Capping methotrexate α-carboxyl groups enhances systemic exposure and retains the cytotoxicity of drug conjugated PEGylated polylysine dendrimers.

Kaminskas, Lisa M.; Kelly, Brian D.; McLeod, Victoria M.; Sberna, Gian; Boyd, Ben J.; Owen, David J.; Porter, Christopher J. H.

doi:10.1021/mp1001872

Cited by 64Dendrimers and Hyperbranched PolymersNanoparticle-Based Drug DeliveryAdvanced Drug Delivery Systems

Capping methotrexate α-carboxyl groups enhances systemic exposure and retains the cytotoxicity of drug conjugated PEGylated polylysine dendrimers.

Kaminskas, Lisa M., Kelly, Brian D., McLeod, Victoria M., Sberna, Gian, Boyd, Ben J., Owen, David J., Porter, Christopher J. H.·2011·Molecular Pharmaceutics

DOI 10.1021/mp1001872

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Abstract

A generation 5 PEGylated (PEG 1100) polylysine dendrimer, conjugated via a stable amide linker to OtBu protected methotrexate (MTX), was previously shown to have a circulatory half-life of 2 days and to target solid tumors in both rats and mice. Here, we show that deprotection of MTX and substitution of the stable linker with a matrix metalloproteinase (MMP) 2 and 9 cleavable linker (PVGLIG) dramatically increased plasma clearance and promoted deposition in the liver and spleen (50-80% of the dose recovered in the liver 3 days post dose). Similar rapid clearance was also seen using a scrambled peptide suggesting that clearance was not dependent on the cleavable nature of the linker. Surprisingly, dendrimers where OtBu capped MTX was linked to the dendrimer surface via the hexapeptide linker showed equivalent in vitro cytotoxicity against HT1080 cells when compared to the uncapped dendrimer and also retained the long circulating characteristics of the stable constructs. The OtBu capped MTX conjugated dendrimer was subsequently shown to significantly reduce tumor growth in HT1080 tumor bearing mice compared to control. In contrast the equivalent dendrimer comprising uncapped MTX conjugated to the dendrimer via the same hexapeptide linker did not reduce tumor growth, presumably reflecting very rapid clearance of the construct. The results are consistent with the suggestion that protection of the α-carboxyl group of methotrexate may be used to improve the circulatory half-life and reduce the liver accumulation of similar MTX-conjugated dendrimers, while still retaining antitumor activity in vivo.

