c mice/4T1Breast cancerIn vivo/in vitro(25)
Via gold nanoparticlesBSA-capped GNPsGold4T1Breast cancerIn vitro(26)
Via silver nanoparticlesPEGylated AgNPsSilverBALB/c nude mice/C6GliomaIn vivo/in vitro(27)
Photodynamic therapyVia fluorescent gold nanoparticles-N-methylmesoporphyrin IXHeLaCervical cancerIn vitro(34)
Via aptamer-photosensitizer complex-TMPyP4MCF7Breast cancerIn vitro(33)
Via adenosine triphosphate (ATP)-activatable hybrid micellar nanoparticleZn-QD, DSPE-PEG2000-OMe, DSPE-PEG2000-NH2TMPyP2Nude mice/HeLaCervical cancerIn vivo/in vitro(37)
Via nanoscale coordination polymersCa2+, pHis-PEGChlorine e6, heminBALB/c mice/4T1Breast cancerIn vivo/in vitro(38)
Via aptamer-photosensitizer complex-Pyrochlorophyll-A, heminBALB/c mice/MCF-7Breast cancerIn vivo/in vitro(39)
Via erythrocyte membrane-camouflaged nanoriceFerric oxide loaded (FeTCPP/Fe2O3) MOFsPorphyrin-based MOFsNude mice/KBCervical cancerIn vivo/in vitro(40)

Abbreviations: AgNP, silver nanoparticles; BSA, bovine serum albumin; DSPE-PEG2000, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]; GNPs, gold nanoparticles; MOF, metal-organic framework; pHis, poly(L-histidine); QD, Quantum dot; TMPyP, 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin tetra(p toluenesulfonate); TMPyP4, 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin.

2.3. In Cancer Immunotherapy

Targeting nucleolin for antitumor purposes by simultaneous administration of chemotherapeutic agents and immunostimulants is known as a potent strategy to elicit strong tumoricidal effects alongside immune responses (41). Here we described the development of lipophilic-fused AS1411 aptamer-immunoadjuvant CpG-decorated (Apt-CpG-DSPE) high-density lipoproteins (HDL) for relay drug delivery and pronounced antitumor effects. The complete immune HDL nanodrug, hereafter referred to as imHDL/Apt-CpG-Dox, also carried Dox successively intercalated into the consecutive base pairs of Apt-CpG (41).

Non-methylated cytosine-guanine oligodeoxynucleotides (CpG ODN) are Toll-like receptor 9 (TLR9) agonists capable of activating antigen-presenting cells (APCs), such as macrophages and dendritic cells, as well as eliciting effective immune responses through the initiation of signaling pathways. Such signaling initiation results in the expression of pro-inflammatory cytokines like tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin-12 (IL-12), and various others (42-44). However, the antitumor application of CpG ODN is intertwined with various obstacles such as their in vivo instability, nonspecific biodistribution, and unfavorable pharmacokinetics (41, 45, 46). Despite the development of various nanotechnology-based delivery systems intended to significantly improve the delivery profiles of CpG ODN, there are remaining concerns about the use of these synthetic nanomaterials (41, 45, 46). Therefore, natural material-based nanoscale delivery systems such as those based on human HDL are more desired because of their high molecular-level structural adaptability, biocompatibility profile, and excellent delivery functionality (47, 48). Due to the rapid proliferation of malignant cells, they generally require a high amount of cholesterol; therefore, they up-regulate the expression of HDL-related surface receptors like scavenger receptor class B type I (SR-BI) to trap HDLs from the systemic circulation (41). The monolayered HDLs used in the study by Han et al. (41) are also surface-anchored with the lipophilic macromolecule apolipoprotein A-I (apoA-I) to further stabilize their nanostructure for systemic circulation and tumor site-specific drug translocation (49, 50).

The drug delivery platform discussed here comprises of two sequential modules. As described by Han et al. (41), after intravenous (IV) injection of immune lipoprotein imHDL/Apt-CpG-Dox and their migration to the tumor tissue site, they underwent extracellular structural collapse upon the recognition of surface SR-BI (sequential module I). Following extracellular dissociation of the HDL nanostructures, the endocytosis of the dissociated Apt-CpG-Dox into tumor cells is mediated by the interaction of the AS1411 aptamer with nucleolin (sequential module II) (41). After internalization, Apt-CpG-Dox was translocated to the nucleus via AS1411-nucleolin interaction where Dox release was mediated by the pH level decline in endo-lysosome, which in turn resulted in malignant cell apoptosis alongside in situ tumor-associated antigens release (41). Moreover, the dying tumor cells unleashed the CpG motifs, which then were internalized into the TLR9-rich infiltrated APCs leading to their activation and subsequent promotion of proinflammatory cytokine release that caused potentiated host antitumor immunity (41). In conclusion, this HDL biomimetic-based relay drug delivery system can exhibit therapeutic advantages over its monotherapy counterparts by generating pronounced antitumor effects against malignant tumors (41).

3. Summary and Perspectives

New approaches that can efficiently ameliorate the side effects of common cancer treatment modalities are of great importance, as the side effects can be success limiting and life-threatening based on the disease condition of the patients. Radiation therapy and photodynamic therapy are primary options frequently used for the treatment of various cancers. Radiotherapy-related side effects, the slow recovery process of patients under radiotherapy, the development of radiation-resistance mechanisms by cancer cells, and the low efficiency of photodynamic therapy are among important factors that have limited the boundaries of success for these approaches. The non-specific cell targeting manner of these approaches also leads to irreversible damages to normal cells while killing cancer cells.

Additionally, the effects of immunotherapy on controlling cancer cells have been investigated by several studies. However, it may cause mild to severe levels of toxicity. To address these unfavorable downsides, cancer immunotherapy can be combined with other novel treatment approaches to create more successful outcomes. In this regard, nanotechnology-based delivery systems are irreplaceable candidates, as they can easily be exploited for achieving the mentioned goal. However, nanotechnology-based delivery systems suffer from drawbacks such as not having a selective redirection system to avoid unwanted damages by discriminating between normal and cancerous tissues. Since these drawbacks have overshadowed the broad applicability of nanotechnology-based delivery systems, they require meticulous optimizations for a precise tumor cell-specific redirection. Despite several advances in the field of nanotechnology-based delivery vehicles for targeted cancer therapy, the main success-creating factor in this field is steering these vehicles only towards cancer cells to achieve the lowest level of off-target toxicity and the highest level of efficiency.

Undoubtedly, the AS1411 aptamer might be considered as a valuable solution for the mentioned problem. This aptamer has also been utilized in the delivery of different types of photo-sensitizers to target cancer cells rendering them susceptible to photodynamic therapy. It has also been exploited in specific delivery of radiosensitizers to target cells, which leads to efficient radiation therapy with less unwanted damages to healthy cells. Cancer immunotherapy is also another field benefiting from the AS1411 aptamer. The utilization of this aptamer in cancer immunotherapy results in the generation of pronounced host antitumor immunity effects. Soon, the AS1411 aptamer can bring more surprising results to the table of common cancer treatment approaches, which will translate into improved results of these therapies. Nevertheless, various studies mentioned that more research is needed to extend our knowledge, particularly regarding the applicability and safety of this technique. Hence, still we cannot conclude that these platforms can mediate promising results in clinical trials since the available outcomes of the herein discussed studies lack certain in-depth assessments. For instance, some of these platforms have only been assessed in vitro, or a large proportion of them have investigated only its effects on cancer cell lines. In this regard, their assessments in preclinical animal models of human tumors might result in high-grade toxicities towards healthy tissues, mainly as a result of their poor tumor-specific uptake in some cases. Furthermore, some of these strategies might not behave in preclinical animal models as they have in vitro. This phenomenon can be attributed to the fact that in vitro studies do not completely mirror the complexity of animal models. In a similar scenario, even if successful outcomes are achieved in the preclinical investigations, the evaluation of clinical trials might present different findings since animal models do not bear the same level of complexity as human beings. However, for now, the mentioned facts make it impossible for these platforms to meet the minimum level of validity for translational purposes.

Footnotes

References

  • 1.

    Josic D, Clifton JG, Kovac S, Hixson DC. Membrane proteins as diagnostic biomarkers and targets for new therapies. Curr Opin Mol Ther. 2008;10(2):116-23. [PubMed: 18386223].

  • 2.

    Yildirim MA, Goh KI, Cusick ME, Barabasi AL, Vidal M. Drug-target network. Nat Biotechnol. 2007;25(10):1119-26. doi: 10.1038/nbt1338. [PubMed: 17921997].

  • 3.

    Parekh P, Kamble S, Zhao N, Zeng Z, Portier BP, Zu Y. Immunotherapy of CD30-expressing lymphoma using a highly stable ssDNA aptamer. Biomaterials. 2013;34(35):8909-17. doi: 10.1016/j.biomaterials.2013.07.099. [PubMed: 23968853]. [PubMed Central: PMC3784013].

  • 4.

    Wang FB, Rong Y, Fang M, Yuan JP, Peng CW, Liu SP, et al. Recognition and capture of metastatic hepatocellular carcinoma cells using aptamer-conjugated quantum dots and magnetic particles. Biomaterials. 2013;34(15):3816-27. doi: 10.1016/j.biomaterials.2013.02.018. [PubMed: 23465488].

  • 5.

    Kim MY, Jeong S. In vitro selection of RNA aptamer and specific targeting of ErbB2 in breast cancer cells. Nucleic Acid Ther. 2011;21(3):173-8. doi: 10.1089/nat.2011.0283. [PubMed: 21749294]. [PubMed Central: PMC3198746].

  • 6.

    Zhang K, Sefah K, Tang L, Zhao Z, Zhu G, Ye M, et al. A novel aptamer developed for breast cancer cell internalization. ChemMedChem. 2012;7(1):79-84. doi: 10.1002/cmdc.201100457. [PubMed: 22170627]. [PubMed Central: PMC3407573].

  • 7.

    Kang D, Wang J, Zhang W, Song Y, Li X, Zou Y, et al. Selection of DNA aptamers against glioblastoma cells with high affinity and specificity. PLoS One. 2012;7(10). e42731. doi: 10.1371/journal.pone.0042731. [PubMed: 23056171]. [PubMed Central: PMC3462804].

  • 8.

    Esposito CL, Passaro D, Longobardo I, Condorelli G, Marotta P, Affuso A, et al. A neutralizing RNA aptamer against EGFR causes selective apoptotic cell death. PLoS One. 2011;6(9). e24071. doi: 10.1371/journal.pone.0024071. [PubMed: 21915281]. [PubMed Central: PMC3167817].

  • 9.

    Seinsoth S, Uhlmann-Schiffler H, Stahl H. Bidirectional DNA unwinding by a ternary complex of T antigen, nucleolin and topoisomerase I. EMBO Rep. 2003;4(3):263-8. doi: 10.1038/sj.embor.embor770. [PubMed: 12634843]. [PubMed Central: PMC1315898].

  • 10.

    Bates PJ, Reyes-Reyes EM, Malik MT, Murphy EM, O'Toole MG, Trent JO. G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms. Biochim Biophys Acta Gen Subj. 2017;1861(5 Pt B):1414-28. doi: 10.1016/j.bbagen.2016.12.015. [PubMed: 28007579].

  • 11.

    Haume K, Rosa S, Grellet S, Smialek MA, Butterworth KT, Solov'yov AV, et al. Gold nanoparticles for cancer radiotherapy: a review. Cancer Nanotechnol. 2016;7(1):8. doi: 10.1186/s12645-016-0021-x. [PubMed: 27867425]. [PubMed Central: PMC5095165].

  • 12.

    Chithrani DB, Jelveh S, Jalali F, van Prooijen M, Allen C, Bristow RG, et al. Gold nanoparticles as radiation sensitizers in cancer therapy. Radiat Res. 2010;173(6):719-28. doi: 10.1667/RR1984.1. [PubMed: 20518651].

  • 13.

    Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 2011;11(4):239-53. doi: 10.1038/nrc3007. [PubMed: 21430696].

  • 14.

    Yang YS, Carney RP, Stellacci F, Irvine DJ. Enhancing radiotherapy by lipid nanocapsule-mediated delivery of amphiphilic gold nanoparticles to intracellular membranes. ACS Nano. 2014;8(9):8992-9002. doi: 10.1021/nn502146r. [PubMed: 25123510]. [PubMed Central: PMC4194056].

  • 15.

    Jain S, Coulter JA, Hounsell AR, Butterworth KT, McMahon SJ, Hyland WB, et al. Cell-specific radiosensitization by gold nanoparticles at megavoltage radiation energies. Int J Radiat Oncol Biol Phys. 2011;79(2):531-9. doi: 10.1016/j.ijrobp.2010.08.044. [PubMed: 21095075]. [PubMed Central: PMC3015172].

  • 16.

    Zhang XD, Luo Z, Chen J, Song S, Yuan X, Shen X, et al. Ultrasmall glutathione-protected gold nanoclusters as next generation radiotherapy sensitizers with high tumor uptake and high renal clearance. Sci Rep. 2015;5:8669. doi: 10.1038/srep08669. [PubMed: 25727895]. [PubMed Central: PMC4345316].

  • 17.

    Zhang XD, Chen J, Luo Z, Wu D, Shen X, Song SS, et al. Enhanced tumor accumulation of sub-2 nm gold nanoclusters for cancer radiation therapy. Adv Healthc Mater. 2014;3(1):133-41. doi: 10.1002/adhm.201300189. [PubMed: 23873780].

  • 18.

    Chen N, Yang W, Bao Y, Xu H, Qin S, Tu Y. BSA capped Au nanoparticle as an efficient sensitizer for glioblastoma tumor radiation therapy. RSC Adv. 2015;5(51):40514-20. doi: 10.1039/c5ra04013b.

  • 19.

    Lien Nghiem TH, Nguyen TT, Fort E, Nguyen TP, Nhung Hoang TM, Nguyen TQ, et al. Capping and in vivo toxicity studies of gold nanoparticles. Adv Nat Sci. 2012;3(1). doi: 10.1088/2043-6262/3/1/015002.

  • 20.

    Mocan L, Matea C, Tabaran FA, Mosteanu O, Pop T, Mocan T, et al. Photothermal treatment of liver cancer with albumin-conjugated gold nanoparticles initiates Golgi Apparatus-ER dysfunction and caspase-3 apoptotic pathway activation by selective targeting of Gp60 receptor. Int J Nanomedicine. 2015;10:5435-45. doi: 10.2147/IJN.S86495. [PubMed: 26346915]. [PubMed Central: PMC4554431].

  • 21.

    Miranda EG, Tofanello A, Brito AM, Lopes DM, Albuquerque LJ, de Castro CE, et al. Effects of Gold Salt Speciation and Structure of Human and Bovine Serum Albumins on the Synthesis and Stability of Gold Nanostructures. Front Chem. 2016;4:13. doi: 10.3389/fchem.2016.00013. [PubMed: 27066476]. [PubMed Central: PMC4814711].

  • 22.

    Singh S. Glucose decorated gold nanoclusters: A membrane potential independent fluorescence probe for rapid identification of cancer cells expressing Glut receptors. Colloids Surf B Biointerfaces. 2017;155:25-34. doi: 10.1016/j.colsurfb.2017.03.052. [PubMed: 28391081].

  • 23.

    Kaur H, Pujari G, Semwal MK, Sarma A, Avasthi DK. In vitro studies on radiosensitization effect of glucose capped gold nanoparticles in photon and ion irradiation of HeLa cells. Nucl Instrum Methods Phys Res B. 2013;301:7-11. doi: 10.1016/j.nimb.2013.02.015.

  • 24.

    Butterworth KT, Nicol JR, Ghita M, Rosa S, Chaudhary P, McGarry CK, et al. Preclinical evaluation of gold-DTDTPA nanoparticles as theranostic agents in prostate cancer radiotherapy. Nanomedicine (Lond). 2016;11(16):2035-47. doi: 10.2217/nnm-2016-0062. [PubMed: 27463088].

  • 25.

    Ghahremani F, Kefayat A, Shahbazi-Gahrouei D, Motaghi H, Mehrgardi MA, Haghjooy-Javanmard S. AS1411 aptamer-targeted gold nanoclusters effect on the enhancement of radiation therapy efficacy in breast tumor-bearing mice. Nanomedicine (Lond). 2018;13(20):2563-78. doi: 10.2217/nnm-2018-0180. [PubMed: 30334677].

  • 26.

    Ghahremani F, Shahbazi-Gahrouei D, Kefayat A, Motaghi H, Mehrgardi MA, Javanmard SH. AS1411 aptamer conjugated gold nanoclusters as a targeted radiosensitizer for megavoltage radiation therapy of 4T1 breast cancer cells. RSC Adv. 2018;8(8):4249-58. doi: 10.1039/c7ra11116a.

  • 27.

    Zhao J, Liu P, Ma J, Li D, Yang H, Chen W, et al. Enhancement of Radiosensitization by Silver Nanoparticles Functionalized with Polyethylene Glycol and Aptamer As1411 for Glioma Irradiation Therapy. Int J Nanomedicine. 2019;14:9483-96. doi: 10.2147/IJN.S224160. [PubMed: 31819445]. [PubMed Central: PMC6897066].

  • 28.

    Milla P, Dosio F, Cattel L. PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery. Curr Drug Metab. 2012;13(1):105-19. doi: 10.2174/138920012798356934. [PubMed: 21892917].

  • 29.

    Mehrnia SS, Hashemi B, Mowla SJ, Nikkhah M, Arbabi A. Radiosensitization of breast cancer cells using AS1411 aptamer-conjugated gold nanoparticles. Radiat Oncol. 2021;16(1):33. doi: 10.1186/s13014-021-01751-3. [PubMed: 33568174]. [PubMed Central: PMC7877080].

  • 30.

    Obaid G, Chambrier I, Cook MJ, Russell DA. Targeting the oncofetal Thomsen-Friedenreich disaccharide using jacalin-PEG phthalocyanine gold nanoparticles for photodynamic cancer therapy. Angew Chem Int Ed Engl. 2012;51(25):6158-62. doi: 10.1002/anie.201201468. [PubMed: 22573473].

  • 31.

    Nombona N, Maduray K, Antunes E, Karsten A, Nyokong T. Synthesis of phthalocyanine conjugates with gold nanoparticles and liposomes for photodynamic therapy. J Photochem Photobiol B. 2012;107:35-44. doi: 10.1016/j.jphotobiol.2011.11.007. [PubMed: 22209036].

  • 32.

    Lim CK, Shin J, Lee YD, Kim J, Park H, Kwon IC, et al. Heavy-atomic construction of photosensitizer nanoparticles for enhanced photodynamic therapy of cancer. Small. 2011;7(1):112-8. doi: 10.1002/smll.201001358. [PubMed: 21132707].

  • 33.

    Shieh YA, Yang SJ, Wei MF, Shieh MJ. Aptamer-based tumor-targeted drug delivery for photodynamic therapy. ACS Nano. 2010;4(3):1433-42. doi: 10.1021/nn901374b. [PubMed: 20166743].

  • 34.

    Ai J, Xu Y, Lou B, Li D, Wang E. Multifunctional AS1411-functionalized fluorescent gold nanoparticles for targeted cancer cell imaging and efficient photodynamic therapy. Talanta. 2014;118:54-60. doi: 10.1016/j.talanta.2013.09.062. [PubMed: 24274270].

  • 35.

    Zhu X, Zhou H, Liu Y, Wen Y, Wei C, Yu Q, et al. Transferrin/aptamer conjugated mesoporous ruthenium nanosystem for redox-controlled and targeted chemo-photodynamic therapy of glioma. Acta Biomater. 2018;82:143-57. doi: 10.1016/j.actbio.2018.10.012. [PubMed: 30316026].

  • 36.

    Jin J, Wang H, Li X, Zhu H, Sun D, Sun X, et al. Multifunctional DNA Polymer-Assisted Upconversion Therapeutic Nanoplatform for Enhanced Photodynamic Therapy. ACS Appl Mater Interfaces. 2020;12(24):26832-41. doi: 10.1021/acsami.0c03274. [PubMed: 32449617].

  • 37.

    Shen Y, Tian Q, Sun Y, Xu JJ, Ye D, Chen HY. ATP-Activatable Photosensitizer Enables Dual Fluorescence Imaging and Targeted Photodynamic Therapy of Tumor. Anal Chem. 2017;89(24):13610-7. doi: 10.1021/acs.analchem.7b04197. [PubMed: 29181974].

  • 38.

    Yang Y, Zhu W, Feng L, Chao Y, Yi X, Dong Z, et al. G-Quadruplex-Based Nanoscale Coordination Polymers to Modulate Tumor Hypoxia and Achieve Nuclear-Targeted Drug Delivery for Enhanced Photodynamic Therapy. Nano Lett. 2018;18(11):6867-75. doi: 10.1021/acs.nanolett.8b02732. [PubMed: 30303384].

  • 39.

    Yang Y, He J, Zhu W, Pan X, Yazd HS, Cui C, et al. Molecular domino reactor built by automated modular synthesis for cancer treatment. Theranostics. 2020;10(9):4030-41. doi: 10.7150/thno.43581. [PubMed: 32226537]. [PubMed Central: PMC7086356].

  • 40.

    Zhao Y, Wang J, Cai X, Ding P, Lv H, Pei R. Metal-Organic Frameworks with Enhanced Photodynamic Therapy: Synthesis, Erythrocyte Membrane Camouflage, and Aptamer-Targeted Aggregation. ACS Appl Mater Interfaces. 2020;12(21):23697-706. doi: 10.1021/acsami.0c04363. [PubMed: 32362109].

  • 41.

    Han Y, Ding B, Zhao Z, Zhang H, Sun B, Zhao Y, et al. Immune lipoprotein nanostructures inspired relay drug delivery for amplifying antitumor efficiency. Biomaterials. 2018;185:205-18. doi: 10.1016/j.biomaterials.2018.09.016. [PubMed: 30245388].

  • 42.

    Shao K, Singha S, Clemente-Casares X, Tsai S, Yang Y, Santamaria P. Nanoparticle-based immunotherapy for cancer. ACS Nano. 2015;9(1):16-30. doi: 10.1021/nn5062029. [PubMed: 25469470].

  • 43.

    Chen N, Wei M, Sun Y, Li F, Pei H, Li X, et al. Self-assembly of poly-adenine-tailed CpG oligonucleotide-gold nanoparticle nanoconjugates with immunostimulatory activity. Small. 2014;10(2):368-75. doi: 10.1002/smll.201300903. [PubMed: 23963797].

  • 44.

    Kheirolomoom A, Ingham ES, Mahakian LM, Tam SM, Silvestrini MT, Tumbale SK, et al. CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery. J Control Release. 2015;220(Pt A):253-64. doi: 10.1016/j.jconrel.2015.10.016. [PubMed: 26471394]. [PubMed Central: PMC4688109].

  • 45.

    Zang X, Zhao X, Hu H, Qiao M, Deng Y, Chen D. Nanoparticles for tumor immunotherapy. Eur J Pharm Biopharm. 2017;115:243-56. doi: 10.1016/j.ejpb.2017.03.013. [PubMed: 28323111].

  • 46.

    Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004;5(2):190-8. doi: 10.1038/ni1028. [PubMed: 14716310].

  • 47.

    Kuai R, Li D, Chen YE, Moon JJ, Schwendeman A. High-Density Lipoproteins: Nature's Multifunctional Nanoparticles. ACS Nano. 2016;10(3):3015-41. doi: 10.1021/acsnano.5b07522. [PubMed: 26889958]. [PubMed Central: PMC4918468].

  • 48.

    Huang M, Hu M, Song Q, Song H, Huang J, Gu X, et al. GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer's Disease. ACS Nano. 2015;9(11):10801-16. doi: 10.1021/acsnano.5b03124. [PubMed: 26440073].

  • 49.

    Cui L, Lin Q, Jin CS, Jiang W, Huang H, Ding L, et al. A PEGylation-Free Biomimetic Porphyrin Nanoplatform for Personalized Cancer Theranostics. ACS Nano. 2015;9(4):4484-95. doi: 10.1021/acsnano.5b01077. [PubMed: 25830219].

  • 50.

    Thaxton CS, Daniel WL, Giljohann DA, Thomas AD, Mirkin CA. Templated spherical high density lipoprotein nanoparticles. J Am Chem Soc. 2009;131(4):1384-5. doi: 10.1021/ja808856z. [PubMed: 19133723]. [PubMed Central: PMC2843502].

  • Copyright © 2021, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
    COMMENTS

    LEAVE A COMMENT HERE: