Polymer therapeutics: concepts and applications.

Polymer therapeutics encompass polymer-protein conjugates, drug-polymer conjugates, and supramolecular drug-delivery systems. Numerous polymer-protein conjugates with improved stability and pharmacokinetic properties have been developed, for example, by anchoring enzymes or biologically relevant proteins to polyethylene glycol components (PEGylation). Several polymer-protein conjugates have received market approval, for example the PEGylated form of adenosine deaminase. Coupling low-molecular-weight anticancer drugs to high-molecular-weight polymers through a cleavable linker is an effective method for improving the therapeutic index of clinically established agents, and the first candidates have been evaluated in clinical trials, including, N-(2-hydroxypropyl)methacrylamide conjugates of doxorubicin, camptothecin, paclitaxel, and platinum(II) complexes. Another class of polymer therapeutics are drug-delivery systems based on well-defined multivalent and dendritic polymers. These include polyanionic polymers for the inhibition of virus attachment, polycationic complexes with DNA or RNA (polyplexes), and dendritic core-shell architectures for the encapsulation of drugs. In this Review an overview of polymer therapeutics is presented with a focus on concepts and examples that characterize the salient features of the drug-delivery systems.

[1]  D. Scherman,et al.  A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Haag,et al.  Supramolecular drug-delivery systems based on polymeric core-shell architectures. , 2004, Angewandte Chemie.

[3]  A. Tolcher,et al.  A phase I and pharmacokinetic study of pegylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  W. Vogel.  Peginterferon-α2a(40 kDa)/ribavirin combination for the treatment of chronic hepatitis C infection , 2003 .

[5]  F. Szoka,et al.  Chloride Accumulation and Swelling in Endosomes Enhances DNA Transfer by Polyamine-DNA Polyplexes* , 2003, Journal of Biological Chemistry.

[6]  Z. Sideratou,et al.  Quaternized Poly(propylene imine) Dendrimers as Novel pH-Sensitive Controlled-Release Systems , 2000 .

[7]  Z. Lu,et al.  HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[8]  J. Schellens,et al.  Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel , 2001, Anti-cancer drugs.

[9]  T. Okano,et al.  Block copolymer micelles as vehicles for hydrophobic drugs , 1994 .

[10]  J. Leroux,et al.  pH-sensitive unimolecular polymeric micelles: synthesis of a novel drug carrier. , 2003, Bioconjugate chemistry.

[11]  J. Drevs,et al.  A novel macromolecular prodrug concept exploiting endogenous serum albumin as a drug carrier for cancer chemotherapy. , 2000, Journal of medicinal chemistry.

[12]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[13]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[14]  D. Kerr,et al.  Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  H. Rosing,et al.  A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin , 2002, British Journal of Cancer.

[16]  G. Whitesides,et al.  Self-Assembled Monolayers of Alkanethiolates Presenting Tri(propylene sulfoxide) Groups Resist the Adsorption of Protein , 1996 .

[17]  G M Whitesides,et al.  A trivalent system from vancomycin.D-ala-D-Ala with higher affinity than avidin.biotin. , 1998, Science.

[18]  P. Sinko,et al.  Polymeric Drug Delivery Systems: An Overview , 1993 .

[19]  B. Říhová,et al.  Clinical implications of N-(2-hydroxypropyl)methacrylamide copolymers. , 2003, Current pharmaceutical biotechnology.

[20]  G. Prestwich,et al.  Cancer-targeted polymeric drugs. , 2002, Current cancer drug targets.

[21]  J. Davies,et al.  Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470 , 2004, Nature Medicine.

[22]  J. Wolff.  The “grand” problem of synthetic delivery , 2002, Nature Biotechnology.

[23]  H. Ringsdorf.  Hermann Staudinger und die Zukunft der Polymerforschung Jubiläumsfeiern – selbstbestimmter Anlass kultureller Frömmigkeit , 2004 .

[24]  R. Edwards,et al.  Infection by HIV‐1 blocked by binding of dextrin 2‐sulphate to the cell surface of activated human peripheral blood mononuclear cells and cultured T‐cells , 1994, British journal of pharmacology.

[25]  R. Haag,et al.  An Approach to Glycerol Dendrimers and Pseudo-Dendritic Polyglycerols , 2000 .

[26]  Kazunori Kataoka,et al.  Block copolymer micelles for delivery of gene and related compounds. , 2002, Advanced drug delivery reviews.

