Therapeutic applications of siRNA-mediated gene silencing appear to be highly dependent on the use of pharmaco-technologic carrier systems, able to protect siRNAs from rapid degradation upon administration, as well as to specifically deliver them to target cells. Actually, while siRNA-expressing viral vectors are burdened with safety concerns for their clinical use, the development of modified liposomal nanocarriers may represent a feasible option to harness the therapeutic potential of targetedantineoplastic siRNAs. Recently, we have successfully developed and characterized effective immunoliposomal nanosystems (ILNs) for targeted delivery of Cidofovir (an anti-herpesviral nucleotideanalogue, also showing antitumor activity) against PEL cell lines, demonstrating a significant improvement of the antineoplastic activity of the drug, especially at lower doses (less than 1nM). Thus, we tried to adapt such PEL-specific ILNs (PEGilated nanovescicles made of cationic/neutral lipids, engineered with anti-CD138 moAb on their surface) to efficiently encapsulate siRNAs and deliver them into PEL cell lines (highly expressing CD138 membrane protein). Our preliminary data showed thatsingle treatments with anti-PEL ILNs, delivering specific siRNAs against Blimp1 (Prdm1), which is a master transcription factor in PEL (a plasmablast/pre-plasmacell lymphoma, consistently Bcl-6 neg, Blimp1 pos), were able to induce a dose-dependent (50-200nM) inhibition of Blimp1 production (as assessed by Blimp1 mRNA and protein levels using RT-PCR and Western Blot, respectively), and this was strongly associated with enhanced cell death (more than 80%, using Annexin V/PI test). In particular, we observed a massive reduction of PEL viability (mean viable cells 8%, range 3-15%) as soon as 48-72 hours after treatment with 100nM anti-Blimp1 siRNAs. Interestingly, these data may resemble those described in multiple myeloma cell lines, after transduction with lentiviral vector constitutively expressing anti-Blimp1 shRNAs. Further studies on PEL murine models are now warranted to assess the efficacy and toxicity profile of in-vivo treatment with PEL-specific ILNs, loadedwith either Cidofovir or anti-Blimp1 siRNAs.
|Data di pubblicazione:||2011|
|Titolo:||Tumor-targeted immunoliposomal nanosystems to deliver either Cidofovir or Antineoplastic SiRNA against Primary Effusion Lymphoma (PEL)|
|Autore/i:||Riva G; Belletti D; Ruozi B; Barozzi P; Vallerini D; Quadrelli C; Zanetti E; Morselli M; Forghieri F; Marasca R; Narni F; Tosi G; Forni F; Vandelli MA; Potenza L; Luppi M|
|Nome del convegno:||43 Congresso Nazionale della Società Italiaa di Ematologia|
|Luogo del convegno:||Napoli|
|Data del convegno:||16-19 Ottobre 2011|
|Citazione:||Tumor-targeted immunoliposomal nanosystems to deliver either Cidofovir or Antineoplastic SiRNA against Primary Effusion Lymphoma (PEL) / Riva G; Belletti D; Ruozi B; Barozzi P; Vallerini D; Quadrelli C; Zanetti E; Morselli M; Forghieri F; Marasca R; Narni F; Tosi G; Forni F; Vandelli MA; Potenza L; Luppi M. - STAMPA. - (2011), pp. 179-179. ((Intervento presentato al convegno 43 Congresso Nazionale della Società Italiaa di Ematologia tenutosi a Napoli nel 16-19 Ottobre 2011.|
|Tipologia||Relazione in Atti di Convegno|
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