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Dendrimer use in biological systems is limited due to complex synthetic procedures and toxicity issues.
“Although, dendrimers have wide application in drug delivery, yet their use in biological systems is limited due to complex synthetic procedures and toxicity issues”
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Therapeutic Nanoparticles for Drug Delivery in Cancer
Cho, K., Wang, X., Nie, S., Chen, Z. (., & Shin, D. M. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1441 · Cited by 2,919 · see citing works
Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues.
Weitman, S. D., Lark, R. H., Coney, L. R., Fort, D. W., Frasca, V., Zurawski, V. R., & Kamen, B. A. (1992) · PubMed · Cited by 1,011 · see citing works
Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics
Padera, T. P., Kadambi, A., di Tomaso, E., Carreira, C. M., Brown, E. B., Boucher, Y., Choi, N. C., Mathisen, D. J., Wain, J. R., Mark, E. J., et al. (2002) · Science · doi:10.1126/science.1071420 · Cited by 964 · see citing works
Nanoparticle Targeting of Anticancer Drug Improves Therapeutic Response in Animal Model of Human Epithelial Cancer
Kukowska‐Latallo, J. F., Candido, K. A., Cao, Z., Nigavekar, S. S., Majoros, I., Thomas, T. P., Balogh, L. P., Khan, M. K., & Baker, J. R. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3921 · Cited by 912 · see citing works
Targeted drug delivery with dendrimers: Comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex
PATRI, A., KUKOWSKALATALLO, J., & BAKERJR, J. (2005) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2005.09.014 · Cited by 597 · see citing works
Dendrimer-platinate: a novel approach to cancer chemotherapy.
Malik, N., Evagorou, E. G., & Duncan, R. (1999) · PubMed · Cited by 417 · see citing works
Dendrimer-platinate
Malik, N., Evagorou, E. G., & Duncan, R. (1999) · Anti-Cancer Drugs · doi:10.1097/00001813-199909000-00010 · Cited by 402 · see citing works
Folate and Folate−PEG−PAMAM Dendrimers: Synthesis, Characterization, and Targeted Anticancer Drug Delivery Potential in Tumor Bearing Mice
Singh, P., Gupta, U. D., Asthana, A., & Jain, N. K. (2008) · Bioconjugate Chemistry · doi:10.1021/bc800125u · Cited by 329 · see citing works
Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery
Taratula, O., Garbuzenko, O. B., Kirkpatrick, P., Pandya, I., Savla, R., Pozharov, V. P., He, H., & Minko, T. (2009) · Journal of Controlled Release · doi:10.1016/j.jconrel.2009.06.019 · Cited by 328 · see citing works
Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice
Oyewumi, M. O., Yokel, R. A., Jay, M., Coakley, T., & Mumper, R. J. (2004) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.01.002 · Cited by 296 · see citing works
Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies
Shenoy, D. B., Little, S. R., Langer, R., & Amiji, M. M. (2005) · Pharmaceutical Research · doi:10.1007/s11095-005-8343-0 · Cited by 246 · see citing works
Synthesis, Purification, and Tumor Cell Uptake of 67Ga-Deferoxamine−Folate, a Potential Radiopharmaceutical for Tumor Imaging
Wang, S. S., Lee, R. J., Mathias, C. J., Green, M. A., & Low, P. S. (1996) · Bioconjugate Chemistry · doi:10.1021/bc9500709 · Cited by 245 · see citing works
Receptor targeted polymers, dendrimers, liposomes: Which nanocarrier is the most efficient for tumor-specific treatment and imaging?
Saad, M., Garbuzenko, O. B., Ber, E., Chandna, P., Khandare, J. J., Pozharov, V. P., & Minko, T. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.05.024 · Cited by 237 · see citing works
Dendrimer Versus Linear Conjugate: Influence of Polymeric Architecture on the Delivery and Anticancer Effect of Paclitaxel
Khandare, J. J., Jayant, S., Singh, A., Chandna, P., Wang, Y., Vorsa, N., & Minko, T. (2006) · Bioconjugate Chemistry · doi:10.1021/bc060240p · Cited by 226 · see citing works
Systemicin vivodistribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides
Aguilera, T. A., Olson, E. S., Timmers, M. M., Jiang, T., & Tsien, R. Y. (2009) · Integrative Biology · doi:10.1039/b904878b · Cited by 199 · see citing works
Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin
Kono, K., Kojima, C., Hayashi, N., Nishisaka, E., Kiura, K., Watarai, S., & Harada, A. (2008) · Biomaterials · doi:10.1016/j.biomaterials.2007.12.017 · Cited by 192 · see citing works
Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy.
Schmitt‐Sody, M., Strieth, S., Krasnici, S., Sauer, B., Schulze, B. G., Teifel, M., Michaelis, U., Naujoks, K., & Dellian, M. (2003) · PubMed · Cited by 192 · see citing works
Synthesis and Characterization of Dextran−Peptide−Methotrexate Conjugates for Tumor Targeting via Mediation by Matrix Metalloproteinase II and Matrix Metalloproteinase IX
Chau, Y., Tan, F. E., & Langer, R. (2004) · Bioconjugate Chemistry · doi:10.1021/bc0499174 · Cited by 187 · see citing works
The Impact of Molecular Weight and PEG Chain Length on the Systemic Pharmacokinetics of PEGylated Poly l -Lysine Dendrimers