[27]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[28]  R. Duncan,et al.  Potential of low molecular mass chitosan as a DNA delivery system: biocompatibility, body distribution and ability to complex and protect DNA. , 1999, International journal of pharmaceutics.

[29]  Teruo Okano,et al.  Challenges in polymer therapeutics: state of the art and prospects of polymer drugs. , 2003, Advances in experimental medicine and biology.

[30]  R. Roy,et al.  Syntheses and some applications of chemically defined multivalent glycoconjugates. , 1996, Current opinion in structural biology.

[31]  R. Duncan.  N-(2-Hydroxypropyl) methacrylamide Copolymer , 2005 .

[32]  R. Duncan,et al.  Dendrimer biocompatibility and toxicity. , 2005, Advanced drug delivery reviews.

[33]  H. Maeda,et al.  Tumoritropic and lymphotropic principles of macromolecular drugs. , 1989, Critical reviews in therapeutic drug carrier systems.

[34]  A. Aigner,et al.  Physicochemical and biological characterization of polyethylenimine-graft-poly(ethylene glycol) block copolymers as a delivery system for oligonucleotides and ribozymes. , 2004, Bioconjugate chemistry.

[35]  Meijer,et al.  The Localization of Guests in Water-Soluble Oligoethyleneoxy-Modified Poly(propylene imine) Dendrimers This work was supported by the Netherlands Foundation for Chemical Research (CW), with financial aid from the Netherlands Organisation for Scientific Research (NWO). The authors thank Stefan Mesker , 2000, Angewandte Chemie.

[36]  L. Zacharski,et al.  Heparin and Cancer , 1998, Thrombosis and Haemostasis.

[37]  L. Murray,et al.  Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  R. Haag,et al.  Dendritic polyglycerol sulfates as new heparin analogues and potent inhibitors of the complement system. , 2004, Bioconjugate chemistry.

[39]  J. Dennig,et al.  Gene transfer into eukaryotic cells using activated polyamidoamine dendrimers. , 2002, Journal of biotechnology.

[40]  R. Schiffelers,et al.  Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. , 2004, Nucleic acids research.

[41]  R. Haag,et al.  pH-responsive molecular nanocarriers based on dendritic core-shell architectures. , 2002, Angewandte Chemie.

[42]  R. Satchi‐Fainaro.  Targeting Tumor Vasculature: Reality or a Dream? , 2002, Journal of drug targeting.

[43]  Ruth Duncan,et al.  Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation , 2004, Nature Biotechnology.

[44]  R. Haag.  Supramolekulare Wirkstoff‐Transportsysteme auf der Basis polymerer Kern‐Schale‐Architekturen , 2004 .

[45]  K. Shakesheff,et al.  Polymeric systems for controlled drug release. , 1999, Chemical reviews.

[46]  Hans Schupp,et al.  Polymere Antitumormittel auf molekularer und zellulärer Basis , 1981 .

[47]  K. Kataoka,et al.  Block copolymer micelles for drug delivery: design, characterization and biological significance. , 2001, Advanced drug delivery reviews.

[48]  E. W. Meijer,et al.  Host-Guest Chemistry of Dendritic Molecules , 2000 .

[49]  A. Wunder,et al.  Enhanced albumin uptake by rat tumors. , 1997, International journal of oncology.

[50]  R. Duncan,et al.  Polymer-drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[51]  J. Herbert,et al.  The Synthetic Pentasaccharide Fondaparinux: First in the Class of Antithrombotic Agents that Selectively Inhibit Coagulation Factor Xa , 2002, Seminars in thrombosis and hemostasis.

[52]  R. Langer,et al.  Drug delivery and targeting. , 1998, Nature.

[53]  J. BeMiller.  Carbohydrates and carbohydrate polymers: edited by Manssur Yalpani, ATL press, 1993. $180.00 (v + 314 pages) ISBN 1 882360 40 0 , 1993 .

[54]  V. Bilim.  Technology evaluation: PK1, Pfizer/Cancer Research UK. , 2003, Current opinion in molecular therapeutics.

[55]  J. Double,et al.  Pharmacokinetics of PK1 and doxorubicin in experimental colon tumor models with differing responses to PK1. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[56]  D. A. Tomalia,et al.  Starburst‐Dendrimere: Kontrolle von Größe, Gestalt, Oberflächenchemie, Topologie und Flexibilität beim Übergang von Atomen zu makroskopischer Materie , 1990 .

[57]  I. Tannock,et al.  Acid pH in tumors and its potential for therapeutic exploitation. , 1989, Cancer research.

[58]  K. Ulbrich,et al.  Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier. , 1995, European journal of cancer.

[59]  Atsushi Harada,et al.  Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. , 2003, Angewandte Chemie.

[60]  H. Maeda,et al.  Macromolecular Therapeutics , 2003, Clinical pharmacokinetics.

[61]  G M Whitesides,et al.  Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition. , 1995, Journal of medicinal chemistry.

[62]  A. Oliff,et al.  Drug-targeting strategies in cancer therapy. , 2001, Current opinion in genetics & development.

[63]  D. Mukhopadhyay,et al.  Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. , 2005, Cancer cell.

[64]  D. Isenberg,et al.  Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. , 2002, Rheumatology.

[65]  S. Choi.  Synthetic Multivalent Molecules , 2004 .

[66]  D. Tsiourvas,et al.  Poly(propyleneimine) Dendrimers as pH‐Sensitive Controlled‐Release Systems , 1999 .

[67]  T. Okano,et al.  Development of the polymer micelle carrier system for doxorubicin. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[68]  R. Roy,et al.  Synthesis of New α-Thiosialodendrimers and Their Binding Properties to the Sialic Acid Specific Lectin from Limax flavus , 1997 .

[69]  R. Duncan.  The dawning era of polymer therapeutics , 2003, Nature Reviews Drug Discovery.

[70]  J. Weiler,et al.  Heparin and modified heparin inhibit complement activation in vivo. , 1992, Journal of immunology.

[71]  K. Kono,et al.  Design of biocompatible dendrimers with environment sensitivity , 2003 .

[72]  S. Shaffer,et al.  Poly-(L)-glutamic acid-paclitaxel (CT-2103) [XYOTAX], a biodegradable polymeric drug conjugate: characterization, preclinical pharmacology, and preliminary clinical data. , 2003, Advances in experimental medicine and biology.

[73]  S. Pedder.  Pegylation of Interferon Alfa: Structural and Pharmacokinetic Properties , 2003, Seminars in liver disease.

[74]  L. Brannon-Peppas,et al.  Nanoparticle and targeted systems for cancer therapy. , 2004, Advanced drug delivery reviews.

[75]  P. Caliceti,et al.  Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. , 2003, Advanced drug delivery reviews.

[76]  H. Ringsdorf.  Hermann Staudinger and the future of polymer research jubilees-beloved occasions for cultural piety. , 2004, Angewandte Chemie.

[77]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[78]  F. Diederich,et al.  Amphiphilic dendrimers: novel self-assembling vectors for efficient gene delivery. , 2003, Angewandte Chemie.

[79]  Kinam Park,et al.  Hydrotropic dendrimers of generations 4 and 5: synthesis, characterization, and hydrotropic solubilization of paclitaxel. , 2004, Bioconjugate chemistry.

[80]  G. Whitesides,et al.  Monomeric inhibitors of influenza neuraminidase enhance the hemagglutination inhibition activities of polyacrylamides presenting multiple C-sialoside groups. , 1996, Chemistry & biology.

[81]  R. Price,et al.  Superior therapeutic profile of poly-L-glutamic acid-paclitaxel copolymer compared with taxol in xenogeneic compartmental models of human ovarian carcinoma. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[82]  R. Buckley,et al.  HPMA Copolymers Platinates Containing Dicarboxylato Ligands. Preparation, Characterisation and In Vitro and In Vivo Evaluation , 2002, Journal of drug targeting.

[83]  F. Kratz,et al.  Maleimide-oligo(ethylene glycol) derivatives of camptothecin as albumin-binding prodrugs: synthesis and antitumor efficacy. , 2003, Bioconjugate chemistry.

[84]  S. Brocchini,et al.  New strategies for polymer development in pharmaceutical science — a short review , 2001, The Journal of pharmacy and pharmacology.

[85]  Maurice Petitou,et al.  Ein synthetisches Antithrombin III bindendes Pentasaccharid ist jetzt ein Wirkstoff! Was kommt danach? , 2004 .

[86]  S. Alban,et al.  Partial synthetic glucan sulfates as potential new antithrombotics: a review. , 2001, Biomacromolecules.

[87]  Shiladitya Sengupta,et al.  Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system , 2005, Nature.

[88]  K. Kono,et al.  Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs. , 2000, Bioconjugate chemistry.

[89]  A. Wunder,et al.  Phase I trial of methotrexate-albumin in a weekly intravenous bolus regimen in cancer patients. Phase I Study Group of the Association for Medical Oncology of the German Cancer Society. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[90]  F. Szoka,et al.  In vitro gene delivery by degraded polyamidoamine dendrimers. , 1996, Bioconjugate chemistry.

[91]  Roey J. Amir,et al.  Self-immolative dendrimers. , 2003, Angewandte Chemie.

[92]  H. Maeda,et al.  Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[93]  R. Duncan,et al.  HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo. , 1999, European journal of cancer.

[94]  V. Labhasetwar,et al.  Nanosystems in Drug Targeting: Opportunities and Challenges , 2005 .

[95]  C. Lee,et al.  Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity. , 1998, Bioorganic & medicinal chemistry.

[96]  C. Conover,et al.  Poly(ethylene glycol) conjugated drugs and prodrugs: a comprehensive review. , 2000, Critical reviews in therapeutic drug carrier systems.

[97]  Yokoyama Masayuki,et al.  Block copolymer micelles as vehicles for drug delivery , 1993 .

[98]  H. Fiebig,et al.  Pre‐clinical evaluation of a methotrexate–albumin conjugate (MTX‐HSA) in human tumor xenografts in vivo , 2001, International journal of cancer.

[99]  I. Phillips,et al.  Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with multiple mechanisms of action against Gram-positive bacteria. , 2004, The Journal of antimicrobial chemotherapy.

[100]  E. Ohman,et al.  Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. , 2001, Chest.

[101]  F. Kratz,et al.  Drug-polymer conjugates containing acid-cleavable bonds. , 1999, Critical reviews in therapeutic drug carrier systems.

[102]  L. Hsu.  Heparin-coated cardiopulmonary bypass circuits: current status , 2001, Perfusion.

[103]  R. Duncan,et al.  PDEPT: polymer-directed enzyme prodrug therapy , 2001, British Journal of Cancer.

[104]  R. Lerner,et al.  Single-triggered trimeric prodrugs. , 2005, Angewandte Chemie.

[105]  Rakesh K. Jain,et al.  Transport of molecules across tumor vasculature , 2004, Cancer and Metastasis Reviews.

[106]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[107]  R. Haag,et al.  Dendritic Polyamines: Simple Access to New Materials with Defined Treelike Structures for Application in Nonviral Gene Delivery , 2004, Chembiochem : a European journal of chemical biology.

[108]  K. Ley,et al.  Sulfated polysaccharides in inflammation. , 1993, The Journal of laboratory and clinical medicine.

[109]  J. Baker,et al.  Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[110]  William A. Goddard,et al.  Starburst Dendrimers: Molecular‐Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter , 1990 .

[111]  George M. Whitesides,et al.  Design, Synthesis, and Characterization of a High-Affinity Trivalent System Derived from Vancomycin and l-Lys-d-Ala-d-Ala , 2000 .

[112]  H. Engelberg.  Heparin, non-heparin glycosaminoglycans, and heparinoids: an overview of their application in atherosclerosis. , 1991, Seminars in thrombosis and hemostasis.

[113]  E. Meijer,et al.  The dendritic box, shape-selective liberation of encapsulated guests , 1995 .

[114]  G. M. Whitesides,et al.  Polyvalente Wechselwirkungen in biologischen Systemen: Auswirkungen auf das Design und die Verwendung multivalenter Liganden und Inhibitoren , 1998 .

[115]  H. Ringsdorf,et al.  Polymeric Antitumor Agents on a Molecular and on a Cellular Level , 1981 .

[116]  D. Fraier,et al.  Determination of MAG-camptothecin, a new polymer-bound camptothecin derivative, and free camptothecin in dog plasma by HPLC with fluorimetric detection. , 2000, Journal of pharmaceutical and biomedical analysis.

[117]  G. Whitesides,et al.  Generation and in Situ Evaluation of Libraries of Poly(acrylic acid) Presenting Sialosides as Side Chains as Polyvalent Inhibitors of Influenza-Mediated Hemagglutination , 1997 .

[118]  J. Feijen,et al.  Polymeric Drug Delivery Systems , 1980 .

[119]  J. Schellens,et al.  A Phase I and Pharmacological Study with Imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent , 2004, Clinical Cancer Research.

[120]  R. Read,et al.  Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands , 2000, Nature.

[121]  George M Whitesides,et al.  Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors. , 1998, Angewandte Chemie.

[122]  P. Sabbatini,et al.  Phase II study of CT-2103 in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[123]  A. El-Aneed,et al.  An overview of current delivery systems in cancer gene therapy. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[124]  K. Ulbrich,et al.  Polymeric anticancer drugs with pH-controlled activation. , 2004, Advanced drug delivery reviews.

[125]  R. Fernandez-Botran.  Soluble cytokine receptors: novel immunotherapeutic agents , 2000, Expert opinion on investigational drugs.

[126]  G. Molineux.  Pegfilgrastim: using pegylation technology to improve neutropenia support in cancer patients , 2003, Anti-cancer drugs.

[127]  H. Ringsdorf.  Structure and properties of pharmacologically active polymers , 1975 .

[128]  I. Fichtner,et al.  A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2. , 2003, Cancer research.

[129]  G. Whitesides,et al.  Binding of a dimeric derivative of vancomycin to L-Lys-D-Ala-D-lactate in solution and at a surface. , 1999, Chemistry & biology.

[130]  J. Crawford.  Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapy-induced neutropenia. , 2003, Seminars in oncology.

[131]  Satoko Kawauchi,et al.  Supramolecular nanocarrier of anionic dendrimer porphyrins with cationic block copolymers modified with polyethylene glycol to enhance intracellular photodynamic efficacy. , 2005, Angewandte Chemie.

[132]  J. Baker,et al.  DNA complexing with polyamidoamine dendrimers: implications for transfection. , 1999, Bioconjugate chemistry.

[133]  Jean Campbell,et al.  Bioinspired pH-responsive polymers for the intracellular delivery of biomolecular drugs. , 2003, Bioconjugate chemistry.

[134]  D. Rognan,et al.  Probing the cysteine-34 position of endogenous serum albumin with thiol-binding doxorubicin derivatives. Improved efficacy of an acid-sensitive doxorubicin derivative with specific albumin-binding properties compared to that of the parent compound. , 2002, Journal of medicinal chemistry.

[135]  T. Choueiri,et al.  Evolving role of pegylated interferons in metastatic renal cell carcinoma , 2003, Expert review of anticancer therapy.

[136]  F. Szoka,et al.  Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. , 1993, Bioconjugate chemistry.

[137]  J. Davies,et al.  PDEPT: polymer-directed enzyme prodrug therapy. 2. HPMA copolymer-beta-lactamase and HPMA copolymer-C-Dox as a model combination. , 2003, Bioconjugate chemistry.

[138]  Winkelhake Jl.  Will complex carbohydrate ligands of vascular selectins be the next generation of non-steroidal anti-inflammatory drugs? , 1991 .

[139]  J. M. Harris,et al.  Effect of pegylation on pharmaceuticals , 2003, Nature Reviews Drug Discovery.

[140]  I. Szleifer.  Polymers and proteins: interactions at interfaces , 1997 .

[141]  H. Fujita.  [Anticancer drugs]. , 1995, Nihon rinsho. Japanese journal of clinical medicine.

[142]  Z. Sawa.  Energy Levels in 70Ga , 1970 .

[143]  M. Walker,et al.  Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs. , 1999, Pharmacology & therapeutics.

[144]  Paras N. Prasad,et al.  Photosensitization of Singlet Oxygen via Two-Photon-Excited Fluorescence Resonance Energy Transfer in a Water-Soluble Dendrimer , 2005 .

[145]  S. Krause,et al.  pH‐spaltbare molekulare Nanotransporter auf der Basis dendritischer Kern‐Schale‐Architekturen , 2002 .

[146]  K. Ulbrich,et al.  Doxorubicin bound to a HPMA copolymer carrier through hydrazone bond is effective also in a cancer cell line with a limited content of lysosomes. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[147]  J. Singer,et al.  Water-soluble poly-(L-glutamic acid)-Gly-camptothecin conjugates enhance camptothecin stability and efficacy in vivo. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[148]  C. V. van Boeckel,et al.  A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? , 2004, Angewandte Chemie.