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Despite functional evidence for acid sensitive bond cleavage of dendritic polyglycerol drug-conjugates in cellular compartments, the mechanistic details pertaining to such process (e.g. kinetics and sites of cleavage) remain unexplored. To address these questions directly, we are working on the synthesis of a novel FRET-based polymer conjugates that changes its fluorescence upon drug release. Fluorescence analysis of the first conjugates revealed that pH dependent bond cleavage can be measured by fluorescence spectrophotometry at endosomal and lysosomal pHs. A new approach would be the introduction of targeting moieties (e.g. peptides, antibodies) to improve selectivity to specified tissue or sites.

Imaging of Doxorubicin Release from Theranostic Macromolecular Prodrugs via Fluorescence Resonance Energy Transfer. H.R. Krüger, I. Schütz, A. Justies,  K. Licha, P. Welker, V. Haucke, M. Calderón*. Journal of Controlled Release (2014), 194, 189-196.


Dendritic polymer imaging systems for the evaluation of conjugate uptake and cleavage. H. R. Krüger, G. Nagel, S. Wedepohl, M. Calderón*. Nanoscale (2015). Manuscript accepted.

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We have established a platform technology for PEGylated nanoparticles based on dendritic polyglycerol. The design of this multifunctional approach allowed to fine-tune the drug-polymer conjugates with respect to drug loading and molecular weight and to prepare macromolecular prodrugs with similar surface charge and diameter, with different drugs and drug loading ratios as well as combination therapeutics that enable the release of at least two drugs. Furthermore, the multifunctional drug delivery system can easily be adapted to incorporate targeting ligands and diagnostic probes.

 

Selected Publications

- In vivo comparative study of distinct polymeric architectures bearing a combination of paclitaxel and doxorubicin at a synergistic ratio. H. Baabur-Cohen,§ L. Vossen,§ H.R. Krüger, A. Eldarboock, E. Yeini, N. Landa-Rouben, G. Tiram, S. Wedepohl, E. Markovsky, J. Leor, M. Calderón*, R. Satchi-Fainaro*. Journal of Controlled Release (2017), http://dx.doi.org/10.1016/j.jconrel.2016.06.037.

- Bispecific Antibodies for Targeted Delivery of Dendritic Polyglycerol (dPG) Prodrug Conjugates. F. Sheikhi-Mehrabadi, J. Adelmann, S. Gupta,S. Wedepohl, M. Calderón, U. Brinkmann, Rainer Haag. Current Cancer Drug Targets (2016), 16, 639-649.

- Dendritic Polyglycerol Sulfate as a Novel Platform for Paclitaxel Delivery: Pitfalls of Ester Linkage. A. Sousa-Herves, P. Würfel, N. Wegner, J. Khandare, K. Licha, R. Haag, P. Welker*, and M. Calderón*. Nanoscale (2015), 7, 3923-3932.

- Receptor mediated cellular uptake of low molecular weight dendritic polyglycerols. M. Calderón*, S. Reichert, P. Welker, K. Licha, F. Kratz, R. Haag. Journal of Biomedical Nanotechnology (2014), 10, 92-99.

- Targeted delivery of dendritic polyglycerol-doxorubicin conjugates by scFv-SNAP fusion protein suppresses EGFR+ cancer cell growth. A. Hussain, H.R. Krüger, F. Kampmeier, T. Weissbach, K. Licha, F. Kratz, R. Haag, M. Calderón*, S. Barth*. Biomacromolecules (2013), 14, 2510–2520.

- Multifunctional Dendritic Polymers in Nanomedicine: Opportunities and Challenges. J. Khandare§, M. Calderón§, N. Dagia, R. Haag, Chemical Society Reviews 41 (2012), 2824-2848.

- Development of efficient acid cleavable multifunctional prodrugs derived from dendritic polyglycerol with poly(ethylene glycol) shell. M. Calderón, P. Welker, K. Licha, I. Fitchner, R. Graeser, R. Haag, F. Kratz, Journal of Controlled Release151 (2011), 295–301.

- Dendritic polymers in Oncology: Facts, features, and applications. M. A. Quadir, M. Calderón, R. Haag, Book chapter in ‘Drug Delivery in Oncology: From Basic Research to Cancer Therapy’ –Wiley (2011), 513-551.

- Size-dependant cellular uptake of dendritic polyglycerol. S. Reichert, M. Calderón, J. Khandare, P. Welker, D. Mangoldt, K. Licha, R.K. Kainthan, D.E. Brooks, and R. Haag, Small 7 (2011), 820-829.

- Functional dendritic polymer architectures as stimuli-responsive nanocarriers. M. Calderón, M. Quadir, M. Strumia, R. Haag, Biochimie, 92 (2010), 1242-1251.

- Dendritic polyglycerol for biomedical applications. M. Calderón, M. Quadir, S. Sharma, R. Haag, Advanced Materials 22 (2010), 190-218.

- Development of enzymatically cleavable prodrugs derivated from dendritic polyglycerol. M. Calderón, R. Graeser, F. Kratz, R. Haag, Bio-organic and Medical Letters 19 (2009), 3725-3728.

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The combination of nanogel properties and thermo-responsiveness generates a promising candidate for the development of smart nanocarrier systems, which can be influenced by temperature with high responsiveness, reveal high loading capacity, can improve drug stability, and thus can be used for stimuli-controlled release in drug delivery. Our hypothesis treats the preparation of a new thermo-responsive glycerol based nanogel system and the investigation of their phase behavior with respect to potential biomedical applications. Initial focus was given to fabricate nanogels with size control over the range of 50 - 400 nm and narrow size distributions.

