How to cite this WIREs title:
WIREs Nanomed Nanobiotechnol

Impact Factor: 7.689

Dendrimer‐based nanocarriers: a versatile platform for drug delivery

Advanced Review

Hao‐Jui Hsu, Jason Bugno, Seung‐ri Lee, Seungpyo Hong

Published Online: Apr 29 2016

DOI: 10.1002/wnan.1409

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Advances in nanotechnology have had profound impacts on therapeutic delivery, leading to the development of nanomaterials engineered with large carrying capabilities and targeting functionalities. Among the nanomaterials, dendrimers have garnered particular attention from researchers owing to their well‐defined structure, near‐monodispersity, and ease of multifunctionalization. As hyperbranched, three‐dimensional macromolecules, dendrimers can be engineered to target and deliver a wide range of therapeutic agents, including small molecules, peptides, and genes, reducing their systemic toxicities and enhancing efficacies. In this review, we provide a comprehensive overview of the commonly employed dendrimer‐based nanocarrier designs, including dendrimer conjugates, Janus dendrimers, and linear‐dendritic block copolymers. The discussion will progress through the basic synthetic strategies of dendrimer‐based nanocarriers, followed by the potential clinical applications related to their unique structural properties. Finally, the major challenges that these nanocarriers are currently facing in their clinical translation and possible solutions to address these issues will be discussed, with the aim to provide researchers in the drug delivery field a good understanding of the potential utilities of dendrimer‐based nanocarriers. WIREs Nanomed Nanobiotechnol 2017, 9:e1409. doi: 10.1002/wnan.1409 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

A linear‐dendritic block copolymer (LDBC)‐based micelle system that exhibits superior hydrodynamic stability to linear‐block copolymer‐based micelles. (a) An illustration of a self‐assembled LDBC micelle built from polycaprolactone (PCL)‐polyester G3‐poly(ethylene glycol) (PEG) copolymers. (b) Critical micelle concentration (CMC) comparison of LDBCs (red circle) and linear‐block copolymers (blue square). LDBCs exhibit lower CMCs than linear‐block copolymers in the same hydrophilic–lipophilic balance (HLB) range, demonstrating the improved thermodynamic stability of the LDBC‐based micelles. (Reprinted with permission from Ref . Copyright 2011 Royal Society of Chemistry)

[ Normal View | Magnified View ]

Linear‐dendritic block copolymer (LDBC) synthetic strategies: (a) coupling, (b) linear polymer‐first, and (c) dendron‐first.

[ Normal View | Magnified View ]

Synthetic strategies of Janus dendrimers: (a) direct focal conjugation of two dendrons with complementary focal groups, (b) conjugation of two dendrons via a multifunctional linker, and (c) growth of the second dendron from the focal point of the first dendron.

[ Normal View | Magnified View ]

Commonly used dendrimers in drug delivery: (a) a schematic illustration showing the three components of a dendrimer molecule and chemical structures of (b) poly(amidoamine) (PAMAM), (c) poly(propylenimine) (PPI), and (d) poly(l‐lysine) (PLL) dendrimers.

[ Normal View | Magnified View ]

Representative synthetic routes for dendrimers: (a) convergent and (b) divergent approaches.

[ Normal View | Magnified View ]

Prevention of viral infection using surface‐modified dendrimers through (a) direct binding to the viral epitope or (b) prebinding to receptors of host cells.

[ Normal View | Magnified View ]

An illustration of a hybrid nanoparticle (NP) system that combines targeted dendrimers and PEGylated polymeric NPs to achieve sequential passive and ligand‐mediated targeting. The PEGylated, larger NP shell allows the hybrid NPs to passively accumulate at the tumor site through the enhanced permeability and retention (EPR) effect. The folic acid (FA)‐targeted dendrimers can be released from the carrier NPs and permeate the tumor mass to actively bind to tumor cells. (Reprinted with permission from Ref . Copyright 2014 Elsevier)

[ Normal View | Magnified View ]

