Streptomyces-Derived Nano-Doxorubicin: Clinical Status and Patents Granted
Abstract
Streptomyces have been presented as a great source of antibiotics and anti-cancer drugs over the past century. Especially Streptomyces living in adverse conditions produce certain metabolites with cytolytic and anti-microbial activities, which have been utilised for manufacturing antimicrobial and anticancer drugs. Doxorubicin (DOX) is a potent anti-cancer drug derived from Streptomyces, that is widely used for various cancers, including cancers of the ovary, urinary bladder, GI tract, breast, thyroid gland, lung, bone, kidney (nephroblastoma) and blood (leukaemia). This anthracycline antibiotic is limited by its adverse effect profile, with the main adverse effects being nausea, vomiting, alopecia, infertility, cardiotoxicity, myelosuppression and nephrotoxicity. Nanoparticle delivery systems present a good solution to avoid adverse effects. Some nano-based formulations have reached the clinics, while many new ones in the pipeline show promising results. This review attempts to compile the existing literature on the clinical status of DOX highlight the need for the development of nanoparticles (NPs) that may serve as drug delivery agents, imaging probes and other multifunctional particulates. The integration of nanotechnology with Streptomyces-derived compounds can help shape the anti-cancer therapy of the future.
References
Waksman SA, Schatz A, Reynolds DM. Production of antibiotic substances by actinomycetes. Ann N Y Acad Sci. 2010 Dec;1213:112-24. doi: 10.1111/j.1749-6632.2010.05861.x.
Sarmiento-Vizcaíno A, Espadas J, Martin J, Brana AF, Reyes F, Garcia LA, et al. Atmospheric precipitations, hailstone and rainwater, as a novel source of streptomyces producing bioactive natural products. Front Microbiol. 2018 Apr; 9. doi: 10.3389/fmicb.2018.00773.
Cunha BR, Fonseca LP, Calado CRC. Antibiotic discovery: Where have we come from, where do we go? Antibiotics. 2019 Apr; 8:45. doi: 10.3390/antibiotics8020045.
Chater KF. Streptomyces inside-out: A new perspective on the bacteria that provide us with antibiotics. Philos Trans R Soc Lond B Biol Sci. 2006 Feb; 361:761-8. doi: 10.1098/rstb.2005.1758.
McDonald BR, Curriea CR. Lateral gene transfer dynamics in the ancient bacterial genus Streptomyces. MBio. 2017 Jun; 8. doi: 10.3390/genes13081402.
Chater KF. Recent advances in understanding streptomyces. F1000Res. 2016 Nov; 5:2795. doi: 10.12688/f1000research.9534.1.
Bansal H, Singla RK, Behzad S, Chopra H, Grewal AS, Shen B. Unleashing the potential of microbial natural products in drug discovery: focusing on streptomyces as antimicrobials goldmine. Curr. Top. Med. Chem. 2021 Sep; 21:2374-2396. doi: 10.2174/1568026621666210916170110.
Kekuda TRP, Onkarappa R, Jayanna N. Characterization and antibacterial activity of a glycoside antibiotic from streptomyces variabilis PO-178. Sci. Technol. Arts Res J. 2014 Dec; 3:116-21. doi: 10.4314/star.v3i4.17.
Sathya A, Vijayabharathi R, Srinivas V, Gopalakrishnan S. Plant growth-promoting actinobacteria on chickpea seed mineral density: an upcoming complementary tool for sustainable biofortification strategy. 3 Biotech. 2016 Jun; 6:138. doi: 10.1007/s13205-016-0458-y.
Watve MG, Tickoo R, Jog MM, Bhole BD. How many antibiotics are produced by the genus Streptomyces? Arch Microbiol. 2001 Nov; 176:386-90. doi: 10.1007/s002030100345.
Singh V, Haque S, Singh H, Verma J, Vinbha K, Singh R, et. al. Isolation, screening, and identification of novel isolates of actinomycetes from India for antimicrobial applications. Front Microbiol. 2016 Dec; 7. doi: https://doi.org/10.3389/fmicb.2016.01921.
Hayakawa M, Sadakata T, Kajiura T, Nonomura H. New methods for the highly selective isolation of Micromonospora and Microbispora from soil. J Ferment Nioeng. 1991; 72:320-6. doi: 10.1016/0922-338X(91)90080-Z.
Minnotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004 Jun; 56:185-229. doi: 10.1124/pr.56.2.6.
McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovas Drugs Ther. 2017 Feb; 31:63-75. doi: 10.1007/s10557-016-6711-0.
Chaires JB. Biophysical chemistry of the daunomycin-DNA interaction. Biophys Chem. 1990 Apr; 35:191-202. doi: 10.1016/0301-4622(90)80008-u.
Wang AH, Ughetto G, Quigley GJ, Rich A. Interactions between an Anthracycline Antibiotic and DNA: Molecular Structure of Daunomycin Complexed to d(CpGpTpApCpG) at 1.2-Å Resolution. Biochem. 1987 Feb; 26:1152-63. doi: 10.1021/bi00378a025.
Chaires JB, Fox KR, Herrera JE, Britt M, Waring MJ. Site and sequence specificity of the daunomycin-DNA Interaction. Biochem. 1987 Dec; 26:2227-36. doi: 10.1021/bi00399a031.
Tarasiuk J, Frezard F, Garnier- Suillerot A, Gattegno L. Anthracycline incorporation in human lymphocytes. Kinetics of uptake and nuclear concentration. Biochim Biophys Acta. 1989 Sep; 1013:1009-17. doi: 10.1016/0167-4889(89)90038-4.
Belloc F, Lacombe F, Dumain P, Lopez F, Bernard P, Boisseau MR, Reifers J. Intercalation of anthracyclines into living cell DNA analyzed by flow cytometry. Cytometry. 1992;13(8):880-5. doi: 10.1002/cyto.990130811.
Ashley N, Poulton J. Mitochondrial DNA is a direct target of anti-cancer anthracycline drugs. Biochem Biophys Res Commun. 2009 Jan; 378:450-5. doi: 10.1016/j.bbrc.2008.11.059.
Kaye S, Merry S. Tumour cell resistance to anthracyclines--a review. Cancer Chemother Pharmacol. 1985;14(2):96-103. doi: 10.1007/BF00434344.
Lam V, McPherson JP, Salmena L, Lees J, Chu W, Sexsmith E, et al. p53 gene status and chemosensitivity of childhood acute lymphoblastic leukemia cells to adriamycin. Leuk Res. 1999 Oct;23(10):871-80. doi: 10.1016/s0145-2126(99)00102-2.
Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012 Jun;52(6):1213-25. doi: 10.1016/j.yjmcc.2012.03.006.
Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest. 2001;19(4):424-36. doi: 10.1081/cnv-100103136.
Rivankar S. An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther. 2014 Oct-Dec;10(4):853-8. doi: 10.4103/0973-1482.139267.
Kim SH, Kim KJ, Kim JH, Kwak JH, Song H, Cho JY, et al. Comparision of doxorubicin-induced cardiotoxicity in the ICR mice of different sources. Lab Anim Res. 2017 Jun;33(2):165-170. doi: 10.5625/lar.2017.33.2.165.
Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011 Nov;7(4):214-20. doi: 10.2174/157340311799960645.
Bhinge KN, Gupta V, Hosain SB, Satyanarayanajois SD, Meyer SA, Blaylock B, et al. The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase. Int J Biochem Cell Biol. 2012 Nov;44(11):1770-8. doi: 10.1016/j.biocel.2012.06.010.
Naidu MU, Ramana GV, Rani PU, Mohan IK, Suman A, Roy P. Chemotherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treatment of cancer. Neoplasia. 2004 Sep-Oct;6(5):423-31. doi: 10.1593/neo.04169.
Kwon Y. Mechanism-based management for mucositis: option for treating side effects without compromising the efficacy of cancer therapy. Onco Targets Ther. 2016 Apr 5;9:2007-16. doi: 10.2147/OTT.S96899.
Zhao X, Zhang J, Tong N, Chen Y, Luo Y. Protective effects of berberine on doxorubicin-induced hepatotoxicity in mice. Biol Pharm Bull. 2012;35(5):796-800. doi: 10.1248/bpb.35.796.
Afsar T, Razak S, Almajwal A, Al-Disi D. Doxorubicin-induced alterations in kidney functioning, oxidative stress, DNA damage, and renal tissue morphology; Improvement by Acacia hydaspica tannin-rich ethyl acetate fraction. Saudi J Biol Sci. 2020 Sep;27(9):2251-60. doi: 10.1016/j.sjbs.2020.07.011.
[33] Liu Y, Miyoshi H, Nakamura M. Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. Int J Cancer. 2007 Jun 15;120(12):2527-37. doi: 10.1002/ijc.22709.