Selected Publications

- Overcoming drug resistance with on-demand charged thermoresponsive dendritic nanogels by enhanced doxorubicin uptake. M. Molina, S. Wedepohl, E. Miceli, M. Calderón*. Nanomedicine (2017), 12, 117-129.

- Dendritic polyglycerol and N-isopropylacrylamide based thermoresponsive nanogels as smart carriers for controlled delivery of drugs through the hair follicle. F.F. Sahle, M. Giulbudagian, J. Bergueiro, J. Lademann*, M. Calderón*. Nanoscale (2017), 9, 172-182.

- Transferrin Decorated Thermoresponsive Nanogels as MagneticTrap Devices for Circulating Tumor Cells. M- Asadian-Birjand, C. Biglione, J. Bergueiro, A. Cappelletti, C. Rahane, G. Chate, J. Khandare, B. Klemke, M.C. Strumia, M. Calderon*. Macromolecular Rapid Communications (2016), 37, 439-445.

- Polymeric near-infrared absorbing dendritic nanogels for efficient in vivo photothermal cancer therapy. M. Molina, S. Wedepohl, M. Calderón*. Nanoscale (2016), 8, 5852–5856.

- Thermosensitive Dendritic Polyglycerol-Based Nanogels for Cutaneous Delivery of Biomacromolecules. M. Witting§, M. Molina§, K. Obst, H.C. Hennies, M. Calderón, W. Frieß, S. Küchler. Nanomedicine: Nanotechnology, Biology, and Medicine (2015), 11, 1179-1187

- One-pot synthesis of doxorubicin-loaded multiresponsive nanogels based on hyperbranched polyglycerol. A. Sousa-Herves, S. Wedepohl, M. Calderón*. Chemical Communications (2015), 51, 5264-5267.

- Fabrication of Thermoresponsive Nanogels by Thermo-Nanoprecipitation and in situ Encapsulation of Bioactives. M. Giulbudagian,§ M. Asadian-Birjand,§ D. Steinhilber, K. Achazi, M. A. Molina, and M. Calderón. Polymer Chemistry (2014), 5, 6909-6913.

- Thermoresponsive Nanodevices in Biomedical Applications. J. Bergueiro, M. Calderón. Macromolecular Bioscience (2014), DOI: 10.1002/mabi.201400362.

- Positively Charged Thermoresponsive Nanogels for Anticancer Drug Delivery. M. A. Molina, M. Giulbudagian, and M. Calderón. Macromolecular Chemistry and Physics (2014), DOI: 10.1002/macp.201400286.

- Functional nanogels for biomedical applications. M. Asadian, J. Cuggino, D. Steinhilber, A. Souza, M. Calderón, Current Medicinal Chemistry (2012), 19, 5029-5043.

- Thermosensitive nanogels based in dendritic polyglycerol and N-isopropylacrylamide for biomedical applications. J. Cuggino, C.I. Alvarez I., M. Strumia, P. Welker, K. Licha, D. Steinhilber, R.-C- Mutihac and M. Calderón, Soft Matter 7 (2011), 11259-11266.

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Successful gene therapy relies on a rational design approach which considers the distinctive structural requirements that are necessary to create an efficient and safe gene carrier. Cationic lipids, polymers, and dendrimers are among the most promising synthetic non-viral vectors so far. Combination of their essential features led to the realization of hybrid systems for prospective use as gene vehicles.

Selected Publications

- Double-degradable responsive self-assembled multivalent arrays – temporary nanoscale recognition between dendrons and DNA. A. Barnard, P. Posocco, M. Fermeglia, A. Tschiche, M. Calderón, S. Pricl, and D.K. Smith. Organic and Biomolecular Chemistry (2014),12, 446-455.

- Glycin-terminated dendritic amphiphiles for nonviral gene delivery. S. Malhotra, H. Bauer, A. Tschiche, A. Staedtler, A. Mohr, M. Calderón, V. Parmar, L. Hoeke, S. Sharbati, R. Einspanier, R. Haag, Biomacromolecules 13 (2012),3087–3098.

- Investigating the Effects of a PEG Additive on the Biomolecular Interactions of Self-Assembled Hybrid Nanoscale Architectures. A. Barnard, M. Calderón, A. Tschiche, R. Haag, D.K. Smith, Org. Biomol. Chem. 10 (2012), 8403-8409.

- Degradable Self-Assembling Dendrons for Gene Delivery – Experimental and Theoretical Insights into the Barriers to Cellular Uptake. A. Barnard, P. Posocco, S. Pricl, M. Calderón, R. Haag, M.E. Hwang, V.W. Shum, D.W. Pack, D.K. Smith, Journal of the American Chemical Society 133 (2011), 20288-20300.

- Dendritic polyglycerols with oligoamine shells show low toxicity and high siRNA transfection efficiency in vitro. W. Fischer, M. Calderón, A. Schulz, I. Andreou, M. Weber, R. Haag, Bioconjugate Chemistry 21 (2010), 1744-1752.

- In vivo delivery of siRNA to tumors and their vasculature by novel dendritic nanocarriers. P. Ofek, W. Fischer, M. Calderón, R. Haag and R. Satchi-Fainaro, FASEB J. 24 (2010), 3122-3134.

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