Kaminskas, L. M., Boyd, B. J., Karellas, P., Krippner, G. Y., Lessene, R., Kelly, B. D., & Porter, C. J. H. (2008) · Molecular Pharmaceutics · doi:10.1021/mp7001208 · Cited by 178 · see citing works
From Conventional to Stealth Liposomes a new Frontier in Cancer Chemotherapy
Cattel, L., Ceruti, M., & Dosio, F. (2003) · Tumori Journal · doi:10.1177/030089160308900302 · Cited by 175 · see citing works
Cationic Poly- l -lysine Dendrimers: Pharmacokinetics, Biodistribution, and Evidence for Metabolism and Bioresorption after Intravenous Administration to Rats
Boyd, B. J., Kaminskas, L. M., Karellas, P., Krippner, G. Y., Lessene, R., & Porter, C. J. H. (2006) · Molecular Pharmaceutics · doi:10.1021/mp060032e · Cited by 167 · see citing works
Activity of Dendrimer−Methotrexate Conjugates on Methotrexate-Sensitive and -Resistant Cell Lines
Gurdag, S., Khandare, J. J., Stapels, S. E., Matherly, L. H., & Kannan, R. M. (2006) · Bioconjugate Chemistry · doi:10.1021/bc0501855 · Cited by 165 · see citing works
Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis
Wang, Y., Zhao, R., Russell, R. G., & Goldman, I. D. (2001) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(01)00340-6 · Cited by 151 · see citing works
Pharmacokinetics and Tumor Disposition of PEGylated, Methotrexate Conjugated Poly- l -lysine Dendrimers
Kaminskas, L. M., Kelly, B. D., McLeod, V. M., Boyd, B. J., Krippner, G. Y., Williams, E. D., & Porter, C. J. H. (2009) · Molecular Pharmaceutics · doi:10.1021/mp900049a · Cited by 140 · see citing works
The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter
Whetstine, J. R., Flatley, R. M., & Matherly, L. H. (2002) · Biochemical Journal · doi:10.1042/bj20020512 · Cited by 136 · see citing works
Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models
Chau, Y., Padera, R. F., Dang, N. M., & Langer, R. (2005) · International Journal of Cancer · doi:10.1002/ijc.21495 · Cited by 124 · see citing works
The effect of dendrimers on the pharmacodynamic and pharmacokinetic behaviors of non-covalently or covalently attached drugs
Cheng, Y., & Xu, T. (2008) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2007.12.021 · Cited by 123 · see citing works
Structure function relationships in the lymphatic system and implications for cancer biology
Witte, M. H., Jones, K., Wilting, J., Dictor, M. R., Selg, M., McHale, N. G., Gershenwald, J. E., & Jackson, D. G. (2006) · Cancer and Metastasis Reviews · doi:10.1007/s10555-006-8496-2 · Cited by 123 · see citing works
Dextran conjugated dendritic nanoconstructs as potential vectors for anti-cancer agent
Agarwal, A., Gupta, U. D., Asthana, A., & Jain, N. K. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.03.016 · Cited by 119 · see citing works
Conjugates of doxorubicin with graft HPMA copolymers for passive tumor targeting
Etrych, T., Chytil, P., Mrkvan, T., Šírová, M., Řı́hová, B., & Ulbrich, K. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.04.017 · Cited by 98 · see citing works
Investigation of Targeting Mechanism of New Dextran-Peptide-Methotrexate Conjugates Using Biodistribution Study in Matrix-Metalloproteinase-Overexpressing Tumor Xenograft Model
Chau, Y., Dang, N. M., Tan, F. E., & Langer, R. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20548 · Cited by 94 · see citing works
Recent Advances in Classical and Non-Classical Antifolates as Antitumor and Antiopportunistic Infection Agents: Part I
Gangjee, A., Jain, H. D., & Kurup, S. (2007) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152007781668724 · Cited by 72 · see citing works
Functional activity of the reduced folate carrier in KB, MA104, and IGROV-I cells expressing folate-binding protein.
Westerhof, G. R., Rijnboutt, S., Schornagel, J. H., Pinedo, H. M., Peters, G. J., & Jansen, G. (1995) · PubMed · Cited by 63 · see citing works
Characterizing Extravascular Fluid Transport of Macromolecules in the Tumor Interstitium by Magnetic Resonance Imaging
Pathak, A. P., Artemov, D., Ward, B. D., Jackson, D. G., Neeman, M., & Bhujwalla, Z. M. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3682 · Cited by 59 · see citing works
Methotrexate analogs. 14. Synthesis of new .gamma.-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents
Rosowsky, A., Forsch, R. A., Uren, J. R., & Wick, M. M. (1981) · Journal of Medicinal Chemistry · doi:10.1021/jm00144a016 · Cited by 56 · see citing works
Impact of Surface Derivatization of Poly- l -lysine Dendrimers with Anionic Arylsulfonate or Succinate Groups on Intravenous Pharmacokinetics and Disposition
Kaminskas, L. M., Boyd, B. J., Karellas, P., Henderson, S. A., Giannis, M. P., Krippner, G. Y., & Porter, C. J. H. (2007) · Molecular Pharmaceutics · doi:10.1021/mp070047s · Cited by 55 · see citing works
Dendritic systems in drug delivery applications
Jain, N. K., & Asthana, A. (2007) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.4.5.495 · Cited by 36 · see citing works

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Elkin, I., Banquy, X., Barrett, C. J., & Hildgen, P. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.09.002 · Cited by 19 · see citing works
Quintessential impact of dendrimer bioconjugates in targeted drug delivery
Gholap, A. D., Bhowmik, D. D., Deshmukh, A. Y., & Hatvate, N. T. (2023) · Comprehensive analytical chemistry · doi:10.1016/bs.coac.2023.02.009 · Cited by 18 · see citing works
Subcutaneous delivery of a dendrimer-BH3 mimetic improves lymphatic uptake and survival in lymphoma
Feeney, O. M., Ardipradja, K., Noi, K. F., Mehta, D. C., Rose, R. D., Yuen, D., Johnston, A. P. R., Kingston, L. P., Ericsson, C., Elmore, C. S., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.041 · Cited by 16 · see citing works
The Impact of Polymer Size and Cleavability on the Intravenous Pharmacokinetics of PEG-Based Hyperbranched Polymers in Rats
Marasini, N., Fu, C., Fletcher, N. L., Subasic, C. N., Er, T. K. G., Mardon, K., Thurecht, K. J., Whittaker, A. K., & Kaminskas, L. M. (2020) · Nanomaterials · doi:10.3390/nano10122452 · Cited by 16 · see citing works
Novel morphology change of Au-Methotrexate conjugates: From nanochains to discrete nanoparticles
Wang, W., Zhao, X.-F., Ju, X.-H., Wang, Y., Wang, L., Li, S.-P., & Li, X.-D. (2016) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2016.10.022 · Cited by 13 · see citing works
Preclinical studies of dendrimer prodrugs
Kojima, C. (2015) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2015.1052404 · Cited by 12 · see citing works
Nano-drug for Pain Medicine
Hasanzadeh-Kiabi, F. (2017) · Drug Research · doi:10.1055/s-0043-120661 · Cited by 11 · see citing works
Matrix Metalloproteinase-Sensitive Nanocarriers
Tu, Y., & Zhu, L. (2016) · IMPERIAL COLLEGE PRESS eBooks · doi:10.1142/9781783267231_0003 · Cited by 9 · see citing works
Challenges and Opportunities for Cleavable Linkers Used in Polymer–Drug Conjugates
Karimi, F., Locock, K. E. S., Chiefari, J., Williams, C. C., & Blackman, L. D. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.6c03661 · Cited by 6 · see citing works
Dendrimer-drug conjugates
Pooja, D., Sistla, R., & Kulhari, H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813669-0.00007-5 · Cited by 6 · see citing works
Activation Strategies in Image-Guided Nanotherapeutic Delivery
Choi, S. K. (2020) · Journal of Nanotheranostics · doi:10.3390/jnt1010007 · Cited by 6 · see citing works
Design of dendrimer based prodrugs
Reddy, T. S., & Bhargava, S. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814527-2.00008-1 · Cited by 5 · see citing works
Stimuli-sensitive polymers for drug delivery and diagnostic systems interacting with biosurfaces
Yoshida, T. (2015) · Elsevier eBooks · doi:10.1016/b978-0-85709-713-2.00010-9 · Cited by 4 · see citing works
Dendrimer Bioconjugates: Synthesis and Applications
Nazemi, A., & Gillies, E. R. (2014) · Wiley eBooks · doi:10.1002/9781118775882.ch5 · Cited by 4 · see citing works
Design and Development of Theranostic Nanomedicines
Janjic, J. M., & Bai, M. (2014) · doi:10.1002/9781118873151.ch15 · Cited by 4 · see citing works
Synthesis of a fluorescent analogue of methotrexate lipophilic prodrug
Vlasenko, Y. V., Alekseeva, A. S., & Vodovozova, E. L. (2014) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162014010129 · Cited by 3 · see citing works
Pharmaceutical and Pharmacokinetic Aspects of Nanoformulation Based Drug Delivery Systems for Anti-cancer Drugs
Singh, A. K., Bahadur, S., Yadav, D., & Dabas, H. (2023) · Current Pharmaceutical Design · doi:10.2174/1381612829666230824144727 · Cited by 3 · see citing works
Smart Dendrimers
Kojima, C. (2013) · Royal Society of Chemistry eBooks · doi:10.1039/9781849736800-00094 · Cited by 2 · see citing works
Nano-pharmacokinetics: interface of physics, chemistry and biology
Shirsat, S. D., & Mane, R. S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85050-6.00005-0 · Cited by 2 · see citing works
RNAi Therapeutic Potentials and Prospects in CNS Disease
Cho, K., & Kim, G. W. (2016) · InTech eBooks · doi:10.5772/62896 · Cited by 2 · see citing works
Poly(ethylene oxide)‐graft‐methotrexate Macromolecular Drugs Conjugating via Aminopteridine Ring Exhibit Potent Anticancer Activity
Guo, W., Zheng, M., Zhong, Y., Meng, F., Deng, C., & Zhong, Z. (2013) · Chinese Journal of Chemistry · doi:10.1002/cjoc.201300611 · Cited by 1 · see citing works
L‐lysine Janus Dendrimer Conjugate with Naproxen and Mefenamic Acid and its Anticancer Activity
Castillo‐Rodríguez, I. O., Saavedra‐González, I., Ramírez‐Ápan, T., & Martínez‐García, M. (2024) · ChemistrySelect · doi:10.1002/slct.202303289 · Cited by 1 · see citing works
Dendritic Polymers as Targeting Nanoscale Drug Delivery Systems for Cancer Therapy
Luo, K., & Gu, Z. (2014) · Wiley eBooks · doi:10.1002/9783527672752.ch2 · Cited by 1 · see citing works
Dendrimers
Kojima, C. (2012) · Wiley eBooks · doi:10.1002/0471440264.pst094
Development of an ESR-Based Diagnostic Probe for Matrix Metalloproteinase Activity Using a Spin-Labeled Peptide-Conjugated Styrene-Maleic Acid Copolymer.
Sasaki, M., Kato, K., Ohta, Y., Nakamura, H., Kuniyasu, A., Okazaki, S., & Takeshita, K. (2025) · PubMed · doi:10.1248/bpb.b25-00222
Engineering dendritic architectures to face nanomedicine issues : biodistribution, toxicity, pharmacokinetics or active targeting
Bordeianu, C. (2016) · doi:10.70675/34231e95z4496z4b8ez8b65z3800dbc34701