Peer D, Karp J, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotech. 2007;2,751–60. doi: 10.1038/nnano.2007.387.
Manivasagan P, Bharathiraja S, Bui NQ, Jang B, Oh YO, Lim IG, et al. Doxorubicin-loaded fucoidan capped gold nanoparticles for drug delivery and photoacoustic imaging. Int J Biol Macromol. 2016 Oct;91:578-88. doi: 10.1016/j.ijbiomac.2016.06.007.
Masood F. Polymeric nanoparticles for targeted drug delivery system for cancer therapy. Mater Sci Eng C Mater Biol Appl. 2016 Mar;60:569-78. doi: 10.1016/j.msec.2015.11.067.
Aghdam AM, Bagheri R, Mosafer J, Baradaran B, Hashemzaei M, Baghbanzadeh A, et al. Recent advances on thermosensitive and pH-sensitive liposomes employed in controlled release. J Control Release. 2019 Dec 10;315:1-22. doi: 10.1016/j.jconrel.2019.09.018.
Franco MS, Gomes ER, Roque MC, Oliveira MC. Triggered drug release from liposomes: exploiting the outer and inner tumor environment. Front Oncol. 2021 Mar 16;11:623760. doi: 10.3389/fonc.2021.623760.
Montizaan D, Yang K, Reker-Smit C, Salvati A. Comparison of the uptake mechanisms of zwitterionic and negatively charged liposomes by HeLa cells. Nanomedicine. 2020 Nov;30:102300. doi: 10.1016/j.nano.2020.102300.
Boedtkjer E, Pedersen SF. The acidic tumor microenvironment as a driver of cancer. Annu Rev Physiol. 2020 Feb 10;82:103-26. doi: 10.1146/annurev-physiol-021119-034627.
Torres J, Dhas N, Longhi M, García MC. Overcoming biological barriers with block copolymers-based self-assembled nanocarriers. Recent advances in delivery of anticancer therapeutics. Front Pharmacol. 2020 Nov 30;11:593197. doi: 10.3389/fphar.2020.593197.
García MC, Naitlho N, Calderón-Montaño JM, Drago E, Rueda M, Longhi M, et al. Cholesterol levels affect the performance of aunps-decorated thermo-sensitive liposomes as nanocarriers for controlled doxorubicin delivery. Pharmaceutics. 2021 Jun 27;13(7):973. doi: 10.3390/pharmaceutics13070973.
Park SM, Kim MS, Park SJ, Park ES, Choi KS, Kim YS, et al. Novel temperature-triggered liposome with high stability: formulation, in vitro evaluation, and in vivo study combined with high-intensity focused ultrasound (HIFU). J Control Release. 2013 Sep 28;170(3):373-9. doi: 10.1016/j.jconrel.2013.06.003.
Jain M, Kumar S, Aswal VK, Al-Ghamdi A, Kailasa SK, Malek NI. Amino acid induced self-assembled vesicles of choline oleate: pH responsive nano-carriers for targeted and localized delivery of doxorubicin for breast cancer. J Mol Liquids. 2022 Aug 15;360:119517. doi: 10.1016/j.molliq.2022.119517.
Palanikumar L, Al-Hosani S, Kalmouni M, Nguyen VP, Ali L, Pasricha R, et al. pH-responsive high stability polymeric nanoparticles for targeted delivery of anticancer therapeutics. Commun Biol. 2020 Mar 3;3(1):95. doi: 10.1038/s42003-020-0817-4.
Wen S, Liu H, Cai H, Shen M, Shi X. Targeted and pH-responsive delivery of doxorubicin to cancer cells using multifunctional dendrimer-modified multi-walled carbon nanotubes. Adv Healthc Mater. 2013 Sep;2(9):1267-76. doi: 10.1002/adhm.201200389.
Lee H, Park H, Noh GJ, Lee ES. pH-responsive hyaluronate-anchored extracellular vesicles to promote tumor-targeted drug delivery. Carbohydr Polym. 2018 Dec 15;202:323-33. doi: 10.1016/j.carbpol.2018.08.141.
Fang Y, Xue J, Ke L, Liu Y, Shi K. Polymeric lipid vesicles with pH-responsive turning on-off membrane for programed delivery of insulin in GI tract. Drug Deliv. 2016 Nov;23(9):3582-93. doi: 10.1080/10717544.2016.1212440.
Tanner EEL, Curreri AM, Balkaran JPR, Selig-Wober NC, Yang AB, Kendig C, et al. Design principles of ionic liquids for transdermal drug delivery. Adv Mater. 2019 Jul;31(27):e1901103. doi: 10.1002/adma.201901103.
