Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box

Springer Science and Business Media LLC - Tập 20 Số 9 - Trang 16852-16891
Pedro Martins1, João Pedro Santiago de Jesus2, Sofia Nascimento dos Santos3, Luís R. Raposo4, Catarina Roma‐Rodrigues5, Pedro V. Baptista6, Alexandra R. Fernandes7,8
1UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
2UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal. [email protected].
3UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal. [email protected].
4UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal. [email protected].
5UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal. [email protected].
6UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal. [email protected].
7Centro de Química Estrutural, Complexo 1, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. [email protected].
8UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal. [email protected].

Tóm tắt

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles.

Từ khóa


Tài liệu tham khảo

IUPAC Gold Book—Heterocyclic Compounds. Available online: http://goldbook.iupac.org/H02798.html.

Gomtsyan, 2012, Heterocycles in drugs and drug discovery, Chem. Heterocycl. Compd., 48, 7, 10.1007/s10593-012-0960-z

Dua, 2011, Pharmacological Significance of Synthetic Heterocycles Scaffold : A Review, Adv. Biol. Res. (Rennes)., 5, 120

Eicher, T., Hauptmann, S., and Speicher, A. (2012). The Chemistry of Heterocycles: Structure, Reactions, Synthesis, and Applications, Wiley-VCH. [3rd ed.].

Broughton, 2004, Selection of heterocycles for drug design, J. Mol. Graph. Model., 23, 51, 10.1016/j.jmgm.2004.03.016

Mostafa, 2013, Synthesis and Antimicrobial Activities of Some New Heterocyclic Compounds Based on 6-Chloropyridazine-3 (2H) -thione, J. Chem., 2013, 1, 10.1155/2013/183130

Azab, 2013, Synthesis and antibacterial evaluation of novel heterocyclic compounds containing a sulfonamido moiety, Molecules, 18, 832, 10.3390/molecules18010832

Salem, 2013, Synthesis, antibacterial, and antiviral evaluation of new heterocycles containing the pyridine moiety, Arch. Pharm. (Weinheim)., 346, 766, 10.1002/ardp.201300183

Cao, 2014, Design, Synthesis, and Structure—Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility, J. Med. Chem., 57, 3687, 10.1021/jm4016284

Ebaid, 2013, Synthesis, anti-inflammatory, analgesic and anticonvulsant activities of some new 4,6-dimethoxy-5-(heterocycles)benzofuran starting from naturally occurring visnagin, Arab. J. Chem., 7, 914

Chen, 2014, Synthesis, characterization and anti-proliferative activity of heterocyclic hypervalent organoantimony compounds, Eur. J. Med. Chem., 79, 391, 10.1016/j.ejmech.2014.04.026

Mandour, 2013, Synthesis, antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles. 1st Cancer Update, Arab. J. Chem., 6, 67, 10.1016/j.arabjc.2012.04.003

Mabkhot, 2013, Synthesis, reactions and biological activity of some new bis-heterocyclic ring compounds containing sulphur atom, Chem. Cent. J., 7, 112, 10.1186/1752-153X-7-112

Barluenga, 2011, Heterocyclic Compounds: An Introduction, Mod. Heterocycl. Chem., 1, 1

Top Prescription Drugs by U.S. Sales 2014|Statistic. Available online: http://www.statista.com/statistics/258010/top-branded-drugs-based-on-retail-sales-in-the-us/.

Peer, 2007, Nanocarriers as an emerging platform for cancer therapy, Nat. Nanotechnol., 2, 751, 10.1038/nnano.2007.387

Hambley, 2009, Is anticancer drug development heading in the right direction?, Cancer Res., 69, 1259, 10.1158/0008-5472.CAN-08-3786

Martins, 2014, Nanoparticle Drug Delivery Systems : Recent Patents and Applications in Nanomedicine, Recent Pat. Nanomed., 3, 1

Conde, 2012, De Design of Multifunctional Gold Nanoparticles for in Vitro and in Vivo Gene Silencing, ACS Nano, 6, 8316, 10.1021/nn3030223

Conde, 2012, Noble metal nanoparticles applications in cancer, J. Drug Deliv., 2012, 1, 10.1155/2012/751075

Market Opportunities in Nanotechnology Drug Delivery. Available online: http://www.cientifica.com/research/white-papers/market-opportunities-in-nanotechnology-drug-delivery/.