References

Gradishar, WJ, Tjulandin, S, Davidson, N, Shaw, H, Desai, N, Bhar, P, Hawkins, M, O`Shaughnessy, J. Phase III trial of nanoparticle albumin‐bound paclitaxel compared with polyethylated castor oil–based paclitaxel in women with breast cancer. J Clin Oncol 2005, 23:7794–7803.
Ko, A, Tempero, M, Shan, Y, Su, W, Lin, Y, Dito, E, Ong, A, Wang, Y, Yeh, C, Chen, L. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM‐398) for patients with gemcitabine‐refractory metastatic pancreatic cancer. Br J Cancer 2013, 109:920–925.
Awada, A, Bondarenko, I, Bonneterre, J, Nowara, E, Ferrero, J, Bakshi, A, Wilke, C, Piccart, M, CT4002 Study Group. A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple‐negative breast cancer (TNBC). Ann Oncol 2014, 25:824–831.
Lee, CC, MacKay, JA, Fréchet, JM, Szoka, FC. Designing dendrimers for biological applications. Nat Biotechnol 2005, 23:1517–1526.
Svenson, S, Tomalia, DA. Dendrimers in biomedical applications—reflections on the field. Adv Drug Deliv Rev 2005, 57:2106–2129.
Hawker, CJ, Frechet, JM. Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules. J Am Chem Soc 1990, 112:7638–7647.
Pearson, RM, Sunoqrot, S, H‐j, H, Bae, JW, Hong, S. Dendritic nanoparticles: the next generation of nanocarriers? Ther Deliv 2012, 3:941–959.
Tomalia, DA, Baker, H, Dewald, J, Hall, M, Kallos, G, Martin, S, Roeck, J, Ryder, J, Smith, P. A new class of polymers: starburst‐dendritic macromolecules. Polym J 1985, 17:117–132.
Torchilin, VP. Multifunctional nanocarriers. Adv Drug Deliv Rev 2012, 64:302–315.
Hong, S, Leroueil, PR, Majoros, IJ, Orr, BG, Baker, JR, Holl, MMB. The binding avidity of a nanoparticle‐based multivalent targeted drug delivery platform. Chem Biol 2007, 14:107–115.
Myung, JH, Gajjar, KA, Saric, J, Eddington, DT, Hong, S. Dendrimer‐mediated multivalent binding for the enhanced capture of tumor cells. Angew Chem Int Ed 2011, 123:11973–11976.
Kesharwani, P, Jain, K, Jain, NK. Dendrimer as nanocarrier for drug delivery. Prog Polym Sci 2014, 39:268–307.
Wu, L‐P, Ficker, M, Christensen, JB, Trohopoulos, PN, Moghimi, SM. Dendrimers in medicine: therapeutic concepts and pharmaceutical challenges. Bioconjug Chem 2015, 26:1198–1211.
Bugno, J, Hsu, H‐J, Hong, S. Recent advances in targeted drug delivery approaches using dendritic polymers. Biomater Sci 2014, 3:1025–1034.
Bugno, J, Hsu, H‐J, Hong, S. Tweaking dendrimers and dendritic nanoparticles for controlled nano‐bio interactions: potential nanocarriers for improved cancer targeting. J Drug Target 2015, 23:642–650.
Buhleier, E, Wehner, W, Vögtle, F. "Cascade"‐and" nonskid‐chain‐like" syntheses of molecular cavity topologies. Synthesis 1978, 1978:155–158.
Kannan, RM, Nance, E, Kannan, S, Tomalia, DA. Emerging concepts in dendrimer‐based nanomedicine: from design principles to clinical applications. J Intern Med 2014, 276:579–617.
Caminade, A‐M, Laurent, R, Delavaux‐Nicot, B, Majoral, J‐P. “Janus” dendrimers: syntheses and properties. New J Chem 2012, 36:217–226.
Caminade, A‐M, Turrin, C‐O. Dendrimers for drug delivery. J Mater Chem B 2014, 2:4055–4066.
Malik, N, Wiwattanapatapee, R, Klopsch, R, Lorenz, K, Frey, H, Weener, JW, Meijer, EW, Paulus, W, Duncan, R. Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I‐labelled polyamidoamine dendrimers in vivo. J Control Release 2000, 65:133–148.
Hong, S, Leroueil, PR, Janus, EK, Peters, JL, Kober, M‐M, Islam, MT, Orr, BG, Baker, JR, Banaszak Holl, MM. Interaction of polycationic polymers with supported lipid bilayers and cells: nanoscale hole formation and enhanced membrane permeability. Bioconjug Chem 2006, 17:728–734.
Yang, Y, Pearson, RM, Lee, O, Lee, CW, Chatterton, RT, Khan, SA, Hong, S. Dendron‐based micelles for topical delivery of Endoxifen: a potential chemo‐preventive medicine for breast cancer. Adv Funct Mater 2014, 24:2442–2449.
Yang, Y, Sunoqrot, S, Stowell, C, Ji, J, Lee, C‐W, Kim, JW, Khan, SA, Hong, S. Effect of size, surface charge, and hydrophobicity of poly (amidoamine) dendrimers on their skin penetration. Biomacromolecules 2012, 13:2154–2162.
Hong, S, Bielinska, AU, Mecke, A, Keszler, B, Beals, JL, Shi, X, Balogh, L, Orr, BG, Baker, JR, Banaszak Holl, MM. Interaction of poly (amidoamine) dendrimers with supported lipid bilayers and cells: hole formation and the relation to transport. Bioconjug Chem 2004, 15:774–782.
Padilla De Jesús, OL, Ihre, HR, Gagne, L, Fréchet, JM, Szoka, FC. Polyester dendritic systems for drug delivery applications: in vitro and in vivo evaluation. Bioconjug Chem 2002, 13:453–461.
Pearson, RM, H‐j, H, Bugno, J, Hong, S. Understanding nano‐bio interactions to improve nanocarriers for drug delivery. MRS Bull 2014, 39:227–237.