Pharmacokinetics and Tumor Disposition of PEGylated, Methotrexate Conjugated Poly- l -lysine Dendrimers
Kaminskas, L. M., Kelly, B. D., McLeod, V. M., Boyd, B. J., Krippner, G. Y., Williams, E. D., & Porter, C. J. H. (2009) · Molecular Pharmaceutics · doi:10.1021/mp900049a · Cited by 140 · see citing works
Methotrexate-Conjugated PEGylated Dendrimers Show Differential Patterns of Deposition and Activity in Tumor-Burdened Lymph Nodes after Intravenous and Subcutaneous Administration in Rats
Kaminskas, L. M., McLeod, V. M., Ascher, D. B., Ryan, G. M., Jones, S. A., Haynes, J. M., Trevaskis, N. L., Chan, L. J., Sloan, E. K., Finnin, B. A., et al. (2014) · Molecular Pharmaceutics · doi:10.1021/mp500531e · Cited by 55 · see citing works
Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumour-burdened lymph nodes after intravenous and subcutaneous administration in rats
Kaminskas, L. M., McLeod, V. M., Ascher, D. B., Ryan, G. M., Jones, S. A., Haynes, J. M., Trevaskis, N. L., Chan, L. J., Sloan, E. K., Finnin, B. A., et al. (2015) · QUT ePrints (Queensland University of Technology)
Lymphatic transport and lymph node targeting of methotrexate-conjugated PEGylated dendrimers are enhanced by reducing the length of the drug linker or masking interactions with the injection site
Ryan, G. M., McLeod, V. M., Mehta, D. C., Kelly, B. D., Stanislawski, P. C., Owen, D. J., Kaminskas, L. M., & Porter, C. J. H. (2017) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2017.08.003 · Cited by 27 · see citing works
PEGylated PAMAM dendrimers as a potential drug delivery carrier:in vitroandin vivocomparative evaluation of covalently conjugated drug and noncovalent drug inclusion complex
Jiang, Y., Tang, G., Zhang, L.-H., Kong, S.-Y., Zhu, S., & Pei, Y. (2010) · Journal of drug targeting · doi:10.3109/10611860903494203 · Cited by 72 · see citing works

Authors: Kaminskas, L. M., Kelly, B. D., McLeod, V. M., Sberna, G., Boyd, B. J., Owen, D. J., & Porter, C. J. H.
Affiliations: Monash University (AU)
Starpharma (Australia) (AU)
Corresponding author: Porter, Christopher J. H.
ORCID: Kaminskas, Lisa M.
Kelly, Brian D.
McLeod, Victoria M.
Boyd, Ben J.
Owen, David J.
Porter, Christopher J. H.
Venue: Molecular Pharmaceutics
Publisher: American Chemical Society (ACS)
Published: 2011-01-21
Volume: 8
Issue: 2
Pages: 338-349
ISSN: 1543-8384 (ISSN-L)
1543-8392
DOI: 10.1021/mp1001872
OpenAlex: W2327486849
Cited by: 64
References: 37
Citations by year: 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 8 · 2016: 8 · 2015: 8 · 2014: 9 · 2013: 5 · 2012: 9
FWCI: 3.97
Type: journal article
Language: en
Open access: closed
Locations: Molecular Pharmaceutics (publishedVersion)
PubMed (publishedVersion)
Funders: National Health and Medical Research Council
Topics: Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords: methotrexate, PEGylation, plasma clearance, circulatory half-life, liver accumulation, tumor targeting, cytotoxicity, anticancer activity, drug conjugation
MeSH terms: Animals, Antimetabolites, Antineoplastic, Fibrosarcoma, Kidney, Male, Metabolic Clearance Rate, Methotrexate, Mice, Inbred BALB C, Mice, Nude, Polyethylene Glycols, Polylysine, Tissue Distribution, Tumor Cells, Cultured, Drug Delivery Systems, Rats, Sprague-Dawley, Apoptosis, Cell Proliferation, Dendrimers, Mice, Rats

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Capping methotrexate α-carboxyl groups enhances systemic exposure and retains the cytotoxicity of drug conjugated PEGylated polylysine dendrimers.

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