Research, C. for D.E. and New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products, Available online: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/default.htm.

Click2Drug—Encyclopedia—Chemical Compounds—Most Frequent Rings in FDA Approved Drugs. Available online: http://www.click2drug.org/encyclopedia/chemistry/fda-based-rings.html.

Vitaku, 2014, Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals, J. Med. Chem., 57, 10257, 10.1021/jm501100b

Ali, 2013, Chemistry and biology of indoles and indazoles: a mini-review, Mini Rev. Med. Chem., 13, 1792, 10.2174/1389557511313120009

Kaushik, 2013, Biomedical importance of indoles, Molecules, 18, 6620, 10.3390/molecules18066620

Sherer, 2015, Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives, Eur. J. Med. Chem., 97, 552, 10.1016/j.ejmech.2014.11.007

Brancale, 2007, Indole, a core nucleus for potent inhibitors of tubulin polymerization, Med. Res. Rev., 27, 209, 10.1002/med.20080

Kumar, S., Mehndiratta, S., Nepali, K., Gupta, M.K., Koul, S., Sharma, P.R., Saxena, A.K., and Dhar, K.L. (2013). Novel indole-bearing combretastatin analogues as tubulin polymerization inhibitors. Org. Med. Chem. Lett., 3.

Huang, 2012, The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse, Int. J. Cancer, 131, 722, 10.1002/ijc.26401

Verma, 2013, Imidazole: Having versatile biological activities, J. Chem., 2013, 1

Sharma, 2014, Imidazole derivatives show anticancer potential by inducing apoptosis and cellular senescence, Med. Chem. Commun., 5, 1751, 10.1039/C4MD00277F

Hou, J., Zhao, W., Huang, Z.-N., Yang, S.-M., Wang, L.-J., Jiang, Y., Zhou, Z.-S., Zheng, M.-Y., Jiang, J.-L., and Li, S.-H. (2014). Evaluation of Novel N -(piperidine-4-yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells. Chem. Biol. Drug Des., 1–9.

Khan, 2013, Triazolothiadiazoles and triazolothiadiazines-Biologically attractive scaffolds, Eur. J. Med. Chem., 63, 854, 10.1016/j.ejmech.2013.01.060

Husain, 2013, Benzimidazole clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: New anticancer agents, Eur. J. Med. Chem., 62, 785, 10.1016/j.ejmech.2012.07.011

Husain, 2012, Benzimidazole bearing oxadiazole and triazolo-thiadiazoles nucleus: Design and synthesis as anticancer agents, Bioorg. Med. Chem. Lett., 22, 5438, 10.1016/j.bmcl.2012.07.038

Kamel, 2014, Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents, Eur. J. Med. Chem., 86, 75, 10.1016/j.ejmech.2014.08.047

Mekhail, 2002, Paclitaxel in cancer therapy, Expert Opin. Pharmacother., 3, 755, 10.1517/14656566.3.6.755

Vrignaud, 2013, Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors, Clin. Cancer Res., 19, 2973, 10.1158/1078-0432.CCR-12-3146

Devriese, 2013, Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole, Investig. New Drugs, 31, 381, 10.1007/s10637-012-9829-3

Yadagiri, 2014, Synthesis of novel building blocks of benzosuberone bearing coumarin moieties and their evaluation as potential anticancer agents, Eur. J. Med. Chem., 79, 260, 10.1016/j.ejmech.2014.04.015

Kontogiorgis, 2012, Coumarin-Based Drugs : A Patent Review (2008–present ), Expert Opin. Ther. Pat., 22, 437, 10.1517/13543776.2012.678835

Kaur, M., Kohli, S., Sandhu, S., Bansal, Y., and Bansal, G. (2015). Coumarin: A Promising Scaffold for Anticancer Agents. Anticancer Agents Med. Chem.

Chen, 2014, Novel Action and Mechanism of Auranofin in Inhibition of Vascular Endothelial Growth Factor Receptor-3-Dependent Lymphangiogenesis|BenthamScience, Anti-Cancer Agents, 14, 946, 10.2174/1871520614666140610102651

Liu, 2014, Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth, Oncotarget, 5, 5453, 10.18632/oncotarget.2113

Park, S.-H., Lee, J., Berek, J., and Hu, M. (2014). Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int. J. Oncol., 1691–1698.

Murti, 2014, Synthesis and evaluation of flavanones as anticancer agents, Indian J. Pharm. Sci., 76, 163

Khanam, 2014, Shamsuzzaman Bioactive Benzofuran derivatives: A review, Eur. J. Med. Chem., 97, 483, 10.1016/j.ejmech.2014.11.039

Choi, 2015, Design, synthesis, and biological evaluation of benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives as anticancer agents and inhibitors of NF-κB, Bioorg. Med. Chem. Lett., 25, 2545, 10.1016/j.bmcl.2015.04.050

Rodrigues, 2014, Mefloquine-Oxazolidine Derivatives: A New Class of Anticancer Agents, Chem. Biol. Drug Des., 83, 126, 10.1111/cbdd.12210

Andrade, 2014, Synthesis of a novel series of 2,3,4-trisubstituted oxazolidines designed by isosteric replacement or rigidification of the structure and cytotoxic evaluation, Med. Chem. Commun., 5, 1693, 10.1039/C4MD00136B

Khatik, 2012, 1,2,4-Oxadiazoles: A new class of anti-prostate cancer agents, Bioorg. Med. Chem. Lett., 22, 1912, 10.1016/j.bmcl.2012.01.059

Valente, 2014, 1,3,4-Oxadiazole-containing histone deacetylase inhibitors: Anticancer activities in cancer cells, J. Med. Chem., 57, 6259, 10.1021/jm500303u

Torroba, 2005, Special Issue: Sulfur-Nitrogen Heterocycles, Molecules, 10, 318, 10.3390/10020318

Marcos, 1997, From Hiinig’s Base to Bis([l,2]dithiolo)-[1,4]thiazines in One Pot: The Fast Route to Highly Sulfurated Heterocycles, Angew. Chem. Int. Ed. Engl., 36, 281, 10.1002/anie.199702811

Makki, 2011, Synthesis of New Bioactive Sulfur Compounds Bearing Heterocyclic Moiety and Their Analytical Applications, Int. J. Chem., 3, 181, 10.5539/ijc.v3n1p181

Toohey, 2014, Thiosulfoxide (Sulfane) Sulfur: New Chemistry and New Regulatory Roles in Biology, Molecules, 19, 12789, 10.3390/molecules190812789

Said, 2014, Synthesis, anticancer activity and structure-activity relationship of some anticancer agents based on Cyclopenta (b) thiophene scaffold, Pak. J. Pharm. Sci., 27, 885

Ghorab, 2014, Novel thiophene derivatives with sulfonamide, isoxazole, benzothiazole, quinoline and anthracene moieties as potential anticancer agents, Acta Pharm., 64, 419, 10.2478/acph-2014-0035

Carter, 1999, Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors, Bioorg. Med. Chem. Lett., 9, 1171, 10.1016/S0960-894X(99)00157-2

Rudolph, 2001, seco-Cyclothialidines: new concise synthesis, inhibitory activity toward bacterial and human DNA topoisomerases, and antibacterial properties, J. Med. Chem., 44, 619, 10.1021/jm0010623

Liu, 2009, Synthesis, antifungal activities and 3D-QSAR study of N-(5-substituted-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamides, Eur. J. Med. Chem., 44, 2782, 10.1016/j.ejmech.2009.01.012

Bell, 1995, Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs, J. Med. Chem., 38, 4929, 10.1021/jm00025a010

Laczkowski, 2014, Synthesis and in Vitro Antiproliferative Activity of Thiazole-Based Nitrogen Mustards: The Hydrogen Bonding Interaction between Model Systems and Nucleobases, Anti-Cancer Agents, 14, 1271, 10.2174/1871520614666140723115347

Penthala, 2012, Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents, MedChemComm, 4, 1073, 10.1039/c3md00130j

Molica, 2013, The emerging role of ibrutinib in the treatment of chronic lymphocytic leukemia, Expert Rev. Hematol., 4, 1

Fiorcari, 2013, The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells, PLoS ONE, 8, e83830, 10.1371/journal.pone.0083830

Fact Sheets by Population. Available online: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.

Cadoo, 2014, Palbociclib: An evidence-based review of its potential in the treatment of breast cancer, Dove Press, 4, 123

Home—PubChem Compound—NCBI, Available online: http://www.ncbi.nlm.nih.gov/pccompound.

Noori, H.R., and Spanagel, R. (2013). In silico pharmacology: Drug design and discovery’s gate to the future. Silico Pharmacol., 1.

Meyer, 2000, Molecular modelling and drug design, Pharmacol. Ther., 85, 113, 10.1016/S0163-7258(99)00069-8

Chaniyara, 2012, Synthesis and antitumor evaluation of novel Benzo[d]pyrrolo[2,1-b]thiazole derivatives, Eur. J. Med. Chem., 53, 28, 10.1016/j.ejmech.2012.03.030

Baptista, 2015, Gold nanoparticle-based theranostics: Disease diagnostics and treatment using a single nanomaterial, Nanobiosen. Dis. Diagn., 4, 11, 10.2147/NDD.S60285

Xu, 2015, Cancer nanomedicine: From targeted delivery to combination therapy, Trends Mol. Med., 21, 223, 10.1016/j.molmed.2015.01.001

Sagnella, 2014, Drug delivery: Beyond active tumour targeting, Nanomed. Nanotechnol. Biol. Med., 10, 1131, 10.1016/j.nano.2014.04.012

Wicki, 2015, Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications, J. Control. Release, 200, 138, 10.1016/j.jconrel.2014.12.030

Estanqueiro, 2015, Nanotechnological carriers for cancer chemotherapy: The state of the art, Colloids Surf. B Biointerfaces, 126, 631, 10.1016/j.colsurfb.2014.12.041

Zhang, 2008, Nanoparticles in Medicine : Therapeutic Applications and Developments, Clin. Pharmacol. Ther., 83, 761, 10.1038/sj.clpt.6100400

Allen, 2013, Liposomal drug delivery systems: From concept to clinical applications, Adv. Drug Deliv. Rev., 65, 36, 10.1016/j.addr.2012.09.037

2015, Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy, Eur. J. Pharm. Biopharm., 93, 52, 10.1016/j.ejpb.2015.03.018

Wang, 2012, Nanoparticle delivery of cancer drugs, Annu. Rev. Med., 63, 185, 10.1146/annurev-med-040210-162544

Szebeni, 2005, Complement activation-related pseudoallergy: A new class of drug-induced acute immune toxicity, Toxicology, 216, 106, 10.1016/j.tox.2005.07.023

Parhi, 2012, Nanotechnology-based combinational drug delivery: An emerging approach for cancer therapy, Drug Discov. Today, 17, 1044, 10.1016/j.drudis.2012.05.010

Nazir, 2014, Nanomaterials in combating cancer: Therapeutic applications and developments, Nanomedicine, 10, 19, 10.1016/j.nano.2013.07.001

Gillies, 2005, Dendrimers and dendritic polymers in drug delivery, Drug Discov. Today, 10, 35, 10.1016/S1359-6446(04)03276-3

Kesharwani, 2014, Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery, Drug Discov. Today, 20, 536, 10.1016/j.drudis.2014.12.012

Sanna, 2014, Targeted therapy using nanotechnology: Focus on cancer, Int. J. Nanomed., 9, 467

Chari, 2014, Antibody-drug conjugates: An emerging concept in cancer therapy, Angew. Chem. Int. Ed., 53, 3796, 10.1002/anie.201307628

Elzoghby, 2012, Albumin-based nanoparticles as potential controlled release drug delivery systems, J. Control. Release, 157, 168, 10.1016/j.jconrel.2011.07.031

Cabral, 2013, The Chemistry and Biology of Gold Nanoparticle-Mediated Photothermal Therapy: Promises and Challenges, Nano Life, 3, 1330001, 10.1142/S179398441330001X

Peralta, 2015, Hybrid Paclitaxel and Gold Nanorod-Loaded Human Serum Albumin Nanoparticles for Simultaneous Chemotherapeutic and Photothermal Therapy on 4T1 Breast Cancer Cells, ACS Appl. Mater. Interfaces, 7, 7101, 10.1021/acsami.5b00858

Zolot, 2013, Antibody–drug conjugates, Nat. Rev. Drug Discov., 12, 259, 10.1038/nrd3980

Teicher, 2014, Antibody drug conjugates, Curr. Opin. Oncol., 26, 476, 10.1097/CCO.0000000000000108

Panowski, 2014, Site-specific antibody drug conjugates for cancer therapy, MAbs, 6, 34, 10.4161/mabs.27022

Dhillon, 2015, Dinutuximab: First Global Approval, Drugs, 75, 923, 10.1007/s40265-015-0399-5

Falchook, 2015, Nivolumab: Another weapon in the growing immunotherapy arsenal, Lancet Oncol., 16, 350, 10.1016/S1470-2045(15)70109-9

Robert, 2015, Nivolumab in Previously Untreated Melanoma without BRAF Mutation, N. Engl. J. Med., 372, 320, 10.1056/NEJMoa1412082

Flygare, 2013, Antibody-Drug Conjugates for the Treatment of Cancer, Chem. Biol. Drug Des., 81, 113, 10.1111/cbdd.12085

Ornes, 2013, Antibody–drug conjugates, Proc. Natl. Acad. Sci. USA, 110, 13695, 10.1073/pnas.1314120110

Casi, 2012, Antibody-drug conjugates: Basic concepts, examples and future perspectives, J. Control. Release, 161, 422, 10.1016/j.jconrel.2012.01.026

Muggia, 1997, Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation, J. Clin. Oncol., 15, 987, 10.1200/JCO.1997.15.3.987

Khemapech, 2013, Salvage chemotherapy in recurrent platinum-resistant or refractory epithelial ovarian cancer with Carboplatin and distearoylphosphatidylcholine pegylated liposomal Doxorubicin (lipo-dox®), Asian Pac. J. Cancer Prev., 14, 2131, 10.7314/APJCP.2013.14.3.2131

Batist, 2001, Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer, J. Clin. Oncol., 19, 1444, 10.1200/JCO.2001.19.5.1444

Granai, 2002, Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer, Expert Rev. Anticancer Ther., 2, 143, 10.1586/14737140.2.2.143

European Medicines Agency—Find Medicine—Myocet. Available online: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000297/human_med_000916.jsp&mid=WC0b01ac058001d124.

European Medicines Agency—Find medicine—Caelyx. Available online: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000089/human_med_000683.jsp&mid=WC0b01ac058001d124.

Awada, 2013, Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: A randomised phase 2 study, Lancet Oncol., 14, 1216, 10.1016/S1470-2045(13)70429-7

Feldman, 2011, First-in-man study of CPX-351: A liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia, J. Clin. Oncol., 29, 979, 10.1200/JCO.2010.30.5961

Sarris, 2000, Liposomal vincristine in relapsed non-Hodgkin’s lymphomas: Early results of an ongoing phase II trial, Ann. Oncol., 11, 69, 10.1023/A:1008348010437

Conde, 2014, V Gold-nanobeacons for gene therapy: Evaluation of genotoxicity, cell toxicity and proteome profiling analysis, Nanotoxicology, 8, 521, 10.3109/17435390.2013.802821

R. Fernandes, A., and Viana Baptista, P. (2013). Nanotechnology for Cancer Diagnostics and Therapy – An Update on Novel Molecular Players. Curr. Cancer Ther. Rev., 164–172.

