Vol 5, No 3 (2018) > Mini Review Article >

Synthesis of Polymer-Drug Conjugates Using Natural Polymer: What, Why and How?

Erny Sagita , Rezi Riadhi Syahdi , Arif Arrahman



For years, natural polymers have played a significant role in pharmaceutical field due to their biocompatibility and biodegradability. In Indonesia, most research in natural polymers focus on application of the polymers as inert pharmaceutical excipients or as drug matrix in micro- and nano- particle. Meanwhile, research about polymers in the world (mostly synthetic polymers) have been progressed to advanced drug delivery system. In this system, the polymer can act as either pharmacologically active molecules, or sophisticated carrier in targeted prodrug delivery system. The latter is called polymer-drug conjugates, a system where the drugs are covalently attached to a polymeric carrier, rather than simply entrapped in polymer matrix. Natural polymers have been one of the materials to use for the carrier due to their biocompatibility and biodegradability. This review article emphasizes the opportunity, challenges and strategies to use natural polymers as carrier in polymer-drug conjugates. Moreover, we also discuss some aspects in regards of the synthesis and analysis, to give some perspectives and encouragement for the Indonesian researcher who are interested in exploring this research field.

Keywords: natural polymer; polymer; polymer-drug conjugates; polymer therapeutic

Published at: Vol 5, No 3 (2018) pages: 97-115

DOI: 10.7454/psr.v5i3.4376

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Adliani, N., & Bangun, H. (2016). Preparation and Evaluation of Floating-Mucoadhesive Alginate Beads as Gastroretentive Drug Delivery System of Antacids. International Journal of PharmTech Research, 9(5), 212–222.

Agilent. (2015). An Introduction to Gel Permeation Chromatography and Size Exclusion Chromatography. Agilent Technologies Inc.

Ahn, S., Lee, I.-H., Lee, E., Kim, H., Kim, Y.-C., & Jon, S. (2013). Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan. Journal of Controlled Release, 170, 226–232.

Aminlashgari, N., & Hakkarainen, M. (2011). Emerging Mass Spectrometric Tools for Analysis of Polymers and Polymer Additives. In M. Hakkarainen (Ed.), Mass Spectrometry of Polymers – New Techniques (pp. 1–37). Berlin: Springer.

Ariani, L., Surini, S., & Hayun. (2016). Formulation of diclofenac sodium sustained release tablet using coprocessed excipients of crosslinked amylose–xanthan gum as matrix. International Journal of Pharmacy and Pharmaceutical Research, 8(6), 151–155.

Arianto, A., Bangun, H., Harahap, U., & Ilyas, S. (2015). Effect of Alginate Chitosan Ratio on the Swelling, Mucoadhesive, and Release of Ranitidine from Spherical Matrices of Alginate-Chitosan. International Journal of PharmTech Research (Vol. 8).

Aryal, S., Hu, C.-M. J., & Zhang, L. (2010). Polymer−Cisplatin Conjugate Nanoparticles for Acid-Responsive Drug Delivery. ACS Nano, 4(1), 251–258.

Atkinson, S. P., Andreu, Z., & Vicent, M. J. (2018). Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment. Jornal of Personalized Medicine, 8(1).

Balazs, E. A., Laurent, T. C., & Jeanloz, R. W. (1985). Nomenclature of hyaluronic acid. Biochem. J., 235(1934), 903.

Barthel, B. L., Rudnicki, D. L., Kirby, T. P., Colvin, S. M., Burkhart, D. J., & Koch, T. H. (2012). Synthesis and Biological Characterization of Protease-Activated Prodrugs of Doxazolidine. Journal of Medicinal Chemistry, 55, 6595–6607.

Baumann, M. G. D. and, & Conner, A. H. (1994). Carbohydrate Polymers as Adhesives. Handbook of Adhesive Technology, 299–313.

BeMiller, J. N. (2003). Dextrin. In Encyclopedia of Food Sciences and Nutrition (pp. 1772–1773). Elsevier Science.

Bender, H., Lehmann, J., & Wallenfels, K. (1959). Pullulan, ein extracelluläres Glucan von Pullularia pullulans. Biochim. Biophys. Acta, 36(2), 309–316.