Jorge LR, Harada LK, Silva EC, Campos WF, Moreli FC, Shimamoto G, et al. Non-invasive transdermal delivery of human insulin using ionic liquids: in vitro studies. Front Pharmacol. 2020 Apr 23;11:243. doi: 10.3389/fphar.2020.00243.
Voges M, Prikhodko IV, Prill S, Hübner M, Sadowski G, Held C. Influence of pH value and ionic liquids on the solubility of L-alanine and L-glutamic acid in aqueous solutions at 30 °C. J Chem Eng Data. 2017 Jan;9: 52-61. doi: 10.1021/acs.jced.6b00367.
Klein R, Müller E, Kraus B, Brunner G, Estrine B, Touraud D, et al. Biodegradability and cytotoxicity of choline soaps on human cell lines: Effects of chain length and the cation. RSC Adv. 2013 Oct; 3: 23347-54. doi: 10.1039/c3ra42812e.
Klein R, Touraud D, Kunz W. Choline carboxylate surfactants: Biocompatible and highly soluble in water. Green Chem. 2008 Feb;10:433-5. doi: 10.1039/b718466b.
Ouellette RJ, Rawn JD. Amino Acids, Peptides, and Proteins. Princ Org Chem. 2015 Jan; 5 :371–96. doi: 10.1002/9783527631827.
Shah MUH, Sivapragasam M, Moniruzzaman M, Talukderet RM, Suzana Y, Goto M. Aggregation behavior and antimicrobial activity of a micellar system of binary ionic liquids. J Mol Liq. 2018 Sep;266:568–76. doi: 10.1007/s00396-008-1976-x.
Forde BG, Lea PJ. Glutamate in plants: metabolism, regulation, and signalling. J Exp Bot. 2007 Jul; 58: 2339–58. doi: 10.1093/jxb/erm121.
Hashem AH, Hasanin M, Kamel P, Dacrory S. A new approach for antimicrobial and antiviral activities of biocompatible nanocomposite based on cellulose, amino acid and graphene oxide. Colloids Surfaces B Biointerfaces. 2022 Oct;209:86-9. doi: 10.1016/j.colsurfb.2021.112172.
Wang C, Zhang Z, Chen B, Gu L, Li Y, Yu S. Design and evaluation of galactosylated chitosan/graphene oxide nanoparticles as a drug delivery system. J Colloid Interface Sci. 2018 Apr 15; 516: 332-41. doi: 10.1016/j.jcis.2018.01.073.
Zainal-Abidin MH, Hayyan M, Ngoh GC, Wong WF. Doxorubicin loading on functional graphene as a promising nanocarrier using ternary deep eutectic solvent systems. ACS Omega. 2020 Jan 15;5:1656-68. doi: 10.1021/acsomega.9b03709.
Hasanin M, Taha NF, Abdou AR, Emara LH. Green decoration of graphene oxide Nano sheets with gelatin and gum Arabic for targeted delivery of doxorubicin. Biotechnol Reports. 2022 Jun; 34: 722. doi: 10.1016/j.btre.2022.e00722.
Hernandes EP, Lazarin-Bidóia D, Bini RD, Nakamura CV, Cotica LF, Lautenschlager SOS. Doxorubicin-loaded iron oxide nanoparticles induce oxidative stress and cell cycle arrest in breast cancer cells. Antioxidants. 2023 Jan; 12: 237. doi: 10.3390/antiox12020237.
Żelechowska-Matysiak K, Salvanou EA, Bouziotis P, Budlewski T, Bilewicz A, Majkowska-Pilip A. Improvement of the effectiveness of HER2+ cancer therapy by use of doxorubicin and trastuzumab modified radioactive gold nanoparticles. Mol Pharm. 2023 Sep; 20: 4676–86. doi: 10.1021/acs.molpharmaceut.3c00414.
CN-114525269-A - Method for immobilizing laccase based on covalent bonding of polyethylene glycol and superparamagnetic iron oxide nanoparticles [Internet]. [Cited: 1-Avg-2024]. Available from: https://portal.unifiedpatents.com/patents/patent/CN-114525269-A.
RU-2808909-C1 - Method of combined therapy for connective tissue sarcoma m-1 in rats using a conjugate of dipropoxybacteriopurpurin with doxorubicin [Internet]. [Cited: 1-Avg-2024]. Available from: https://portal.unifiedpatents.com/patents/patent/RU-2808909-C1.
