Regulated release of Pt-based drugs from multi-component Au-nanocarriers

Final Report Summary - NOBLEMED (Regulated release of Pt-based drugs from multi-component Au-nanocarriers)

The NOBLEMED research proposal described the synthesis of a thioether-based coated-gold nanoparticle system, to which a cleavable peptide was attached to render control over the delivery of a platinum-based prodrug to the cancer cell. The work plan described in the original proposal was divided in 3 years; the first two years at MIT consisted of the synthesis, characterization and preliminary evaluation of such system in cancer cells, and the last year at UU was available for more in-depth in vitro studies. However, during the outgoing period at MIT the objectives of NOBLEMED work package were modified from those listed in the original grant proposal. Because the research group at MIT reported the development of new platinum(IV) prodrugs conjugated to DNA-AuNPs [1] and further studies were required on this system, the task of the researcher at MIT was to improve the published delivery system and study it further in vitro and in vivo. Despite the efforts, the coupling reaction reported between the oligonucleotide-coated gold nanoparticle and the platinum(IV) complex [1] was difficult to reproduce and characterize. Several attempts to reproduce and to improve the system were undertaken by the researcher. Unfortunately, these attempts were not successful or publishable, and a new work plan to accomplish the desired nano-delivery system was required during the return phase at UU.
A new approach was followed during the return phase to develop new gold nanoparticle delivery systems. The researcher designed, synthesized and characterized two new platinum complexes with an appended biotin moiety. Commercially available streptavidin-coated gold nanoparticles were purchased and used to study their potential as nanocarriers, given the high binding affinity between streptavidin and biotin. Both platinum complexes were successfully conjugated to the nanocarrier, confirming the potential of the approach to deliver these new complexes to the cells. The cytotoxic studies performed on a panel of ovarian cancer cells were unfortunately not very successful, showing no or poor improvement as compared to the cytotoxicity displayed by free cisplatin.
In view of the results obtained with the gold nanoparticle-based delivery systems, the researcher decided to work on active targeting of cisplatin nanocapsules to gain additional experience with a different nanoconstruct and to increase the chances of success. The new work plan to actively target cisplatin nanocapsules to cancer cells was based on a method developed at the host group more than a decade ago to encapsulate cisplatin in a lipid bilayer [2]. Upon hydration of a lipid film with a well-equilibrated, saturated aqueous solution of cisplatin and subsequent freeze-thaw cycles, the so-called cisplatin nanocapsules were prepared, consisting of solid aggregates of cisplatin encapsulated in a lipid bilayer. In vitro studies of such cisplatin nanocapsules revealed an improved cytotoxic effect against a large panel of cancer cells compared to the free drug [3]. To actively target cancer, the outer leaflet of the nanocapsules was modified using a phosphine-activated group, which allowed functionalization of the nanocarrier with azido-containing molecules via Staudinger ligation. This ligation was explored in several experiments, including in vitro studies in cancer cells.
This research is described in more detail in the attached periodic report 2013-2014. The possibility to actively deliver platinum-based drugs in a more selective manner to cancer cells over healthy cells is highly relevant in this research field. The research summarized herein is a contribution to the investigations towards formulations that improve drug administration to cancer patients using targeting molecules to render treatment more efficient. The results of this research will be published in a peer reviewed journal, which will contribute to the scientific progress in this field, thereby highlighting the quality of European research.

[1]. S. Dhar, W. L. Daniel, D. A. Giljohann, C. A. Mirkin and S. J. Lippard, (2009) J. Am. Chem. Soc., 131, 14652-14653.
[2]. Burger KN1, Staffhorst RW, de Vijlder HC, Velinova MJ, Bomans PH, Frederik PM, de Kruijff B. (2002) Nat. Med., 8, 81-4.
[3]. Hamelers, I.H. Staffhorst, R.W. Voortman, J., de Kruijff, B., Reedijk. J., van Bergen en Henegouwen, P.M. and de Kroon, A.I. (2009) Clin. Cancer Res.,15, 1259-1268.

Final Report Summary - NOBLEMED (Regulated release of Pt-based drugs from multi-component Au-nanocarriers)

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