Budianto, E., Al-Shidqi, M. F., & Cahyana, A. H. (2017). Effects of pore forming agents on chitosan-graft-poly(N-vinylpyrrolidone) hydrogel properties for use as a matrix for floating drug delivery. IOP Conf. Series: Materials Science and Engineering, 223.

Chang, M., Zhang, F., Wei, T., Zuo, T., Guan, Y., Lin, G., & Shao, W. (2016). Smart linkers in polymer-drug conjugates for tumor-targeted delivery. Journal of Drug Targeting, 24(6), 475–491.

Cheewatanakornkool, K., Niratisai, S., Manchun, S., Dass, C. R., & Sriamornsak, P. (2017). Characterization and in vitro release studies of oral microbeads containing thiolated pectin–doxorubicin conjugates for colorectal cancer treatment. Asian Journal of Pharmaceutical Science, 12(6), 509–520.

Chen, W., Shi, Y., Feng, H., Du, M., Zhang, J. Z., Hu, J., & Yang, D. (2012). Preparation of Copolymer Paclitaxel Covalently Linked via a Disulfide Bond and Its Application on Controlled Drug Delivery. The Journal of Physical Chemistry, 116, 9231–9237.

Cheng, K. C., Demirci, A., & Catchmark, J. M. (2011). Pullulan: Biosynthesis, production, and applications. Appl. Microbiol. Biotechnol., 92(1), 29–44.

Chiellini, F., Piras, A. M., Errico, C., & Chiellini, E. (2008). Micro/nanostructured polymeric systems for biomedical and pharmaceutical applications. Nanomedicine (London, England), 3(3), 367–393.

Choi, H. S., Liu, W., Misra, P., Tanaka, E., Zimmer, J. P., Bawendi, M. G., & Frangioni, J. V. (2007). Renal clearance of quantum dots. Nature Biotechnology, 25(10), 1165–1170.

Cowman, M. K., & Matsuoka, S. (2005). Experimental approaches to hyaluronan structure. Carbohydrate Research, 340(5), 791–809.

Crecelius, A. C., Vitz, J., & Schubert, U. S. (2014). Mass spectrometric imaging of synthetic polymers. Analytica Chimica Acta, 808, 10–17.

Crotty, S., Gerişlioğlu, S., Endres, K. J., Wesdemiotis, C., & Schubert, U. S. (2016). Polymer architectures via mass spectrometry and hyphenated techniques: A review. Analytica Chimica Acta, 932, 1–21.

Danhier, F. (2016). To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine? Journal of Controlled Release, 244, 108–121.

Danhier, F., Feron, O., & Préat, V. (2010). To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of Controlled Release, 148(2), 135–146.

Danson, S., Ferry, D., Alakhov, V., Margison, J., Kerr, D., Jowle, D., …

Ranson, M. (2004). Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer. British Journal of Cancer, 90, 2085–2091.

Dessy, R., Siahaan, N., & Bangun, H. (2018). In Vitro and In Vivo Evaluation of Floating Gastroretentive Drug Delivery System of Cimetidine Using Hard Alginate Capsules. Asian Journal of Pharmaceutical and Clinical Research, 11(6).

DiCiccio, J. E., & Steinberg, B. E. (2011). Lysosomal pH and analysis of the counter ion pathways that support acidification. The Journal of General Physiology, 137(4), 385–390.

dos Santos, M. A., & Grenha, A. (2015). Polysaccharide Nanoparticles for Protein and Peptide Delivery: Exploring Less-Known Materials. Advances in Protein Chemistry and Structural Biology, 98, 223–261.

Du, J.-Z., Du, X.-J., Mao, C.-Q., & Wang, J. (2011). Tailor-Made Dual pH-Sensitive Polymer-Doxorubicin Nanoparticles for Efficient Anticancer Drug Delivery. Journal of the American Chemical Society, 133, 17560–17563.

Duncan, R. (2014). Polymer therapeutics: Top 10 selling pharmaceuticals - What next? Journal of Controlled Release, 190, 371–380.

Duncan, R. (2017). Polymer therapeutics at a crossroads? Finding the path for improved translation in the twenty-first century. Journal of Drug Targeting, 25(9–10), 759–780.

Duncan, R., & Vicent, M. J. (2013). Polymer therapeutics-prospects for 21st century: The end of the beginning. Advanced Drug Delivery Reviews, 65, 60–70.

Edvinsson, T. (2002). On the Size and Shape of Polymers and Polymer Complexes A Computational and Light Scattering Study. Acta Universitatis Upsaliensis.

Elgart, A., Farber, S., Domb, A. J., Polacheck, I., & Hoffman, A. (2010). Polysaccharide Pharmacokinetics: Amphotericin B Arabinogalactan Conjugate-A Drug Delivery System or a New Pharmaceutical Entity? Biomacromolecules, 11, 1972–1977.

Emeje, A. P., & Anwunobi, M. O. (2011). Recent Applications of Natural Polymers in Nanodrug Delivery. Journal of Nanomedicine & Nanotechnology, s4(01).

Ernsting, M. J., Tang, W.-L., MacCallum, N. W., & Li, S.-D. (2012). Preclinical pharmacokinetic, biodistribution, and anti-cancer efficacy studies of a docetaxel-carboxymethylcellulose nanoparticle in mouse models. Biomaterials, 33(5), 1445–1454.

Etrych, T., Milada, S., Starovoytova, L., Blanka, R., & Ulbrich, K. (2010). HPMA Copolymer Conjugates of Paclitaxel and Docetaxel with pH-Controlled Drug Release. Mocelular Pharmaceutics, 7(4), 1015–1026.

Fallacara, A., Baldini, E., Manfredini, S., & Vertuani, S. (2018). Hyaluronic acid in the third millennium. Polymers, 10(7).

Fang, J., Iyer, A. K., Seki, T., Nakamura, H., Greish, K., & Maeda, H. (2009). SMA–copolymer conjugate of AHPP: A polymeric inhibitor of xanthine oxidase with potential antihypertensive effect. Journal of Controlled Release, 135(3), 211–217.

Fang, J., Nakamura, H., & Maeda, H. (2011). The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Advanced Drug Delivery Reviews, 63(3), 136–151.

Favier, A., Charreyre, M. T., & Pichot, C. (2004). A detailed kinetic study of the RAFT polymerization of a bi-substituted acrylamide derivative: Influence of experimental parameters. Polymer, 45(26), 8661–8674.

Ferguson, E. L., Azzopardi, E., Roberts, J. L., Walsh, T. R., & Thomas, D. W. (2014). Dextrin−Colistin Conjugates as a Model Bioresponsive Treatment for Multidrug Resistant Bacterial Infections. Molecular Pharmaceutics, 11, 4437–4447.

Ferguson, E. L., & Duncan, R. (2009). Dextrin-Phospholipase A 2 : Synthesis and Evaluation as a Bioresponsive Anticancer Conjugate. Biomacromolecules, 10, 1358–1364.

Flutto, L. (2003). PECTIN | Food Use. In B. Caballero (Ed.), Encyclopedia of Food Sciences and Nutrition (Second Edition) (Second Edi, pp. 4449–4456). Oxford: Academic Press.

Forrest, M. L., Yá, J. A., Remsberg, C. M., Ohgami, Y., Kwon, G. S., &

Davies, N. M. (2008). Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(e-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity. Pharmaceutical Research, 25(1)

Gamcsik, M. P., Kasibhatla, M. S., Teeter, S. D., & Colvin, O. M. (2012). Glutathione levels in human tumors. Biomarkers, 17(8), 671–691.

Gawkowska, D., Cybulska, J., & Zdunek, A. (2018). Structure-related gelling of pectins and linking with other natural compounds: A review. Polymers, 10(7).

Grenier, P., de Oliveira Viana, I. M., Lima, E. M., & Bertrand, N. (2018). Anti-polyethylene glycol antibodies alter the protein corona deposited on nanoparticles and the physiological pathways regulating their fate in vivo. Journal of Controlled Release, 287(August), 121–131.

Gunaseelan, S., Debrah, O., Wan, L., Leibowitz, M. J., Rabson, A. B., Stein, S., & Sinko, P. J. (2004). Synthesis of Poly(ethylene glycol)-Based Saquinavir Prodrug Conjugates and Assessment of Release and Anti-HIV-1 Bioactivity Using a Novel Protease Inhibition Assay. Bioconjugate Chemistry, 15, 1322–1333.

Halid, N. H. A., Sutriyo, Mutalib, A., Pujiyanto, A., & Gunawan, A. H. (2017). Clearance profile of radioactive gold nanoparticle ( 198 Au ) conjugates- poliamidoamin generation 4-nimotuzumab ; potential radio-pharmaceutical theranostic agent Profil klirens konjugat nanopartikel emas radioaktif ( 198 Au ) -poliamidoamin generasi 4-n. Pharmaciana, 7(2), 239–248.

Halim, A., Arianti, O., & Umar, S. (2011). Mikroenkapsulasi Parasetamol dengan Metode Penguapan Pelarut menggunakan Polimer Natrium Karboksimetil ( NaCMC ). Jurnal Farmasi Higea, 3(2), 84–93.

Hamed, I., Özogul, F., & Regenstein, J. M. (2016). Industrial applications of crustacean by-products (chitin, chitosan, and chitooligosaccharides): A review. Trends in Food Science and Technology, 48, 40–50.

Hardwicke, J., Ferguson, E. L., Moseley, R., Stephens, P., Thomas, D. W., & Duncan, R. (2008). Dextrin-rhEGF conjugates as bioresponsive nanomedicines for wound repair. Journal of Controlled Release, 130, 275–283

Hariyadi, D. M., Hendradi, E., Purwanti, T., Diba Genie Permana Fadil, F., & Nourmasari Ramadani, C. (2014). Effect of cross linking agent and polymer on the characteristics of ovalbumin loaded alginate microspheres. International Journal of Pharmacy and Pharmaceutical Sciences, 6(4).

Hatada, K., & Kitayama, T. (2004). NMR Spectroscopy of Polymers. Springer-Verlag Berlin Heidelberg.

He, C., Hu, Y., Yin, L., Tang, C., & Yin, C. (2010). Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials, 31(13), 3657–3666.

Hermanson, G. T. (2013). Bioconjugate Chemistry (ACS. Bioconjugate Chemistry. London: Elsevier Inc.

Homma, A., Sato, H., Tamura, T., Okamachi, A., Emura, T., Ishizawa, T., …Suzuki, R. (2010). Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis. Bioorganic & Medicinal Chemistry, 18, 1062–1075.

Hreczuk-Hirst, D., Chicco, D., German, L., & Duncan, R. (2001). Dextrins as potential carriers for drug targeting: tailored rates of dextrin degradation by introduction of pendant groups. International Journal of Pharmaceutics, 230, 57–66.

Hu, X., Li, J., Lin, W., Huang, Y., Jing, X., & Xie, Z. (2014). Paclitaxel prodrug nanoparticles combining chemical conjugation and physical entrapment for enhanced antitumor efficacy. RSC Advances, 4(72), 38405–38411.

Human Metabolomic Database. (2018). HMDB0003402.

Islam, S., Bhuiyan, M. A. R., & Islam, M. N. (2017). Chitin and Chitosan: Structure, Properties and Applications in Biomedical Engineering. Journal of Polymers and the Environment, 25(3), 854–866.

Izunobi, J. U., & Higginbotham, C. L. (2011). Polymer Molecular Weight Analysis by 1HNMR Spectroscopy. J. Chem. Educ, 88, 1098–1104.

Kumar, D., Saini, N., Pandit, V., & Ali, S. (2012). An Insight To Pullulan: A Biopolymer in Pharmaceutical Approaches. International Journal of Basic and Applied Sciences, 1(3).

Kurtoglu, Y. E., Mishra, M. K., Kannan, S., & Kannan, R. M. (2010). Drug release characteristics of PAMAM dendrimer–drug conjugates with different linkers. International Journal of Pharmaceutics, 384(1–2), 189–194.

Kusmardi, K., Ramadhan Tamzir, A., Widiasari, S., & Estuningtyas, A. (2018). Suppression effect of mahkota dewa (Phaleria macrocarpa) leaf extract in chitosan nanoparticles on the small intestine of dextran sulfate sodium-induced mice: focus on mitosis and hyperplasia. Asian Journal of Pharmaceutical and Clinical Research, 11(6).

Lammers, T., Subr, V., Ulbrich, K., Peschke, P., Huber, P. E., Hennink, W. E., & Storm, G. (2009). Simultaneous delivery of doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers. Biomaterials, 30, 3466–3475.

Lee, E., Lee, J., Lee, I.-H., Yu, M., Kim, H., Chae, S. Y., & Jon, S. (2008). Conjugated Chitosan as a Novel Platform for Oral Delivery of Paclitaxel. Journal of Medicinal Chemistry, 51, 6442–6449.

Lee, H., Lee, K., & Park, T. G. (2008). Hyaluronic Acid-Paclitaxel Conjugate Micelles: Synthesis, Characterization, and Antitumor Activity. Bioconjugate Chemistry, 19, 1319–1325.

Li, C., Yu, D. F., Newman, R. A., Cabral, F., Stephens, L. C., Hunter, N., … Wallace, S. (1998). Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid) paclitaxel conjugate. Cancer Research, 58(11), 2404–2409.

Li, W., Li, Z., Jing, F., Deng, Y., Wei, L., Liao, P., … Lei, H. (2008). Synthesis and evaluation of Gd-DTPA-labeled arabinogalactans as potential MRI contrast agents. Carbohydrate Research, 343, 685–694.

Li, X.-Q., Wen, H.-Y., Dong, H.-Q., Xue, W.-M., Pauletti, G. M., Cai, X.-J., … Li, Y.-Y. (2011). Self-assembling nanomicelles of a novel camptothecin prodrug engineered with a redox-responsive release mechanismw. Chemical Communications, 47, 8647–8649.

Liang, L., Lin, S.-W., Dai, W., Lu, J.-K., Yang, T.-Y., Xiang, Y., … Zhang, Q. (2012). Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity. Journal of Controlled Release, 160(3), 618–629.

Luo, K., Yang, J., Kope Ckov, P., & Rich Kope, J. (2011). Biodegradable Multiblock Poly[N-(2-hydroxypropyl)methacrylamide] via Reversible Addition-Fragmentation Chain Transfer Polymerization and Click Chemistry. Macromolecules, 44, 2481–2488.

Lutjen, A. B., Quirk, M. A., Barbera, A. M., & Kolonko, E. M. (2018). Synthesis of (E)-cinnamyl ester derivatives via a greener Steglich esterification. Bioorganic & Medicinal Chemistry.

Lutz, R., Aserin, A., Wicker, L., & Garti, N. (2009). Structure and physical properties of pectins with block-wise distribution of carboxylic acid groups. Food Hydrocolloids, 23(3), 786–794.

Lv, S., Tang, Z., Zhang, D., Song, W., Li, M., Lin, J., … Chen, X. (2014). Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel. Journal of Controlled Release, 194, 220–227.

Maeda, H. (2015). Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Advanced Drug Delivery Reviews, 91, 3–6.

Manju, S., & Sreenivasan, K. (2011). Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability. Journal of Colloid and Interface Science, 359, 318–325.

Martien, R., Sa’adah, N., & Saifullah, T. N. S. (2016). Formulation and characterization insulin nanoparticle using low molecular weight chitosan and pectin polymers with ionic gelation method. International Journal of Pharmaceutical and Clinical Research, 8(5), 500–506.

Martin, L., Gody, G., & Perrier, S. (2015). Preparation of complex multiblock copolymers via aqueous RAFT polymerization at room temperature. Polymer Chemistry, 6(27), 4875–4886.

Mikhailenko, M. A., Shakhtshneider, T. P., Eltsov, I. V, Kozlov, A. S., Kuznetsova, S. A., Karacharov, A. A., & Boldyrev, V. V. (2016). Supramolecular architecture of betulin diacetate complexes with arabinogalactan from Larix sibirica. Carbohydrate Polymers, 138, 1–7.

Mizrahy, S., & Peer, D. (2012). Polysaccharides as building blocks for nanotherapeutics. Chemical Society Reviews, 41(7), 2623–2640.

Mohnen, D. (2008). Pectin structure and biosynthesis. Current Opinion in Plant Biology, 11(3), 266–277.

Morris, G., Kok, S., Harding, S., & Adams, G. (2010). Polysaccharide drug delivery systems based on pectin and chitosan. Biotechnology & Genetic Engineering Reviews, 27, 257–284.

Muangsiri, W., & Kirsch, L. E. (2006). The protein-binding and drug release properties of macromolecular conjugates containing daptomycin and dextran. International Journal of Pharmaceutics, 315(1–2), 30–43.

Namazi, H., Fathi, F., & Heydari, A. (2012). Nanoparticles Based on Modified Polysaccharides. International Journal of Biological Macromolecules, (May), 150–184.

Necas, J., Bartosikova, L., Brauner, P., & Kolar, J. (2008). Hyaluronic acid (hyaluronan): A review. Veterinarni Medicina, 53(8), 397–411.

Nishiyama, N. (2007). Nanomedicine: Nanocarriers shape up for long life. Nature Nanotechnology, 2(4), 203–204.

Paine, M. R. L., Barker, P. J., & Blanksby, S. J. (2014). Ambient ionisation mass spectrometry for the characterisation of polymers and polymer additives: A review. Analytica Chimica Acta, 808, 70–82.

Pang, X., Jiang, Y., Xiao, Q., Leung, A. W., Hua, H., & Xu, C. (2016). pH-responsive polymer–drug conjugates: Design and progress. Journal of Controlled Release, 222, 116–129.

Park, J. K., & Khan, T. (2009). 21 - Other microbial polysaccharides: pullulan, scleroglucan, elsinan, levan, alternant, dextran. In G. O. Phillips & P. A.

Williams (Eds.), Handbook of Hydrocolloids (Second Edition) (Second Edi, pp. 592–614). Woodhead Publishing.

Paulsen, B. S., & Barsett, H. (2005). Bioactive Pectic Polysaccharides. Advance Polymer Science, 186, 69–101.

Pertiwi, D., Martien, R., Sismindari, & Ismail, H. (2018). Formulation of nanoparticles ribosome inactivating proteins from Mirabilis jalapa L. (RIP MJ) conjugated AntiEpCAM antibody using low chain chitosan-pectin and cytotoxic activity against breast cancer cell line. Pakistan Journal of Pharmaceutical Sciences, 31(2), 379–384.

Pinhassi, R. I., Assaraf, Y. G., Farber, S., Stark, M., Ickowicz, D., Drori, S., …

Livney, Y. D. (2010). Arabinogalactan-Folic Acid-Drug Conjugate for Targeted Delivery and Target-Activated Release of Anticancer Drugs to Folate Receptor-Overexpressing Cells. Biomacromolecules, 11, 294–303.

Putri, K. S. S., Sulistomo, B., & Surini, S. (2017). Kompleks Polielektrolit Kitosan-Xanthan sebagai Matriks Sediaan Mukoadhesif Chitosan-Xanthan Polyelectrolyte Complex as Matrix of Mucoadhesive Dosage Form Abstrak. Pharmaceutical Sciences and Research, 4(1), 1–12.

Rahmania, H., Mutalib, A., Ramli, M., & Levita, J. (2015). Synthesis and stability test of radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab as SPECT-MRI molecular imaging agent for diagnosis of HER-2 positive breast cancer. Journal of Radiation Research and Applied Sciences, 8(1), 91–99.

Ringsdorf, H. (1975). Structure and properties of pharmacologically active polymers. Journal of Polymer Science: Polymer Symposia, 51, 135–153.

Sagita, E., Djajadisastra, J., & Mutalib, A. (2016). Cytotoxicity Enhancement of Doxorubicin in Conjugation with PAMAM G4.5 Dendrimer Containing Gold Nanoparticles. International Journal of PharmTech Research, 9(6), 348–356.

Saranya, N., Moorthi, A., Saravanan, S., Pandima Devi, M., & Selvamurugan, N. (2010). Chitosan and its derivatives for gene delivery. International Journal of Biological Macromolecules, 48, 234–238.

Sarrut, M., Crétier, G., & Heinisch, S. (2014). Theoretical and practical interest in UHPLC technology for 2D-LC. TrAC - Trends in Analytical Chemistry, 63, 104–112.

Scomparin, A., Salmaso, S., Bersani, S., Satchi-Fainaro, R., & Caliceti, P. (2011). Novel folated and non-folated pullulan bioconjugates for anticancer drug delivery. European Journal of Pharmaceutical Sciences, 42, 547–558.

Singh, R. S., Kaur, N., Rana, V., & Kennedy, J. F. (2017). Pullulan: A novel molecule for biomedical applications. Carbohydrate Polymers, 171, 102–121.

Šírová, M., Strohalm, J., Chytil, P., Lidický, O., Tomala, J., Říhová, B., &

Etrych, T. (2017). The structure of polymer carriers controls the efficacy of the experimental combination treatment of tumors with HPMA copolymer conjugates carrying doxorubicin and docetaxel. Journal of Controlled Release, 246, 1–11.

Song, Y., Onishi, H., & Naai, T. (1992). Synthesis and Drug-Release Characteristics of the Conjugates of Mitomycin C with N-Succinyl-chitosan and Carboxymethyl-chitin. Chemical and Pharmaceutical Bulletin, 40(10), 2882–2825.

Srinivasan, S., Manchanda, R., Fernandez-Fernandez, A., Lei, T., & Mcgoron, A. J. (2013). Near-infrared fluorescing IR820-chitosan conjugate for multifunctional cancer theranostic applications. Journal of Photochemistry and Photobiology B: Biology, 119, 52–59.

Stepto, R. F. T. (2010). Dispersity in polymer science (iupac recommendation 2009) international union of pure and applied chemistry, polymer division, sub-committee on polymer terminology. Polymer International, 59(1), 23–24.

Su, Y., Hu, Y., Du, Y., Huang, X., He, J., You, J., … Hu, F. (2015). Redox-Responsive Polymer−Drug Conjugates Based on Doxorubicin and Chitosan Oligosaccharide-g-stearic Acid for Cancer Therapy. Molecular Pharmaceutics, 12, 1193–1202.

Surini, S., Nizma, N., & Azizahwati, A. (2017). Enzymatic Degradation of Cross-Linked Excipient MAtrix of Co-Processed Xanthan Gum-Amylose and Dissolution Profile of Diclofenac Sodium Tablet. International Journal of Applied Pharmaceutics, 9(Suppl 1).

Surini, S., Wati, D. R., & Syahdi, R. R. (2018). Preparation and characterization of cross-linked excipient of coprocessed xanthan gum-acacia gum as matrix for sustained release tablets. AIP Conference Proceedings, 1933.

Svens, C., & Rodhe, P. (2013). Chapter 33 - Intravascular Volume Replacement Therapy. In Physiology and Pharmacology for Anesthesia (pp. 574–592).

Tang, H., Zhang, J., Tang, J., Shen, Y., Guo, W., Zhou, M., … Yu, Q. (2018). Tumor Specific and Renal Excretable Star-like Triblock Polymer− Doxorubicin Conjugates for Safe and Efficient Anticancer Therapy. Biomacromolecules, 19, 2849–2862.

Tang, X.-H., Xie, P., Ding, Y., Chu, L.-Y., Hou, J.-P., Yang, J.-L., … Xie, Y.-M. (2010). Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin-adriamycin conjugate. Bioorganic & Medicinal Chemistry, 18, 1599–1609.

Trathnigg, B. (1995). Determination of MWD and chemical composition of polymers by chromatographic techniques. Progress in Polymer Science, 20, 615–650.

Trinetta, V., & Cutter, C. N. (2016). Chapter 30 - Pullulan: A Suitable Biopolymer for Antimicrobial Food Packaging Applications. In J. Barros-Velázquez (Ed.), Antimicrobial Food Packaging (pp. 385–397). San Diego: Academic Press.

Valeur, E., & Bradley, M. (2009). Amide bond formation: Beyond the myth of coupling reagents. Chemical Society Reviews, 38(2), 606–631.

Varshosaz, J., Emami, J., Ahmadi, F., Tavakoli, N., Minaiyan, M., Fassihi, A., … Dorkoosh, F. (2011). Preparation of budesonide-dextran conjugates using glutarate spacer as a colon-targeted drug delivery system: In vitro/in vivo evaluation in induced ulcerative colitis. Journal of Drug Targeting, 19(2), 140–153.

Vasey, P. A., Kaye, S. B., Morrison, R., Twelves, C., Wilson, P., Duncan, R., … Frigerio, E. (1999). Phase I Clinical and Pharmacokinetic Study of PK1 [N-(2- Hydroxypropyl) methacrylamide Copolymer Doxorubicin]: First Member of a New Class of Chemotherapeutic. Clinical Cancer Research, 5(January), 83–94.

Verhoef, J. J. F., & Anchordoquy, T. J. (2013). Questioning the use of PEGylation for drug delivery. Drug Delivery and Translational Research, 3(6), 499–503.

Vicent, M. J., & Duncan, R. (2006). Polymer conjugates: Nanosized medicines for treating cancer. Trends in Biotechnology, 24(1), 39–47

Vicent, M. J., Greco, F., Nicholson, R. I., Paul, A., Griffiths, P. C., & Duncan, R. (2005). Polymer Therapeutics Designed for a Combination Therapy of Hormone-Dependent Cancer. Angewandte Chemie International Edition, 44(26), 4061–4066.

Vittorio, O., Cirillo, G., Iemma, F., Di Turi, G., Jacchetti, E., Curcio, M., … Picci, N. (2012). Dextran-Catechin Conjugate: A Potential Treatment Against the Pancreatic Ductal Adenocarcinoma. Pharmaceutical Research, 29, 2601–2614.

Wang, F. C. Y. (1999). Polymer analysis by pyrolysis gas chromatography. Journal of Chromatography A, 843(1–2), 413–423.

Wishart, D. S., Feunang, Y. D., Marcu, A., Guo, A. C., Liang, K., Vázquez-Fresno, R., … Scalbert, A. (2018). HMDB 4.0: The human metabolome database for 2018. Nucleic Acids Research, 46(D1), D608–D617.

Wong, P. T., & Choi, S. K. (2015). Mechanisms of Drug Release in Nanotherapeutic Delivery Systems. Chemical Reviews, 115(9), 3388–3432.

Yapo, B. M. (2011). Pectic substances: From simple pectic polysaccharides to complex pectins-A new hypothetical model. Carbohydrate Polymers, 86, 373–385.

Yim, H., Yang, S.-G., Sun Jeon, Y., Suh Park, I., Kim, M., Haeng Lee, D., … Na, K. (2011). The performance of gadolinium diethylene triamine pentaacetate-pullulan hepatocyte-specific T1 contrast agent for MRI. Biomaterials, 32, 5187–5194.

Yin, S., Huai, J., Chen, X., Yang, Y., Zhang, X., Gan, Y., … Li, J. (2015). Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid. Acta Biomaterialia, 26, 274–285.

Zhang, H., Li, F., Yi, J., Gu, C., Fan, L., Qiao, Y., … Wu, H. (2011). Folate-decorated maleilated pullulan-doxorubicin conjugate for active tumor-targeted drug delivery. European Journal of Pharmaceutical Sciences, 42, 517–526

Zhang, R., Yang, J., Sima, M., Zhou, Y., & Kopecek, J. (2014). Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Proceedings of the National Academy of Sciences, 111(33), 12181–12186.

Zhao, D., Zhang, H., Yang, S., He, W., & Luan, Y. (2016). Redox-sensitive mPEG-SS-PTX/TPGS mixed micelles: An efficient drug delivery system for overcoming multidrug resistance. International Journal of Pharmaceutics, 515, 281–292.

Zhao, Y., & Tu, Y. (2013). Introduction on a kind of environmental biological materials---dextrins. Advanced Materials Research, 671–674, 1889–1892.