Zhao, 2011, Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials, Small, 7, 1322, 10.1002/smll.201100001

Iversen, 2011, Endocytosis and intracellular transport of nanoparticles: Present knowledge and need for future studies, Nano Today, 6, 176, 10.1016/j.nantod.2011.02.003

Shukla, 2005, Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: A microscopic overview, Langmuir, 21, 10644, 10.1021/la0513712

Murugan, 2013, Biofabrication of gold nanoparticles and its biocompatibility in human breast adenocarcinoma cells (MCF-7), J. Ind. Eng. Chem., 20, 1713, 10.1016/j.jiec.2013.08.021

Alkilany, 2010, Toxicity and cellular uptake of gold nanoparticles: What we have learned so far?, J. Nanopart. Res., 12, 2313, 10.1007/s11051-010-9911-8

Coradeghini, 2013, Size-dependent toxicity and cell interaction mechanisms of gold nanoparticles on mouse fibroblasts, Toxicol. Lett., 217, 205, 10.1016/j.toxlet.2012.11.022

Patlolla, 2010, Multi-walled carbon nanotubes induce cytotoxicity, genotoxicity and apoptosis in normal human dermal fibroblast cells, Ethn. Dis., 20, 1

Kumarathasan, 2015, Cytotoxicity of carbon nanotube variants: A comparative: In vitro exposure study with A549 epithelial and J774 macrophage cells, Nanotoxicology, 9, 148, 10.3109/17435390.2014.902519

Chithrani, 2006, Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells, Nano Lett., 6, 662, 10.1021/nl052396o

Chithrani, 2010, Intracellular uptake, transport, and processing of gold nanostructures, Mol. Membr. Biol., 27, 299, 10.3109/09687688.2010.507787

Oh, 2014, Endocytosis and exocytosis of nanoparticles in mammalian cells, Int. J. Nanomed., 9, 51

Win, 2005, Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs, Biomaterials, 26, 2713, 10.1016/j.biomaterials.2004.07.050

Nativo, 2008, Uptake and intracellular fate of surface-modified gold nanoparticles, ACS Nano, 2, 1639, 10.1021/nn800330a

Sahay, 2010, Endocytosis of nanomedicines, J. Control. Release, 145, 182, 10.1016/j.jconrel.2010.01.036

Moghimi, 2014, Just so stories: The random acts of anti-cancer nanomedicine performance, Nanomedicine, 8, 1661, 10.1016/j.nano.2014.04.011

Taurin, 2012, Anticancer nanomedicine and tumor vascular permeability; Where is the missing link?, J. Control. Release, 164, 265, 10.1016/j.jconrel.2012.07.013

Toy, 2014, Shaping cancer nanomedicine: The effect of particle shape on the in vivo journey of nanoparticles, Nanomedicine (Lond)., 9, 121, 10.2217/nnm.13.191

Kim, 2007, Nanotechnology platforms and physiological challenges for cancer therapeutics, Nanomedicine, 3, 103, 10.1016/j.nano.2006.12.002

Mirkin, C., Meade, Th.J., Petrosko, S.H., and Stegh, A.H. (2015). Nanotechnology-Based Precision Tools for the Detection and Treatment of Cancer, Springer.

Naguib, 2014, Nanomedicine: The promise and challenges in cancer chemotherapy, Adv. Exp. Med. Biol., 811, 207, 10.1007/978-94-017-8739-0_11

Doane, 2012, The unique role of nanoparticles in nanomedicine: Imaging, drug delivery and therapy, Chem. Soc. Rev., 41, 2885, 10.1039/c2cs15260f

Fubini, 2010, Physico-chemical features of engineered nanoparticles relevant to their toxicity, Nanotoxicology, 4, 347, 10.3109/17435390.2010.509519

Kettiger, 2013, Engineered nanomaterial uptake and tissue distribution: from cell to organism, Int. J. Nanomed., 8, 3255

Stone, 2009, Development of in vitro systems for nanotoxicology: methodological considerations, Crit. Rev. Toxicol., 39, 613, 10.1080/10408440903120975

Hamburg, 2012, Science and regulation. FDA’s approach to regulation of products of nanotechnology, Science, 336, 299, 10.1126/science.1205441

Desai, 2012, Challenges in development of nanoparticle-based therapeutics, AAPS J., 14, 282, 10.1208/s12248-012-9339-4