Modi, DA, Sunoqrot, S, Bugno, J, Lantvit, DD, Hong, S, Burdette, JE. Targeting of follicle stimulating hormone peptide‐conjugated dendrimers to ovarian cancer cells. Nanoscale 2014, 6:2812–2820.
Sunoqrot, S, Bae, JW, Pearson, RM, Shyu, K, Liu, Y, Kim, D‐H, Hong, S. Temporal control over cellular targeting through hybridization of folate‐targeted dendrimers and PEG‐PLA nanoparticles. Biomacromolecules 2012, 13:1223–1230.
Agarwal, A, Saraf, S, Asthana, A, Gupta, U, Gajbhiye, V, Jain, NK. Ligand based dendritic systems for tumor targeting. Int J Pharm 2008, 350:3–13.
Kukowska‐Latallo, JF, Candido, KA, Cao, Z, Nigavekar, SS, Majoros, IJ, Thomas, TP, Balogh, LP, Khan, MK, Baker, JR. Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Res 2005, 65:5317–5324.
Quintana, A, Raczka, E, Piehler, L, Lee, I, Myc, A, Majoros, I, Patri, A, Thomas, T, Mulé, J, Baker, J Jr. Design and function of a dendrimer‐based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res 2002, 19:1310–1316.
Myung, JH, Gajjar, KA, Chen, J, Molokie, RE, Hong, S. Differential detection of tumor cells using a combination of cell rolling, multivalent binding, and multiple antibodies. Anal Chem 2014, 86:6088–6094.
Myung, JH, Launiere, CA, Eddington, DT, Hong, S. Enhanced tumor cell isolation by a biomimetic combination of E‐selectin and anti‐EpCAM: implications for the effective separation of circulating tumor cells (CTCs). Langmuir 2010, 26:8589–8596.
van Dongen, MA, Silpe, JE, Dougherty, CA, Kanduluru, AK, Choi, SK, Orr, BG, Low, PS, Banaszak Holl, MM. Avidity mechanism of dendrimer–folic acid conjugates. Mol Pharm 2014, 11:1696–1706.
Leroueil, PR, DiMaggio, S, Leistra, AN, Blanchette, CD, Orme, C, Sinniah, K, Orr, BG, Banaszak Holl, MM. Characterization of folic acid and poly(amidoamine) dendrimer interactions with folate binding orotein: a force‐pulling study. J Phys Chem B 2015, 119:11506–11512.
Wurm, F, Frey, H. Linear–dendritic block copolymers: the state of the art and exciting perspectives. Prog Polym Sci 2011, 36:1–52.
Esfand, R, Tomalia, DA. Poly (amidoamine)(PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov Today 2001, 6:427–436.
Labieniec‐Watala, M, Watala, C. PAMAM dendrimers: destined for success or doomed to fail? Plain and modified PAMAM dendrimers in the context of biomedical applications. J Pharm Sci 2015, 104:2–14.
Gillies, ER, Frechet, JM. Dendrimers and dendritic polymers in drug delivery. Drug Discov Today 2005, 10:35–43.
Boas, U, Christensen, JB, Heegaard, PM. Dendrimers: design, synthesis and chemical properties. J Mater Chem 2006, 16:3785–3798.
Shao, N, Su, Y, Hu, J, Zhang, J, Zhang, H, Cheng, Y. Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity. Int J Nanomed 2011, 6:3361–3372.
Richter‐Egger, DL, Tesfai, A, Tucker, SA. Spectroscopic investigations of poly (propyleneimine) dendrimers using the solvatochromic probe phenol blue and comparisons to poly (amidoamine) dendrimers. Anal Chem 2001, 73:5743–5751.
Kannaiyan, D, Imae, T. pH‐dependent encapsulation of pyrene in PPI‐core: PAMAM‐shell dendrimers. Langmuir 2009, 25:5282–5285.
Denkewalter, R, Kole, J, Lukasavage, W. Macromolecular highly branched homogeneous compound based on lysine units. US Patent 4289872, 1981.
Falkovich, S, Markelov, D, Neelov, I, Darinskii, A. Are structural properties of dendrimers sensitive to the symmetry of branching? Computer simulation of lysine dendrimers. J Chem Phys 2013, 139:064903.
Gillies, ER, Dy, E, Fréchet, JM, Szoka, FC. Biological evaluation of polyester dendrimer: poly (ethylene oxide)“bow‐tie” hybrids with tunable molecular weight and architecture. Mol Pharm 2005, 2:129–138.
Gillies, ER, Fréchet, JM. Designing macromolecules for therapeutic applications: polyester dendrimer poly (ethylene oxide)“bow‐tie” hybrids with tunable molecular weight and architecture. J Am Chem Soc 2002, 124:14137–14146.
Zhang, S, Sun, H‐J, Hughes, AD, Moussodia, R‐O, Bertin, A, Chen, Y, Pochan, DJ, Heiney, PA, Klein, ML, Percec, V. Self‐assembly of amphiphilic Janus dendrimers into uniform onion‐like dendrimersomes with predictable size and number of bilayers. Proc Natl Acad Sci USA 2014, 111:9058–9063.
Gitsov, I, Wooley, KL, Frechet, JM. Novel polyether copolymers consisting of linear and dendritic blocks. Angew Chem Int Ed Engl 1992, 31:1200–1202.
Rosen, BM, Wilson, CJ, Wilson, DA, Peterca, M, Imam, MR, Percec, V. Dendron‐mediated self‐assembly, disassembly, and self‐organization of complex systems. Chem Rev 2009, 109:6275–6540.
Bae, JW, Pearson, RM, Patra, N, Sunoqrot, S, Vukovic, L, Kral, P, Hong, S. Dendron‐mediated self‐assembly of highly PEGylated block copolymers: a modular nanocarrier platform. Chem Commun 2011, 47:10302–10304.
