TY  - THES
T1  - Cationically-modified nanoparticles for the pulmonary delivery of the telomerase inhibitor 2';-O-Methyl RNA for the treatment of lung cancer
A1  - Nafee,Noha
Y1  - 2009/01/07
N2  - Lung cancer is one of the main causes of cancer-related death worldwide. One of the reasons behind the extensive tumour growth is telomerase enzyme, which is notably expressed in cancer cells. Recent strategies for cancer therapy include, therefore, telomerase inhibition with antisense RNA. A major challenge is the weak cellular uptake of these nucleotide-based drugs which necessitates the choice of appropriate carrier systems. The aim of this study was hence to evaluate chitosan-modified PLGA nanoparticles (cNP) as carrier for the antisense oligonucleotide 2'-O-Methyl-RNA (OMR) and their efficacy as inhalation therapy. Modification of the process parameters revealed the tuneability of the NP synthesis in terms of size and surface charge. Studying the cellular uptake of fluorescent cNPs with increasing amounts of chitosan showed better uptake in A549 than in Calu-3 cells. Chitosan significantly improved the uptake and binding with OMR; however, higher chitosan content reduced the uptake efficiency. Uptake studies under in vivo mimicking conditions using air-interface cultures showed superior cellular uptake of OMR/cNP nanoplexes compared to free OMR. As a proof of the concept, the ability of OMR to reduce telomerase activity was demonstrated.

In conclusion, the concept of telomerase inhibition based on nanoscale delivery of antisense oligonucleotides represents a step forward to a new generation of cancer therapeutics.
KW  - Nanopartikel
KW  - Chitosan
KW  - Telomerase
KW  - Lungenkrebs
KW  - Antisense-Oligonucleotide
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2009/2029
ER  -