CN-115444810-B - Preparation method of doxorubicin-loaded nanoparticle composite temperature-sensitive gel. [Internet]. [Cited: 1-Avg-2024]. Available from: https://portal.unifiedpatents.com/patents/patent/CN-115444810-B.
Fu Z, Xiang J. Aptamer-functionalized nanoparticles in targeted delivery and cancer therapy. Int J Mol Sci. 2020 Dec; 21:1–39.
RU-2794798-C1 - pharmaceutical composition containing doxorubicin as part of phospholipid nanoparticles using selective DNA aptamer molecules for targeted transport to tumor cells [Internet]. [Cited: 1-Avg-2024]. Available from: https://portal.unifiedpatents.com/patents/patent/RU-2794798-C1.
US5672662A. Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications [Internet]. [Cited: 1-Avg-2024]. Available from: https://patents.google.com/patent/US5672662A/en.
Chopra H, Bibi S, Kumar S, Khan MS, Kumar P, Singh I. Preparation and evaluation of chitosan/pva based hydrogel films loaded with honey for wound healing application. Gels. 2022 Feb 11;8:111-8. doi: 10.3390/gels8020111.
Chopra H, Mishra AK, Singh I, Mohanta YK, Sharma R, Bin Emran T, et al. Nano-chitosan: A novel material for glioblastoma treatment. Int J Surg. 2022 May; 104: 106713. doi: 10.1155/2022/4155729.
Chopra H, Bibi S, Singh I, Hasan MM, Khan MS, Yousafi Q, et al. Green metallic nanoparticles: biosynthesis to applications. Front Bioeng Biotechnol. 2022 Apr 6; 10: 548. doi: 10.3389/fbioe.2022.874742.
Bakshi IS, Chopra H, Sharma M, Kaushik D, Pahwa R, Haryanto. Herbal bioactives for wound healing application. Herb Bioact Drug Deliv Syst. 2022 Jan: 259–82. doi: 10.1016/B978-0-12-824385-5.00003-0.
Bhattacharya T, Soares GABE, Chopra H, Rahman MM, Hasan Z, Swain SS, et al. Applications of phyto-nanotechnology for the treatment of neurodegenerative disorders. Materials. 2022; 15:1–32. doi: 10.3390%2Fma15030804.
Walia V, Kaushik D, Mittal V, Kumar K, Verma R, Parashar J, et al. Delineation of neuroprotective effects and possible benefits of antioxidants therapy for the treatment of Alzheimer’s diseases by targeting mitochondrial-derived reactive oxygen species: Bench to Bedside. Mol Neurobiol. 2022; 59: 657–80. doi: 10.1007/s12035-021-02617-1.
Chopra H, Gandhi S, Gautam RK, Kamal MK. Bacterial nanocellulose based wound dressings: current and future prospects. Curr Pharm Des. 2021; 28: 570–80. doi: 10.2174/1381612827666211021162828.
Saleem S, Bibi S, Yousafi Q, Hassan T, Khan MS, Hasan MM, et al. Identification of effective and nonpromiscuous antidiabetic drug molecules from penicillium species. Evidence-Based Complement Altern Med. 2022 Jun 8; 1–15. doi: 10.1155/2022/7040547.
Khalil MS, Shakeel M, Gulfam N, Ahmad SU, Aziz A, Ahmad J, et al. Fabrication of silver nanoparticles from ziziphus nummularia fruit extract: effect on hair growth rate and activity against selected bacterial and fungal strains. J Nanomater. 2022 June 25; 2022: 1–14. doi: 10.1155/2022/3164951.
Pandey P, Chopra H, Kaushik D, Verma R, Purohit D, Parashar J, et al. Multifunctional patented nanotherapeutics for cancer intervention: 2010-onwards. recent pat anticancer. Drug Discov. 2022;17: 38-52. doi: 10.2174/1574892817666220322085942.
Singla RK, Sai CS, Chopra H, Behzad S, Bansal H, Goyal R, et al. Natural products for the management of castration-resistant prostate cancer: special focus on nanoparticles based studies. Front cell Dev Biol. 2021 Nov 5; 9: 1-15. doi: 10.3389/fcell.2021.745177.
Meel RV, Sulheim E, Shi Y, Kiessling F, Mulder WJM, Lammers T. Smart cancer nanomedicine. Nat Nanotechnol. Nov 2019; 14: 1007–17. doi: 10.1038/s41565-019-0567-y.
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