Yang, B, Sun, Y‐X, Yi, W‐J, Yang, J, Liu, C‐W, Cheng, H, Feng, J, Zhang, X‐Z, Zhuo, R‐X. A linear‐dendritic cationic vector for efficient DNA grasp and delivery. Acta Biomater 2012, 8:2121–2132.
Medina, SH, El‐Sayed, ME. Dendrimers as carriers for delivery of chemotherapeutic agents. Chem Rev 2009, 109:3141–3157.
Naylor, AM, Goddard, WA, Kiefer, GE, Tomalia, DA. Starburst dendrimers. 5. Molecular shape control. J Am Chem Soc 1989, 111:2339–2341.
Morgan, MT, Carnahan, MA, Immoos, CE, Ribeiro, AA, Finkelstein, S, Lee, SJ, Grinstaff, MW. Dendritic molecular capsules for hydrophobic compounds. J Am Chem Soc 2003, 125:15485–15489.
Patri, AK, Kukowska‐Latallo, JF, Baker, JR Jr. Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non‐covalent drug inclusion complex. Adv Drug Deliv Rev 2005, 57:2203–2214.
Kojima, C, Kono, K, Maruyama, K, Takagishi, T. Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs. Bioconjug Chem 2000, 11:910–917.
Malik, N, Evagorou, EG, Duncan, R. Dendrimer‐platinate: a novel approach to cancer chemotherapy. Anticancer Drugs 1999, 10:767–776.
Wu, G, Barth, RF, Yang, W, Kawabata, S, Zhang, L, Green‐Church, K. Targeted delivery of methotrexate to epidermal growth factor receptor–positive brain tumors by means of cetuximab (IMC‐C225) dendrimer bioconjugates. Mol Cancer Ther 2006, 5:52–59.
Kono, K, Kojima, C, Hayashi, N, Nishisaka, E, Kiura, K, Watarai, S, Harada, A. Preparation and cytotoxic activity of poly (ethylene glycol)‐modified poly (amidoamine) dendrimers bearing adriamycin. Biomaterials 2008, 29:1664–1675.
Li, X, Takashima, M, Yuba, E, Harada, A, Kono, K. PEGylated PAMAM dendrimer–doxorubicin conjugate‐hybridized gold nanorod for combined photothermal‐chemotherapy. Biomaterials 2014, 35:6576–6584.
Teow, HM, Zhou, Z, Najlah, M, Yusof, SR, Abbott, NJ, D`Emanuele, A. Delivery of paclitaxel across cellular barriers using a dendrimer‐based nanocarrier. Int J Pharm 2013, 441:701–711.
Nance, E, Porambo, M, Zhang, F, Mishra, MK, Buelow, M, Getzenberg, R, Johnston, M, Kannan, RM, Fatemi, A, Kannan, S. Systemic dendrimer‐drug treatment of ischemia‐induced neonatal white matter injury. J Control Release 2015, 214:112–120.
Kannan, S, Dai, H, Navath, RS, Balakrishnan, B, Jyoti, A, Janisse, J, Romero, R, Kannan, RM. Dendrimer‐based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med 2012, 4:130ra146.
Zhang, C, Pan, D, Luo, K, She, W, Guo, C, Yang, Y, Gu, Z. Peptide dendrimer–doxorubicin conjugate‐based nanoparticles as an enzyme‐responsive drug delivery system for cancer therapy. Adv Healthcare Mater 2014, 3:1299–1308.
Patri, AK, Majoros, IJ, Baker, JR. Dendritic polymer macromolecular carriers for drug delivery. Curr Opin Chem Biol 2002, 6:466–471.
Nguyen, PM, Hammond, PT. Amphiphilic linear‐dendritic triblock copolymers composed of poly (amidoamine) and poly (propylene oxide) and their micellar‐phase and encapsulation properties. Langmuir 2006, 22:7825–7832.
Yang, Y, Hua, C, Dong, C‐M. Synthesis, self‐assembly, and in vitro doxorubicin release behavior of dendron‐like/linear/dendron‐like poly (ε‐caprolactone)‐b‐poly (ethylene glycol)‐b‐poly (ε‐caprolactone) triblock copolymers. Biomacromolecules 2009, 10:2310–2318.
H‐j, H, Sen, S, Pearson, RM, Uddin, S, Král, P, Hong, S. Poly (ethylene glycol) corona chain length controls end‐group‐dependent cell interactions of dendron micelles. Macromolecules 2014, 47:6911–6918.
Percec, V, Wilson, DA, Leowanawat, P, Wilson, CJ, Hughes, AD, Kaucher, MS, Hammer, DA, Levine, DH, Kim, AJ, Bates, FS. Self‐assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures. Science 2010, 328:1009–1014.
She, W, Luo, K, Zhang, C, Wang, G, Geng, Y, Li, L, He, B, Gu, Z. The potential of self‐assembled, pH‐responsive nanoparticles of mPEGylated peptide dendron–doxorubicin conjugates for cancer therapy. Biomaterials 2013, 34:1613–1623.
Li, N, Li, N, Yi, Q, Luo, K, Guo, C, Pan, D, Gu, Z. Amphiphilic peptide dendritic copolymer‐doxorubicin nanoscale conjugate self‐assembled to enzyme‐responsive anti‐cancer agent. Biomaterials 2014, 35:9529–9545.
Peer, D, Karp, JM, Hong, S, Farokhzad, OC, Margalit, R, Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2007, 2:751–760.
Matsumura, Y, Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986, 46:6387–6392.
Wu, W, Driessen, W, Jiang, X. Oligo (ethylene glycol)‐based thermosensitive dendrimers and their tumor accumulation and penetration. J Am Chem Soc 2014, 136:3145–3155.
Kobayashi, H, Kawamoto, S, Saga, T, Sato, N, Hiraga, A, Konishi, J, Togashi, K, Brechbiel, MW. Micro‐MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: reference to pharmacokinetic properties of dendrimer‐based MR contrast agents. J Magn Reson Imaging 2001, 14:705–713.
Agarwal, A, Gupta, U, Asthana, A, Jain, NK. Dextran conjugated dendritic nanoconstructs as potential vectors for anti‐cancer agent. Biomaterials 2009, 30:3588–3596.
Kaminskas, LM, Kelly, BD, McLeod, VM, Boyd, BJ, Krippner, GY, Williams, ED, Porter, CJ. Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly‐l‐lysine dendrimers. Mol Pharm 2009, 6:1190–1204.
http://www.starpharma.com/drug_delivery/dep_docetaxel. (Accessed January 11, 2016).
Zhu, J, Shi, X. Dendrimer‐based nanodevices for targeted drug delivery applications. J Mater Chem B 2013, 1:4199–4211.
Zhang, Y, Thomas, TP, Lee, K‐H, Li, M, Zong, H, Desai, AM, Kotlyar, A, Huang, B, Banaszak Holl, MM, Baker, J JR. Polyvalent saccharide‐functionalized generation 3 poly(amidoamine) dendrimer–methotrexate conjugate as a potential anticancer agent. Bioorg Med Chem 2011, 19:2557–2564.
He, H, Li, Y, Jia, X‐R, Du, J, Ying, X, Lu, W‐L, Lou, J‐N, Wei, Y. PEGylated poly(amidoamine) dendrimer‐based dual‐targeting carrier for treating brain tumors. Biomaterials 2011, 32:478–487.
Thomas, TP, Patri, AK, Myc, A, Myaing, MT, Ye, JY, Norris, TB, Baker, JR. In vitro targeting of synthesized antibody‐conjugated dendrimer nanoparticles. Biomacromolecules 2004, 5:2269–2274.
Shukla, R, Thomas, TP, Peters, JL, Desai, AM, Kukowska‐Latallo, J, Patri, AK, Kotlyar, A, Baker, JR. HER2 specific tumor targeting with dendrimer conjugated anti‐HER2 mAb. Bioconjug Chem 2006, 17:1109–1115.
Wang, Y, Guo, R, Cao, X, Shen, M, Shi, X. Encapsulation of 2‐methoxyestradiol within multifunctional poly (amidoamine) dendrimers for targeted cancer therapy. Biomaterials 2011, 32:3322–3329.
Fu, F, Wu, Y, Zhu, J, Wen, S, Shen, M, Shi, X. Multifunctional lactobionic acid‐modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer. ACS Appl Mater Interfaces 2014, 6:16416–16425.
Zhu, J, Fu, F, Xiong, Z, Shen, M, Shi, X. Dendrimer‐entrapped gold nanoparticles modified with RGD peptide and α‐tocopheryl succinate enable targeted theranostics of cancer cells. Colloids Surf B 2015, 133:36–42.
Wang, K, Zhang, X, Zhang, L, Qian, L, Liu, C, Zheng, J, Jiang, Y. Development of biodegradable polymeric implants of RGD‐modified PEG‐PAMAM‐DOX conjugates for long‐term intratumoral release. Drug Deliv 2015, 22:389–399.
Han, L, Huang, R, Li, J, Liu, S, Huang, S, Jiang, C. Plasmid pORF‐hTRAIL and doxorubicin co‐delivery targeting to tumor using peptide‐conjugated polyamidoamine dendrimer. Biomaterials 2011, 32:1242–1252.
Somani, S, Blatchford, DR, Millington, O, Stevenson, ML, Dufès, C. Transferrin‐bearing polypropylenimine dendrimer for targeted gene delivery to the brain. J Control Release 2014, 188:78–86.
Kesharwani, P, Tekade, RK, Jain, NK. Generation dependent cancer targeting potential of poly(propyleneimine) dendrimer. Biomaterials 2014, 35:5539–5548.
Kesharwani, P, Tekade, RK, Gajbhiye, V, Jain, K, Jain, NK. Cancer targeting potential of some ligand‐anchored poly (propylene imine) dendrimers: a comparison. Nanomedicine 2011, 7:295–304.
Sideratou, Z, Kontoyianni, C, Drossopoulou, GI, Paleos, CM. Synthesis of a folate functionalized PEGylated poly (propylene imine) dendrimer as prospective targeted drug delivery system. Bioorg Med Chem Lett 2010, 20:6513–6517.
Singh Dhakad, R, Kumar Tekade, R, Kumar Jain, N. Cancer targeting potential of folate targeted nanocarrier under comparative influence of tretinoin and dexamethasone. Curr Drug Deliv 2013, 10:477–491.
Shah, V, Taratula, O, Garbuzenko, OB, Taratula, OR, Rodriguez‐Rodriguez, L, Minko, T. Targeted nanomedicine for suppression of CD44 and simultaneous cell death induction in ovarian cancer: an optimal delivery of siRNA and anticancer drug. Clin Cancer Res 2013, 19:6193–6204.
Jain, K, Gupta, U, Jain, NK. Dendronized nanoconjugates of lysine and folate for treatment of cancer. Eur J Pharm Biopharm 2014, 87:500–509.
Zhu, J, Xiong, Z, Shen, M, Shi, X. Encapsulation of doxorubicin within multifunctional gadolinium‐loaded dendrimer nanocomplexes for targeted theranostics of cancer cells. RSC Adv 2015, 5:30286–30296.
Zhu, J, Zheng, L, Wen, S, Tang, Y, Shen, M, Zhang, G, Shi, X. Targeted cancer theranostics using α‐tocopheryl succinate‐conjugated multifunctional dendrimer‐entrapped gold nanoparticles. Biomaterials 2014, 35:7635–7646.
Sunoqrot, S, Bae, JW, Jin, S‐E, Pearson, RM, Liu, Y, Hong, S. Kinetically controlled cellular interactions of polymer−polymer and polymer−liposome nanohybrid systems. Bioconjug Chem 2011, 22:466–474.
Sunoqrot, S, Bugno, J, Lantvit, D, Burdette, JE, Hong, S. Prolonged blood circulation and enhanced tumor accumulation of folate‐targeted dendrimer‐polymer hybrid nanoparticles. J Control Release 2014, 191:115–122.
Sunoqrot, S, Liu, Y, Kim, D‐H, Hong, S. In vitro evaluation of dendrimer–polymer hybrid nanoparticles on their controlled cellular targeting kinetics. Mol Pharm 2012, 10:2157–2166.
Sun, Q, Sun, X, Ma, X, Zhou, Z, Jin, E, Zhang, B, Shen, Y, Van Kirk, EA, Murdoch, WJ, Lott, JR. Integration of nanoassembly functions for an effective delivery cascade for cancer drugs. Adv Mater 2014, 26:7615–7621.
Bugno, J, Hsu, H‐J, Pearson, RM, Tam, KA, Hong, S. Size and surface charge of engineered poly(amidoamine) dendrimers modulate tumor accumulation and penetration: a model study using multicellular tumor spheroids. Mol Pharm 2016, doi:10.1021/acs.molpharmaceut.5b00946.
Mishra, MK, Kotta, K, Hali, M, Wykes, S, Gerard, HC, Hudson, AP, Whittum‐Hudson, JA, Kannan, RM. PAMAM dendrimer‐azithromycin conjugate nanodevices for the treatment of Chlamydia trachomatis infections. Nanomedicine 2011, 7:935–944.
Gajbhiye, V, Ganesh, N, Barve, J, Jain, NK. Synthesis, characterization and targeting potential of Zidovudine loaded sialic acid conjugated‐mannosylated poly (propyleneimine) dendrimers. Eur J Pharm Sci 2013, 48:668–679.
Choi, SK, Myc, A, Silpe, JE, Sumit, M, Wong, PT, McCarthy, K, Desai, AM, Thomas, TP, Kotlyar, A, Holl, MMB. Dendrimer‐based multivalent vancomycin nanoplatform for targeting the drug‐resistant bacterial surface. ACS Nano 2012, 7:214–228.
Lazniewska, J, Milowska, K, Gabryelak, T. Dendrimers—revolutionary drugs for infectious diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012, 4:469–491.
Sun, B, Slomberg, DL, Chudasama, SL, Lu, Y, Schoenfisch, MH. Nitric oxide‐releasing dendrimers as antibacterial agents. Biomacromolecules 2012, 13:3343–3354.
Lu, Y, Slomberg, DL, Shah, A, Schoenfisch, MH. Nitric oxide‐releasing amphiphilic poly(amidoamine) (PAMAM) dendrimers as antibacterial agents. Biomacromolecules 2013, 14:3589–3598.
Worley, BV, Slomberg, DL, Schoenfisch, MH. Nitric oxide‐releasing quaternary ammonium‐modified poly(amidoamine) dendrimers as dual action antibacterial agents. Bioconjug Chem 2014, 25:918–927.
Landers, JJ, Cao, Z, Lee, I, Piehler, LT, Myc, PP, Myc, A, Hamouda, T, Galecki, AT, Baker, JR. Prevention of influenza pneumonitis by sialic acid–conjugated dendritic polymers. J Infect Dis 2002, 186:1222–1230.
García‐Gallego, S, Díaz, L, Jiménez, JL, Gómez, R, de la Mata, FJ, Muñoz‐Fernández, MÁ. HIV‐1 antiviral behavior of anionic PPI metallo‐dendrimers with EDA core. Eur J Med Chem 2015, 98:139–148.
Rupp, R, Rosenthal, SL, Stanberry, LR. VivaGel™(SPL7013 Gel): A candidate dendrimer–microbicide for the prevention of HIV and HSV infection. Int J Nanomed 2007, 2:561–566.
Telwatte, S, Moore, K, Johnson, A, Tyssen, D, Sterjovski, J, Aldunate, M, Gorry, PR, Ramsland, PA, Lewis, GR, Paull, JR. Virucidal activity of the dendrimer microbicide SPL7013 against HIV‐1. Antiviral Res 2011, 90:195–199.
Chen, W, Turro, NJ, Tomalia, DA. Using ethidium bromide to probe the interactions between DNA and dendrimers. Langmuir 2000, 16:15–19.
Zhou, J, Wu, J, Hafdi, N, Behr, J‐P, Erbacher, P, Peng, L. PAMAM dendrimers for efficient siRNA delivery and potent gene silencing. Chem Commun 2006:2362–2364.
Kabanov, V, Sergeyev, V, Pyshkina, O, Zinchenko, A, Zezin, A, Joosten, J, Brackman, J, Yoshikawa, K. Interpolyelectrolyte complexes formed by DNA and astramol poly (propylene imine) dendrimers. Macromolecules 2000, 33:9587–9593.
Haensler, J, Szoka, FC Jr. Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem 1993, 4:372–379.
Zinselmeyer, BH, Mackay, SP, Schatzlein, AG, Uchegbu, IF. The lower‐generation polypropylenimine dendrimers are effective gene‐transfer agents. Pharm Res 2002, 19:960–967.
Tang, MX, Redemann, CT, Szoka, FC. In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjug Chem 1996, 7:703–714.
Posocco, P, Liu, X, Laurini, E, Marson, D, Chen, C, Liu, C, Fermeglia, M, Rocchi, P, Pricl, S, Peng, L. Impact of siRNA overhangs for dendrimer‐mediated siRNA delivery and gene silencing. Mol Pharm 2013, 10:3262–3273.
Karatasos, K, Posocco, P, Laurini, E, Pricl, S. Poly (amidoamine)‐based dendrimer/siRNA complexation studied by computer simulations: effects of pH and generation on dendrimer structure and siRNA Binding. Macromol Biosci 2012, 12:225–240.
Reyes‐Reveles, J, Sedaghat‐Herati, R, Gilley, DR, Schaeffer, AM, Ghosh, KC, Greene, TD, Gann, HE, Dowler, WA, Kramer, S, Dean, JM. mPEG‐PAMAM‐G4 nucleic acid nanocomplexes: enhanced stability, RNase protection, and activity of splice switching oligomer and poly I: C RNA. Biomacromolecules 2013, 14:4108–4115.
Sun, Y, Jiao, Y, Wang, Y, Lu, D, Yang, W. The strategy to improve gene transfection efficiency and biocompatibility of hyperbranched PAMAM with the cooperation of PEGylated hyperbranched PAMAM. Int J Pharm 2014, 465:112–119.
Arima, H, Kihara, F, Hirayama, F, Uekama, K. Enhancement of gene expression by polyamidoamine dendrimer conjugates with α‐, β‐, and γ‐cyclodextrins. Bioconjug Chem 2001, 12:476–484.
Anno, T, Higashi, T, Motoyama, K, Hirayama, F, Uekama, K, Arima, H. Possible enhancing mechanisms for gene transfer activity of glucuronylglucosyl‐β‐cyclodextrin/dendrimer conjugate. Int J Pharm 2012, 426:239–247.
Wang, M, Liu, H, Li, L, Cheng, Y. A fluorinated dendrimer achieves excellent gene transfection efficacy at extremely low nitrogen to phosphorus ratios. Nat Commun 2014, 5:3053.
Liu, H, Wang, Y, Wang, M, Xiao, J, Cheng, Y. Fluorinated poly(propylenimine) dendrimers as gene vectors. Biomaterials 2014, 35:5407–5413.
Wang, M, Cheng, Y. The effect of fluorination on the transfection efficacy of surface‐engineered dendrimers. Biomaterials 2014, 35:6603–6613.
Wood, KC, Little, SR, Langer, R, Hammond, PT. A family of hierarchically self‐assembling linear‐dendritic hybrid polymers for highly efficient targeted gene delivery. Angew Chem Int Ed 2005, 44:6704–6708.
Liu, X, Zhou, J, Yu, T, Chen, C, Cheng, Q, Sengupta, K, Huang, Y, Li, H, Liu, C, Wang, Y. Adaptive amphiphilic dendrimer‐based nanoassemblies as robust and versatile siRNA delivery systems. Angew Chem Int Ed 2014, 53:11822–11827.
Yu, T, Liu, X, Bolcato‐Bellemin, AL, Wang, Y, Liu, C, Erbacher, P, Qu, F, Rocchi, P, Behr, JP, Peng, L. An amphiphilic dendrimer for effective delivery of small interfering RNA and gene silencing in vitro and in vivo. Angew Chem Int Ed 2012, 51:8478–8484.
Tam, JP. Synthetic peptide vaccine design: synthesis and properties of a high‐density multiple antigenic peptide system. Proc Natl Acad Sci USA 1988, 85:5409–5413.
Tam, JP. Recent advances in multiple antigen peptides. J Immunol Methods 1996, 196:17–32.
Defoort, J‐P, Nardelli, B, Huang, W, Ho, DD, Tam, JP. Macromolecular assemblage in the design of a synthetic AIDS vaccine. Proc Natl Acad Sci USA 1992, 89:3879–3883.
Zhao, G, Lin, Y, Du, L, Guan, J, Sun, S, Sui, H, Kou, Z, Chan, CC, Guo, Y, Jiang, S, et al. An M2e‐based multiple antigenic peptide vaccine protects mice from lethal challenge with divergent H5N1 influenza viruses. Virol J 2010, 7:1–8.
Moreno, CA, Rodriguez, R, Oliveira, GA, Ferreira, V, Nussenzweig, RS, Castro, ZRM, Calvo‐Calle, JM, Nardin, E. Preclinical evaluation of a synthetic Plasmodium falciparum MAP malaria vaccine in Aotus monkeys and mice. Vaccine 1999, 18:89–99.
Nardin, EH, Oliveira, GA, Calvo‐Calle, JM, Castro, ZR, Nussenzweig, RS, Schmeckpeper, B, Hall, BF, Diggs, C, Bodison, S, Edelman, R. Synthetic malaria peptide vaccine elicits high levels of antibodies in vaccinees of defined HLA genotypes. J Infect Dis 2000, 182:1486–1496.
Nardin, EH, Calvo‐Calle, JM, Oliveira, GA, Nussenzweig, RS, Schneider, M, Tiercy, J‐M, Loutan, L, Hochstrasser, D, Rose, K. A totally synthetic polyoxime malaria vaccine containing Plasmodium falciparum B cell and universal T cell epitopes elicits immune responses in volunteers of diverse HLA types. J Immunol 2001, 166:481–489.
Calvo‐Calle, JM, Oliveira, GA, Watta, CO, Soverow, J, Parra‐Lopez, C, Nardin, EH. A linear peptide containing minimal T‐and B‐cell epitopes of Plasmodium falciparum circumsporozoite protein elicits protection against transgenic sporozoite challenge. Infect Immun 2006, 74:6929–6939.
Heegaard, PM, Boas, U, Sorensen, NS. Dendrimers for vaccine and immunostimulatory uses. A review. Bioconjug Chem 2009, 21:405–418.
Schuster, T, Nussbaumer, M, Baumann, P, Bruns, N, Meier, W, Car, A. Polymeric particulates for subunit vaccine delivery. In: Foged C, Rades T, Perrie Y, Hook S, eds. Subunit Vaccine Delivery. New York: Springer; 2015, 181–201.
Niederhafner, P, Reiniš, M, Šebestík, J, Ježek, J. Glycopeptide dendrimers, part III—a review: use of glycopeptide dendrimers in immunotherapy and diagnosis of cancer and viral diseases. J Pept Sci 2008, 14:556–587.
Lo‐Man, R, Vichier‐Guerre, S, Bay, S, Dériaud, E, Cantacuzène, D, Leclerc, C. Anti‐tumor immunity provided by a synthetic multiple antigenic glycopeptide displaying a tri‐Tn glycotope. J Immunol 2001, 166:2849–2854.
Ponchel, G, Irache, J‐M. Specific and non‐specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv Drug Deliv Rev 1998, 34:191–219.
D`Emanuele, A, Jevprasesphant, R, Penny, J, Attwood, D. The use of a dendrimer‐propranolol prodrug to bypass efflux transporters and enhance oral bioavailability. J Control Release 2004, 95:447–453.
Najlah, M, Freeman, S, Attwood, D, D`Emanuele, A. In vitro evaluation of dendrimer prodrugs for oral drug delivery. Int J Pharm 2007, 336:183–190.
Goldberg, DS, Vijayalakshmi, N, Swaan, PW, Ghandehari, H. G3.5 PAMAM dendrimers enhance transepithelial transport of SN38 while minimizing gastrointestinal toxicity. J Control Release 2011, 150:318–325.
Liu, Y, Chiu, GNC. Dual‐functionalized PAMAM dendrimers with improved P‐glycoprotein inhibition and tight junction modulating effect. Biomacromolecules 2013, 14:4226–4235.
Jevprasesphant, R, Penny, J, Attwood, D, McKeown, NB, D`Emanuele, A. Engineering of dendrimer surfaces to enhance transepithelial transport and reduce cytotoxicity. Pharm Res 2003, 20:1543–1550.
Sadekar, S, Thiagarajan, G, Bartlett, K, Hubbard, D, Ray, A, McGill, L, Ghandehari, H. Poly (amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin. Int J Pharm 2013, 456:175–185.
Chauhan, AS, Sridevi, S, Chalasani, KB, Jain, AK, Jain, SK, Jain, NK, Diwan, PV. Dendrimer‐mediated transdermal delivery: enhanced bioavailability of indomethacin. J Control Release 2003, 90:335–343.
Yiyun, C, Na, M, Tongwen, X, Rongqiang, F, Xueyuan, W, Xiaomin, W, Longping, W. Transdermal delivery of nonsteroidal anti‐inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. J Pharm Sci 2007, 96:595–602.
Venuganti, VVK, Perumal, OP. Effect of poly (amidoamine)(PAMAM) dendrimer on skin permeation of 5‐fluorouracil. Int J Pharm 2008, 361:230–238.
Venuganti, VVK, Perumal, OP. Poly (amidoamine) dendrimers as skin penetration enhancers: influence of charge, generation, and concentration. J Pharm Sci 2009, 98:2345–2356.
Duncan, R, Izzo, L. Dendrimer biocompatibility and toxicity. Adv Drug Deliv Rev 2005, 57:2215–2237.
Jain, K, Kesharwani, P, Gupta, U, Jain, N. Dendrimer toxicity: let`s meet the challenge. Int J Pharm 2010, 394:122–142.
Stasko, NA, Johnson, CB, Schoenfisch, MH, Johnson, TA, Holmuhamedov, EL. Cytotoxicity of polypropylenimine dendrimer conjugates on cultured endothelial cells. Biomacromolecules 2007, 8:3853–3859.
Chen, H‐T, Neerman, MF, Parrish, AR, Simanek, EE. Cytotoxicity, hemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery. J Am Chem Soc 2004, 126:10044–10048.
Hong, S, Rattan, R, Majoros, IJ, Mullen, DG, Peters, JL, Shi, X, Bielinska, AU, Blanco, L, Orr, BG, Baker, JR Jr. The role of ganglioside GM1 in cellular internalization mechanisms of poly (amidoamine) dendrimers. Bioconjug Chem 2009, 20:1503–1513.
Pearson, RM, Patra, N, Hsu, H‐J, Uddin, S, Král, P, Hong, S. Positively charged dendron micelles display negligible cellular interactions. ACS Macro Lett 2012, 2:77–81.
Kaminskas, LM, Boyd, BJ, Karellas, P, Henderson, SA, Giannis, MP, Krippner, GY, Porter, CJ. Impact of surface derivatization of poly‐L‐lysine dendrimers with anionic arylsulfonate or succinate groups on intravenous pharmacokinetics and disposition. Mol Pharm 2007, 4:949–961.
Owens, DE, Peppas, NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 2006, 307:93–102.
Kojima, C, Regino, C, Umeda, Y, Kobayashi, H, Kono, K. Influence of dendrimer generation and polyethylene glycol length on the biodistribution of PEGylated dendrimers. Int J Pharm 2010, 383:293–296.
Kaminskas, LM, Boyd, BJ, Karellas, P, Krippner, GY, Lessene, R, Kelly, B, Porter, CJ. The impact of molecular weight and PEG chain length on the systemic pharmacokinetics of PEGylated poly l‐lysine dendrimers. Mol Pharm 2008, 5:449–463.
Wong, C‐H, Zimmerman, SC. Orthogonality in organic, polymer, and supramolecular chemistry: from Merrifield to click chemistry. Chem Commun 2013, 49:1679–1695.
Zeng, F, Zimmerman, SC. Rapid synthesis of dendrimers by an orthogonal coupling strategy. J Am Chem Soc 1996, 118:5326–5327.
Kolb, HC, Finn, M, Sharpless, KB. Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed 2001, 40:2004–2021.
Wu, P, Feldman, AK, Nugent, AK, Hawker, CJ, Scheel, A, Voit, B, Pyun, J, Frechet, JM, Sharpless, KB, Fokin, VV. Efficiency and fidelity in a click‐chemistry route to triazole dendrimers by the copper (I)‐catalyzed ligation of azides and alkynes. Angew Chem Int Ed 2004, 43:3928–3932.

Further Reading

Blanco, E, Shen, H, Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol 2015, 33:941–951.
Couvreur, P. Nanoparticles in drug delivery: past, present and future. Adv Drug Deliv Rev 2013, 65:21–23.
Prabhakar, U, Maeda, H, Jain, RK, Sevick‐Muraca, EM, Zamboni, W, Farokhzad, OC, Barry, ST, Gabizon, A, Grodzinski, P, Blakey, DC. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 2013, 73:2412–2417.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts