Aptamer-Mediated Precision Therapy for Hematologic Malignancy: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Hua Naranmandura.

Hematologic malignancies, including leukemia, lymphoma, myeloproliferative disorder and plasma cell neoplasia, are genetically heterogeneous and characterized by an uncontrolled proliferation of their corresponding cell lineages in the bone marrow, peripheral blood, tissues or plasma. Although there are many types of therapeutic drugs available for the treatment of different malignancies, the relapse, drug resistance and severe side effects due to the lack of selectivity seriously limit their clinical application. Aptamers are ssDNA or RNA oligonucleotides that can also precisely deliver therapeutic agents into cancer cells through specifically recognizing the membrane protein on cancer cells, which is similar to the capabilities of monoclonal antibodies. Aptamers exhibit higher binding affinity, lower immunogenicity and higher thermal stability than antibodies.

  • ApDCs
  • chemical linker
  • hematologic malignancy
  • target therapy

1. Introduction

Hematologic malignancies are commonly classified into three main types: leukemia, lymphoma and myeloma [1]. Of note, leukemia is primarily bone marrow and peripheral-blood-based processes, whereas lymphomas are lymphatic system based and myeloma is predominantly bone-marrow-based diseases. Mechanistically, in hematopoietic progenitor cells, the genetic aberrations (i.e., point mutation, deletion or amplification of genetic material and gain, loss or translocation of chromosomal materials) frequently occur and are thought to be the main causes of hematologic malignancies [2,3,4][2][3][4]. These genetic aberrations can induce proto-oncogenes activation along with inactivation of tumor suppressor genes, which results in abnormal proliferation and self-renewal of hematopoietic progenitor cells, leading to an accumulation of immature blood cells in the bone marrow, tissues and peripheral blood [5].
Although, recently, many therapeutic options for hematologic malignancy treatment, such as tyrosine kinase inhibitors (TKIs) [6[6][7],7], chemotherapy and bone marrow transplantation, have significantly improved prognosis and survival of patients, some refractory (e.g., intrinsic resistance) and relapsed patients respond poorly to all current, available therapeutics [8,9,10][8][9][10]. Moreover, some potent cytotoxic chemotherapeutics can effectively kill cancer cells, but their severe side effects and systemic toxicity often limit their uses in broad terms due to lack of selectivity [11,12][11][12].
Several studies showed that targeted delivery of therapeutic agents into cancer cells through monoclonal antibodies (antibody–drug conjugates, ADCs) is considered as a promising strategy to tackle cancer and to increase therapeutic efficacy and reduce toxicity [13,14][13][14] because mAbs can recognize the biomarkers of a cancer cell and precisely deliver anticancer drugs into cells as drug carrier [15]. To date, more than ten ADCs have been approved for clinical applications, and about 80 ADCs are being evaluated in different phases of clinical trials [16]. Mylotarg (gemtuzumab ozogamicin), a CD33-targeted monoclonal antibody conjugated with cytotoxic drug calicheamicin, was approved for CD33-positive acute myeloid leukemia (AML) treatment. It represents a successful achievement for the site-specific delivery of cytotoxic agents into target leukemia cells through antibody-antigen recognition [17]. Beyond doubt, monoclonal antibodies (mAbs) have many advantages as a targeted molecule for cancer treatment, but they also have some shortcomings such as low stability owing to the protein natural properties, high immunogenicity, high cost and others [18,19,20][18][19][20]. Thus, novel, targeted drug delivery systems urgently need to be explored to overcome these disadvantages.
On the other hand, nucleic-acid-based drugs such as antisense oligonucleotides and aptamers are emerging as potential therapeutics for different diseases including leukemia [21,22][21][22]. Among them, aptamers, a special class of single-stranded DNA or RNA oligonucleotides discovered in nature as well as in laboratory, are beginning to be investigated for clinical use [23]. Similar to monoclonal antibodies, aptamers can precisely recognize and bind to membrane proteins on cancer cells through their unique spatial structure with high affinity [24]. In particular, aptamers indeed do possess advantages such as high thermal/chemical stability, low immunogenicity and cheaper, easier and faster engineering, as well as rapid tissue penetration [23].
In addition, aptamers can serve in aptamer–drug conjugates (ApDCs) to precisely deliver a wide range of therapeutic agents (e.g., cytotoxic agents and others) to targeted cancer cells [25].

2. Aptamer-Mediated Precision Therapy for Hematologic Malignancy

In fact, ADCs have achieved success in targeted therapy of hematologic malignancies, while their productions are costly as well as time consuming, and they can induce severe immune response due to the high immunogenicity [69][26]. As mentioned above, aptamers (termed as chemical antibodies) are a class of single-stranded nucleic acid (ssDNA or RNA) which can precisely recognize their corresponding target molecules through their complex spatial structure with high binding affinity and have a similar function to mAbs [21]. Aptamers are generally screened from a randomized ssDNA or RNA library by an in vitro selection method called systematic evolution of ligands by exponential enrichment (SELEX) [70][27]. Currently, there are a few approaches (protein-, cell- and animal-model-based SELEX, as well as protein real-structure-based automatic design of aptamers by computational method) for screening aptamers with high specificity and high binding affinity (Kd values of nM to pM) [71][28]. More importantly, aptamers can also be screened without any knowledge of target molecules, which also makes them more attractive and promising tools for the discovery of unknown biomarkers [23,72][23][29].
Owing to aptamers’ unique chemical and biological properties, they have been widely used in cancer diagnosis and exhibit great potential for clinical treatment (i.e., targeted therapy) [73][30]. More importantly, aptamers can be easily conjugated with toxic agents, including chemotherapeutic molecules and toxins, as aptamer–drug conjugates (ApDCs) for target therapy of cancers not only enhance therapy efficacy, but also reduce adverse side effects in cancer patients, similar to ADCs [72][29]. Reported ApDCs for cancer treatments are summarized in Table 21. In view of the aforementioned advantages, aptamer-mediated precision therapy is deemed to be considerably efficient in the treatment of hematologic malignancies. A few vital cleavable and non-cleavable linkers as well as drug incorporation methods for constructing aptamer–drug conjugates are introduced herein.
Table 21.
Aptamer–drug conjugates for cancer treatment.
Aptamer Target Drug Cancer Reference
AS1411 Nucleolin Dox Liver Cancer [74][31]
Pacitaxel Ovarian Cancer [75][32]
Gemcitabine Pancreatic Cancer [76][33]
P19 PANC-1 cell MMAE Pancreatic Cancer [77][34]
DM1 Pancreatic Cancer [77][34]
E07 EGFR MMAE Pancreatic Cancer [78][35]
MMAF Pancreatic Cancer [78][35]
Gemcitabine Pancreatic Cancer [79][36]
Waz Transferrin MMAE Pancreatic Cancer [78][35]
MMAF Pancreatic Cancer [78][35]
S30-T1 CD33 Dox Acute Myeloid Leukemia [80][37]
Sgc8 PTK7 Dox Acute Lymphoblastic Leukemia [81][38]
5-FU Colorectal Cancer [82][39]
EpDT3 EpCAM Dox Colorectal Cancer [83][40]
AP-1 CD133 Dox Anaplastic Thyroid Cancer [84][41]
HB-5 HER-2 Dox Breast Cancer [85][42]
MA-3 MUC-1 Dox Lung CancerBreast Cancer [86][43]

2.1. Synthesis of Aptamer–Drug Conjugates through Chemical Linkers

Synthesis of ApDCs depends on several vital research areas including the choice of an appropriate antigen target, discovery of novel, highly potent cytotoxic drugs and conjugation technology [87,88][44][45]. Importantly, the major approach for the synthesis of ApDCs is to utilize appropriate chemical linkers as a bridge to connect the aptamers and cytotoxic payloads through covalent bonds, which are key components for ApDCs to control the release of payloads to blood cancer cells, expressing the target antigen rather than to healthy cells [89][46]. In brief, linkers require high stability in the circulation so that the payload stays connected to the aptamers when it is distributed to the tissue. Once ApDCs are precisely internalized and transported into cellular organelles of cancer cells, the linkers release the attached cytotoxic drug through the dissociation properties. Upon release, the cytotoxic drug can interfere with various cellular mechanisms, eventually leading to cell death.
Since the development of ADC drug construction, different types of linkers have been well established for the conjugation of biomacromolecules and chemical compounds. Additionally, given their dissociation properties, linkers can be divided into two categories, cleavable linkers and non-cleavable linkers. Cleavable linkers are designed to be easily cleaved enzymatically (e.g., cathepsin B, etc.) or chemically (e.g., acid-sensitive linkers and reduction-sensitive linkers), leading to the release of their payload in targeted cells [90][47]. Among them, cathepsin B cleavable linkers/peptide linkers are commonly used in ADCs for various payloads, including MMAE, MMAF, pyrrolobenzodiazepines (PBD) and doxorubicins (DOX) [91,92][48][49]. Currently, the valine–citrulline (Val–Cit), phenylalanine–lysine (Phe–Lys) and valine–alanine (Val–Ala) peptides are the most widely employed cathepsin B cleavable linkers due to their high stability in serum and efficient drug release toward the lysosomes of target cancer cells [93][50]. For instance, a Val–Cit linker with MMAE is used in brentuximab vedotin and polatuzumab vedotin for targeting CD30-positive Hodgkin lymphoma, systemic anaplastic large cell lymphoma and CD79b-positive R/R DLBCL, respectively [94,95][51][52]. Another ADC drug loncastuximab tesirine-lpyl, composed of anti-CD19 mAb conjugated with cytotoxin PBD through peptide linker Val–Ala, has been approved for the clinical treatment of large B-cell lymphoma [96,97][53][54]. Similar to cathepsin B, newly designed enzymatically cleavable linkers, such as the phosphatase cleavable linker, sulfatases cleavable linker, β-galactosidase cleavable linker and β-glucuronidases cleavable linker, have also emerged as effective linkers for drug conjugations (Figure 21).
Figure 21.
Scheme of examples of various aptamer–drug conjugates through chemical linkers. Created with BioRender.com.
There are a few typical chemical linkers, including cleavable and non-cleavable linkers, for connecting aptamers and anticancer drugs, for instance, cleavable linkers, such as phosphtase, cathepsin B, surfatases, β-galactosidase and β-glucuronidase cleavable linkers and non-cleavable linkers succinimidyl-4-[N-maleimidomethyl] cyclohexane-1-carboxylate (SMCC) and maleimidocaproyl (MC).
Until now, there have been numerous chemically cleavable linkers designed to use in ADC drugs for hematologic malignancies. For example, Mylotarg, which consists of an anti-CD33 antibody and calicheamicin through an acid-cleavable hydrazone linker (i.e., chemically cleavable linker), is used for AML therapy [98][55]. Similarly, a hydrazone linker is also used to connect anti-CD22 mAbs to cytotoxins such as calicheamicin (inotuzumab ozogamicin) and pasudotox-tdfk (moxetumomab pasudotox-tdfk) for treatment of CD22-positive ALL and relapsed hairy cell leukemia in clinics, respectively [49,66,99,100][56][57][58][59].
Non-cleavable linkers maintain the coupling integrity of the aptamer and drugs throughout the entire drug action process and usually rely on complete degradation of the aptamer (or antibody) within the lysosomes to release the attached payload [90][47]. Mechanistically, non-cleavable linkers are unable to degrade by proteolysis and do not influence the activity of the payload after conjugation [92][49]. Currently, several non-cleavable alkyl and polymeric linkers are being explored in ADC development. In particular, the most representative linker is the succinimidyl-4-[N-maleimidomethyl] cyclohexane-1-carboxylate (SMCC) crosslinker, which is a heterobifunctional protein crosslinker with a sulfhydryl-reactive maleimide group and an amine-reactive N-hydroxysuccinimide (NHS) ester group [101,102][60][61] (Figure 21). It is applied in trastuzumab emtansine for the conjugation of an-HER-2 antibodies and DM1, which has been approved for the treatment of HER-2-positive breast cancer [103][62]. In addition, CD37-antigen-targeted naratuximab emtansine, which consists of anti-CD37 mAbs and cytotoxin DM1 through an SMCC linker, is beginning to be investigated for diffuse large B-cell lymphoma and follicular lymphoma treatment in clinical trials [104,105][63][64].
On the other hand, B-cell maturation antigen (BCMA) is found to be highly expressed on the surface of neoplastic plasma cells and plays a critical role in the proliferation, survival and tumor progression in multiple myeloma (MM). Recently, an anti-BCMA monoclonal antibody was designed to conjugate with MMAE through a non-cleavable maleimidocaproyl (MC) linker to synthesize a BCMA-targeted ADC (e.g., belantamab mafodotin-blmf) for multiple myeloma treatment [106][65].
In light of these successes, aptamer–drug conjugates can be more easily synthesized by using these linkers and payloads due to their superior chemical properties. Zhang et al. conjugated a nucleolin target aptamer (named AS1411) with paclitaxel (PTX) through a cathepsin B–labile dipeptide linker Val–Cit [75][32]. As the aptamer is highly water soluble, this conjugate dramatically improved the water solubility of PTX and specifically delivered PTX into nucleolin-positive ovarian cancer cells through nucelolin-mediated micropinocytosis, resulting in notable improvement of antitumor activity and reduction of systemic toxicity. The same linker was also used for the conjugation of MMAE and MMAF with aptamers targeting EGFR or transferrin [78][35]. These conjugates exhibit greater anticancer activity in EGFR- and TfR-positive pancreatic cancer cells than in negative cells. Moreover, Huang et al. synthesized an aptamer–drug conjugate consisting of PTK7-targeted aptamer sgc8c linked with Dox through an acid–labile hydrazone linker [81][38]. This ApDC (sgc8c–Dox) effectively inhibited nonspecific uptake of Dox into non-target cells and selectively delivered Dox into targeted cancer cells. All these findings indicate that aptamers can also be conjugated with cytotoxic payload through chemical linkers to synthesize ApDCs in a similar manner to the construction of ADCs; therefore, ApDCs are promising as a supplement for ADCs in the clinical treatment of leukemia.

2.2. Direct Synthesis of Aptamer–Drug Conjugates

Except conjugation through chemical linkers, certain chemotherapeutic agents can be directly incorporated into aptamers to form the aptamer–drug physical conjugate due to their unique chemical properties [107,108][66][67]. Dox, a chemotherapy agent, is widely used for the treatment of a variety of malignancies such as leukemia, lymphoma, myeloma and others through intercalating into the DNA’s double helix, especially in the CG-rich region [108][67]. Since aptamers are able to form tertiary conformations with double-stranded regions, Dox can be physically intercalated within the CG-rich, double-stranded region of aptamers to form an aptamer–Dox conjugate [109,110][68][69]. Moreover, based on the properties of the CG-rich region, newly designed CG cargo, which contains 10~16 base pair CG repeated sequences, can be used for the linkage with aptamers as drug-intercalating sites to improve the capacity of Dox loading [111][70]. Yang et al. synthesized a CD33-targeted aptamer–Dox conjugate for CD33-positive AML treatment. In this study, CG-rich cargo was added into the 5′ end of aptamer S30-T1 to synthesize a S30-T1–Dox conjugate which could precisely recognize the CD33 antigen on HL-60 cells and be rapidly internalized into cells and then release the Dox, finally inducing CD33-positive AML cell death (but not CD33-negative cell death), implying that the ApDC has excellent therapeutic potential for leukemia treatment [80][37].
It has been reported that nucleoside analogs, such as gemcitabine and 5-fluorouracil (5-FU), are able to incorporate into the skeleton of aptamers directly due to their similar structure to that of natural nucleotides [112][71]. Therefore, DNA aptamers containing gemcitabine or 5-FU are considered to be chemically synthesized by using solid-phase DNA synthesis techniques [113][72]. Wang et al. reported that five copies of 5-FU-linked phosphoramidite can be site-specifically loaded onto the aptamer by automated, solid-phase DNA synthesis, which has proven to be highly effective for delivering 5-FU into targeted cancer cells, indicating that such conjugates can also have therapeutic potential in clinical applications for leukemia treatment [82][39]. Additionally, gemcitabine is also able to incorporate into RNA aptamers through transcription reactions catalyzed by special RNA polymerase, such as a mutant T7 RNA polymerase (Y639F), which efficiently utilizes non-canonical NTP for synthesizing RNAs [79,113][36][72]. Likewise, Ray et al. successfully synthesized an EGFR-targeted aptamer–gemcitabine polymer (Gem–E07 polymer) through an enzymatic reaction by taking advantage of mutant T7 RNA polymerase in which seven cytosine sites of aptamer E07 are actually enzymatically replaced by gemcitabine monophosphates. Moreover, the Gem–E07 conjugate also showed a strong inhibition effect on growth of EGFR-positive pancreatic cancer cells after internalization through clathrin-mediated endocytosis [79][36]. Taken together, ApDCs can be rapidly synthesized with a nucleoside analog and chemically modified with diverse functional groups at either the 5′ or the 3′ end to facilitate site-specific conjugation, as well as increase the drug loading capacity.

References

  1. Hodson, D.J.; Screen, M.; Turner, M. RNA-binding proteins in hematopoiesis and hematological malignancy. Blood 2019, 133, 2365–2373.
  2. Sheth, A.; de Melo, V.A.; Szydlo, R.; Szydlo, R.; Macdonald, D.H.; Reid, A.G.; Wagner, S.D. Specific patterns of chromosomal gains and losses associate with t(3;14), t(8;14), and t(14;18) in diffuse large B-cell lymphoma. Cancer Genet. Cytogenet. 2009, 194, 48–52.
  3. Ozery-Flato, M.; Linhart, C.; Trakhtenbrot, L.; Izraeli, S.; Shamir, R. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy. Genome Biol. 2011, 12, R61.
  4. Rustad, E.H.; Yellapantula, V.D.; Glodzik, D.; Maclachlan, K.H.; Diamond, B.; Boyle, E.M.; Ashby, C.; Blaney, P.; Gundem, G.; Hultcrantz, M.; et al. Revealing the Impact of Structural Variants in Multiple Myeloma. Blood Cancer Discov. 2020, 1, 258–273.
  5. Bergh, J.C. Gene amplification in human lung cancer. The myc family genes and other proto-oncogenes and growth factor genes. Am. Rev. Respir. Dis. 1990, 142, S20–S26.
  6. Young, D.J.; Nguyen, B.; Li, L.; Higashimoto, T.; Levis, M.J.; Liu, J.O.; Small, D. A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors. Blood Cancer Discov. 2021, 2, 532–547.
  7. Soverini, S.; Martelli, M.; Bavaro, L.; Benedittis, C.D.; Iurlo, A.; Galimberti, S.; Pregno, P.; Bonifacio, M.; Lunghi, F.; Castagnetti, F.; et al. Detection of Actionable BCR-ABL1 Kinase Domain (KD) Mutations in Chronic Myeloid Leukemia (CML) Patients with Failure and Warning Response to Tyrosine Kinase Inhibitors (TKIs): Potential Impact of Next-Generation Sequencing (NGS) and Droplet Digital PCR (ddPCR) on Clinical Decision Making. Blood 2019, 134 (Suppl. 1), 661.
  8. Shastri, A.; Gonzalez-Lugo, J.; Verma, A. Understanding FLT3 Inhibitor Resistance to Rationalize Combinatorial AML Therapies. Blood Cancer Discov. 2020, 2, 113–115.
  9. Zhang, X.H.; Chen, J.; Han, M.Z.; Huang, H.; Jiang, E.L.; Jiang, M.; Lai, Y.R.; Liu, D.H.; Liu, Q.F.; Liu, T.; et al. The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update. J. Hematol. Oncol. 2021, 14, 1–20.
  10. Walker, B.A. The Chromosome 13 Conundrum in Multiple Myeloma. Blood Cancer Discov. 2020, 1, 16–17.
  11. Zarbo, A.; Axelson, A. Common Cutaneous Side Effects of Anti-cancer Agents. In Practical Guide to Dermatology: The Henry Ford Manual, 2nd ed.; Lim, H.W., Kohen, L.L., Schneider, S.F., Yeager, D., Eds.; Springer International Publishing: Cham, Switzerland, 2020; pp. 289–306.
  12. Stoddart, A.; Wang, J.; Fernald, A.A.; Davis, E.M.; Johnson, C.R.; Hu, C.; Cheng, J.X.; McNerney, M.E.; Le Beau, M.M. Cytotoxic Therapy-Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms. Blood Cancer Discov. 2020, 1, 32–47.
  13. Padma, V.V. An overview of targeted cancer therapy. Biomedicine (Taipei) 2015, 5, 19.
  14. Zhang, T.; Yang, J.; Vaikari, V.P.; Beckford, J.S.; Wu, S.; Akhtari, M.; Alachkar, H. Apolipoprotein C2—CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia. Blood Cancer Discov. 2020, 1, 198–213.
  15. Panchagnula, R.; Dey, C.S. Monoclonal antibodies in drug targeting. J. Clin. Pharm. Ther. 1997, 22, 7–19.
  16. Hafeez, U.; Parakh, S.; Gan, H.K.; Scott, A.M. Antibody-Drug Conjugates for Cancer Therapy. Molecules 2020, 25, 4764.
  17. Kantarjian, H.; Short, N.J.; DiNardo, C.; Stein, E.M.; Daver, N.; Perl, A.E.; Wang, E.S.; Wei, A.; Tallman, M. Harnessing the benefits of available targeted therapies in acute myeloid leukaemia. Lancet Haematol. 2021, 8, E922–E933.
  18. Pittaluga, S.; Nicolae, A.; Wright, G.W.; Melani, C.; Roschewski, M.; Steinberg, S.; Huang, D.; Staudt, L.M.; Jaffe, E.S. Wilson, W.H. Gene Expression Profiling of Mediastinal Gray Zone Lymphoma and Its Relationship to Primary Mediastinal B-cell Lymphoma and Classical Hodgkin Lymphoma. Blood Cancer Discov. 2020, 1, 155–161.
  19. Estey, E.H. Acute myeloid leukemia: 2021 update on risk-stratification and management. Am. J. Hematol. 2020, 95, 1368–1398.
  20. Schurch, C.M. Therapeutic Antibodies for Myeloid Neoplasms-Current Developments and Future Directions. Front. Oncol. 2018, 8, 152.
  21. Chesi, M.; Stein, C.K.; Garbitt, V.M.; Sharik, M.E.; Asmann, Y.W.; Bergsagel, M.; Riggs, D.L.; Welsh, S.J.; Meermeier, E.W.; Kumar, S.K. Monosomic loss of MIR15A/MIR16-1 is a driver of multiple myeloma proliferation and disease progression. Blood Cancer Discov. 2020, 1, 68–81.
  22. Maimaitiyiming, Y.; Ye, L.; Yang, T.; Yu, W.; Naranmandura, H. Linear and Circular Long Non-Coding RNAs in Acute Lymphoblastic Leukemia: From Pathogenesis to Classification and Treatment. Int. J. Mol. Sci. 2022, 23, 4442.
  23. Shigdar, S.; Ward, A.C.; De, A.; Yang, C.J.; Wei, M.; Duan, W. Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies. Br. J. Haematol. 2011, 155, 3–13.
  24. Sicco, E.; Baez, J.; Fernández, M.; Fernández, M.; Cabral, P.; Moreno, M.; Cerecetto, H.; Calzada, V. Sgc8-c Aptamer as a Potential Theranostic Agent for Hemato-Oncological Malignancies. Cancer Biother. Radiopharm. 2020, 35, 262–270.
  25. Kim, D.H.; Seo, J.M.; Shin, K.J.; Yang, S.G. Design and clinical developments of aptamer-drug conjugates for targeted cancer therapy. Biomater Res. 2021, 25, 42.
  26. Ni, S.; Zhuo, Z.; Pan, Y.; Yu, Y.; Li, F.; Liu, J.; Wang, L.; Wu, X.; Li, D.; Wan, Y.; et al. Recent Progress in Aptamer Discoveries and Modifications for Therapeutic Applications. ACS Appl. Mater. Interfaces 2021, 13, 9500–9519.
  27. Darmostuk, M.; Rimpelova, S.; Gbelcova, H.; Ruml, T. Current approaches in SELEX: An update to aptamer selection technology. Biotechnol. Adv. 2015, 33, 1141–1161.
  28. Zhou, J.; Rossi, J. Aptamers as targeted therapeutics: Current potential and challenges. Nat. Rev. Drug Discov. 2017, 16, 181–202.
  29. Xuan, W.; Peng, Y.; Deng, Z.; Peng, T.; Kuai, H.; Li, Y.; He, J.; Jin, C.; Liu, Y.; Wang, R.; et al. A basic insight into aptamer-drug conjugates (ApDCs). Biomaterials 2018, 182, 216–226.
  30. Wu, X.; Chen, J.; Wu, M.; Zhao, J.X. Aptamers: Active targeting ligands for cancer diagnosis and therapy. Theranostics 2015, 5, 322–344.
  31. Trinh, T.L.; Zhu, G.; Xiao, X.; Puszyk, W.M.; Sefah, K.; Wu, Q.; Tan, W.; Liu, C. A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy. PLoS ONE 2015, 10, e0136673.
  32. Zhang, J.; Chen, R.; Chen, F.; Chen, M.; Wang, Y. Nucleolin targeting AS1411 aptamer modified pH-sensitive micelles: A dual-functional strategy for paclitaxel delivery. J. Control. Release 2015, 213, e137–e138.
  33. Park, J.Y.; Cho, Y.L.; Chae, J.R.; Moon, S.H.; Cho, W.G.; Choi, Y.; Lee, S.J.; Kang, W.J. Gemcitabine-Incorporated G-Quadruplex Aptamer for Targeted Drug Delivery into Pancreas Cancer. Mol. Ther. Nucleic Acids 2018, 12, 543–553.
  34. Yoon, S.; Huang, K.W.; Reebye, V.; Spalding, D.; Przytycka, T.M.; Wang, Y.; Swiderski, P.M.; Li, L.; Armstrong, B.; Reccia, I.; et al. Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth. Mol. Ther. Nucleic Acids 2017, 6, 80–88.
  35. Kratschmer, C.; Levy, M. Targeted Delivery of Auristatin-Modified Toxins to Pancreatic Cancer Using Aptamers. Mol. Ther. Nucleic Acids 2018, 10, 227–236.
  36. Ray, P.; Cheek, M.A.; Sharaf, M.L.; Li, N.; Ellington, A.D.; Sullenger, B.A.; Shaw, B.R.; White, R.R. Aptamer-mediated delivery of chemotherapy to pancreatic cancer cells. Nucleic Acid Ther. 2012, 22, 295–305.
  37. Yang, C.; Wang, Y.; Ge, M.H.; Fu, Y.; Hao, R.; Islam, K.; Huang, P.; Chen, F.; Sun, J.; Hong, D.; et al. Rapid identification of specific DNA aptamers precisely targeting CD33 positive leukemia cells through a paired cell-based approach. Biomater. Sci. 2019, 7, 938–950.
  38. Huang, Y.F.; Shangguan, D.; Liu, H.; Phillips, J.A.; Zhang, X.; Chen, Y.; Tan, W. Molecular assembly of an aptamer-drug conjugate for targeted drug delivery to tumor cells. Chembiochem 2009, 10, 862–868.
  39. Wang, R.; Zhu, G.; Mei, L.; Xie, Y.; Ma, H.; Ye, M.; Qing, F.; Tan, W. Automated modular synthesis of aptamer-drug conjugates for targeted drug delivery. J. Am. Chem. Soc. 2014, 136, 2731–2734.
  40. Subramanian, N.; Raghunathan, V.; Kanwar, J.R.; Kanwar, R.K.; Elchuri, S.V.; Khetan, V.; Krishnakumar, S. Target-specific delivery of doxorubicin to retinoblastoma using epithelial cell adhesion molecule aptamer. Mol. Vis. 2012, 18, 2783–2795.
  41. Ge, M.H.; Zhu, X.H.; Shao, Y.M.; Wang, C.; Huang, P.; Wang, Y.; Jiang, Y.; Maimaitiyiming, Y.; Chen, E.; Yang, C.; et al. Synthesis and characterization of CD133 targeted aptamer-drug conjugates for precision therapy of anaplastic thyroid cancer. Biomater. Sci. 2021, 9, 1313–1324.
  42. Liu, Z.; Duan, J.; Song, Y.; Ma, J.; Wang, F.; Lu, X.; Yang, X. Novel HER2 aptamer selectively delivers cytotoxic drug to HER2-positive breast cancer cells In Vitro. J. Transl. Med. 2012, 10, 148.
  43. Hu, Y.; Duan, J.; Zhan, Q.; Wang, F.; Lu, X.; Yang, X. Novel MUC1 aptamer selectively delivers cytotoxic agent to cancer cells In Vitro. PLoS ONE 2012, 7, e31970.
  44. Zhu, G.; Niu, G.; Chen, X. Aptamer-Drug Conjugates. Bioconjugate Chem. 2015, 26, 2186–2197.
  45. Bruno, J.G. A review of therapeutic aptamer conjugates with emphasis on new approaches. Pharmaceuticals 2013, 6, 340–357.
  46. Qi, J.; Zeng, Z.; Chen, Z.; Nipper, C.; Liu, X.; Wan, Q.; Chen, J.; Tung, C.; Zu, Y. Aptamer-Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells. Pharmaceuticals 2022, 15, 558.
  47. Bargh, J.D.; Isidro-Llobet, A.; Parker, J.S.; Spring, D.R. Cleavable linkers in antibody–drug conjugates. Chem. Soc. Rev. 2019, 48, 4361–4374.
  48. Sheyi, R.; de la Torre, B.G.; Albericio, F. Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate. Pharmaceutics 2022, 14, 396.
  49. McCombs, J.R.; Owen, S.C. Antibody drug conjugates: Design and selection of linker, payload and conjugation chemistry. AAPS J. 2015, 17, 339–351.
  50. Kostova, V.; Désos, P.; Starck, J.B.; Kotschy, A. The Chemistry Behind ADCs. Pharmaceuticals 2021, 14, 442.
  51. van de Donk, N.W.; Dhimolea, E. Brentuximab vedotin. Mabs-Austin 2012, 4, 458–465.
  52. Poreba, M. Protease-activated prodrugs: Strategies, challenges, and future directions. FEBS J. 2020, 287, 1936–1969.
  53. Hamadani, M.; Radford, J.; Carlo-Stella, C.; Caimi, P.F.; Reid, E.G.; O’Connor, O.A.; Feingold, J.M.; Ardeshna, K.; Townsend, W.M.; Solh, M.M.; et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 2021, 137, 2634–2645.
  54. Su, Z.; Xiao, D.; Xie, F.; Liu, L.; Wang, Y.; Fan, S.; Zhou, X.; Li, S. Antibody–drug conjugates: Recent advances in linker chemistry. Acta Pharm. Sin. B 2021, 11, 3889–3907.
  55. Vollmar, B.S.; Frantz, C.; Schutten, M.M.; Zhong, F.; del Rosario, G.; Go, M.; Yu, S.; Leipold, D.D.; Kamath, A.V.; Ng, C.; et al. Calicheamicin Antibody-Drug Conjugates with Improved Properties. Mol. Cancer Ther. 2021, 20, 1112–1120.
  56. Thota, S.; Advani, A. Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia. Eur. J. Haematol. 2017, 98, 425–434.
  57. Kreitman, R.J.; Dearden, C.E.; Zinzani, P.L.L.; Delgado, J.; Robak, T.; le Coutre, P.; Gjertsen, B.T.; Troussard, X.; Roboz, G.J.; Karlin, L.; et al. Moxetumomab Pasudotox-Tdfk in Heavily Pretreated Patients with Relapsed/Refractory Hairy Cell Leukemia (HCL): Long-Term Follow-up from the Pivotal Phase 3 Trial. Blood 2019, 134 (Suppl. 1), 2808.
  58. Cordo′, V.; van der Zwet, J.C.G.; Canté-Barrett, K.; Pieters, R.; Meijerink, J. T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies. Blood Cancer Discov. 2020, 2, 19–31.
  59. Kaushal, A.; Nooka, A.K.; Carr, A.R.; Pendleton, K.E.; Barwick, B.G.; Manalo, J.; McCachren, S.S.; Gupta, V.A.; Joseph, N.S.; Hofmeister, C.C.; et al. Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia. Blood Cancer Discov. 2021, 2, 600–615.
  60. Lyon, R.P.; Setter, J.R.; Bovee, T.D.; Doronina, S.O.; Hunter, J.H.; Anderson, M.E.; Balasubramanian, C.L.; Duniho, S.M.; Leiske, C.I.; Li, F.; et al. Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody-drug conjugates. Nat. Biotechnol. 2014, 32, 1059–1062.
  61. Chen, Q.; Gabathuler, R. Efficient Synthesis of Doxorubicin Melanotransferrin p97 Conjugates Through SMCC Linker. Synth. Commun. 2004, 34, 2407–2414.
  62. Barok, M.; Joensuu, H.; Isola, J. Trastuzumab emtansine: Mechanisms of action and drug resistance. Breast Cancer Res. 2014, 16, 209.
  63. Palomba, M.L.; Younes, A. In the spotlight: A novel CD37 antibody-drug conjugate. Blood 2013, 122, 3397–3398.
  64. Liu, Z.; Filip, I.; Gomez, K.; Engelbrecht, D.; Meer, S.; Lalloo, P.N.; Patel, P.; Perner, Y.; Zhao, J.; Wang, J.; et al. Genomic characterization of HIV-associated plasmablastic lymphoma identifies pervasive mutations in the JAK-STAT pathway. Blood Cancer Discov. 2020, 1, 112–125.
  65. Markham, A. Belantamab Mafodotin: First Approval. Drugs 2020, 80, 1607–1613.
  66. Li, X.; Zhao, Q.; Qiu, L. Smart ligand: Aptamer-mediated targeted delivery of chemotherapeutic drugs and siRNA for cancer therapy. J. Control. Release 2013, 171, 152–162.
  67. Bagalkot, V.; Farokhzad, O.C.; Langer, R.; Jon, S. An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. Angew. Chem. Int. Ed. Engl. 2006, 45, 8149–8152.
  68. Xiang, D.; Shigdar, S.; Qiao, G.; Wang, T.; Kouzani, A.Z.; Zhou, S.F.; Kong, L.; Li, Y.; Pu, C.; Duan, W. Nucleic acid aptamer-guided cancer therapeutics and diagnostics: The next generation of cancer medicine. Theranostics 2015, 5, 23–42.
  69. Macdonald, J.; Denoyer, D.; Henri, J.; Jamieson, A.; Burvenich, I.; Pouliot, N.; Shigdar, S. Bifunctional Aptamer-Doxorubicin Conjugate Crosses the Blood-Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells. Nucleic Acid Ther. 2020, 30, 117–128.
  70. Yang, C.; Jiang, Y.; Hao, S.H.; Yan, X.Y.; Hong, D.F.; Naranmandura, H. Aptamers: An emerging navigation tool of therapeutic agents for targeted cancer therapy. J. Mater. Chem. B 2021, 10, 20–33.
  71. Zhu, L.; Yang, J.; Ma, Y.; Zhu, X.; Zhang, C. Aptamers Entirely Built from Therapeutic Nucleoside Analogues for Targeted Cancer Therapy. J. Am. Chem. Soc. 2022, 144, 1493–1497.
  72. Sousa, R.; Padilla, R. A mutant T7 RNA polymerase as a DNA polymerase. EMBO J. 1995, 14, 4609–4621.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback