No abstract

The type 1 insulin-like growth factor receptor (IGF1R) is often overexpressed by tumors and mediates growth and apoptosis protection. We previously showed that antisense reagents complementary to the IGF1R translation start site enhance radio-and chemosensitivity and impair Atm function. However these agents induce relatively modest IGF1R down-regulation and affect insulin receptor levels. To identify alternative sites for molecular targeting, we utilized scanning oligonucleotide arrays to probe the secondary structure of IGF1R mRNA. This strategy enabled selection of antisense oligonucleotides that generated high heteroduplex yield with IGF1R but not insulin receptor transcripts. Antisense oligonucleotides that hybridized strongly to IGF1R mRNA caused IGF1R down-regulation within intact tumor cells, whereas weakly hybridizing oligonucleotides were inactive. Furthermore, the ability of small interfering RNAs (siRNAs) to block IGF1R expression correlated with the accessibility of the target sequence within the transcript. Thus, siRNAs corresponding to weakly hybridizing oligonucleotides caused minor IGF1R down-regulation, whereas siRNAs homologous to accessible targets induced profound sequencespecific IGF1R gene silencing, blocked IGF signaling, and enhanced tumor cell radiosensitivity. This indicates that secondary structure in the target transcript has a major effect on siRNA efficacy. These findings have implications for siRNA design and suggest that IGF1R-targeting agents incorporating this mode of action have potential as anticancer therapy.The type 1 insulin-like growth factor receptor (IGF1R) 1 is often overexpressed by tumors (1-3), and IGF1R activation mediates tumor cell proliferation, motility, and protection from apoptosis (4). Tumor growth can be inhibited in vivo by blocking IGF1R expression using antisense agents targeting the IGF1R translation start site (TSS) (5). We previously showed that TSS antisense oligonucleotides (ASOs) and antisense RNA enhanced tumor cell sensitivity to cytotoxic drugs and ionizing radiation and impaired the function of Atm (6, 7). However we could not suppress IGF1R expression by more than 80% and sought to identify alternative sites for molecular targeting.Intramolecular folding of mRNAs renders all but 5-10% of most transcripts inaccessible to binding of complementary nucleic acids, but the complex secondary structure of long mRNAs is not amenable to accurate modeling (8 -11). We used an array-based screen (12) to identify sites within the human IGF1R transcript that were accessible to RNase-H-mediated cleavage. This information on secondary structure allowed us to identify molecular agents that induced IGF1R down-regulation without affecting insulin receptor (IR) expression. Structural constraints were shown to govern the activity of ASOs and also of small interfering RNAs (siRNAs) that mediate RNA interference (RNAi) in mammalian cells (13). MATERIALS AND METHODSOligonucleotides-A 12-mer deoxyribophosphodiester oligonucleotide library (dN 12 ) was synthesized as de...

No abstract

With the advent of technology, the role of nanomaterials in medicine has grown exponentially in the last few decades. The main advantage of such materials has been exploited in drug delivery applications, due to their effective targeting that in turn reduces systemic toxicity compared to the conventional routes of drug administration. Even though these materials offer broad flexibility based on targeting tissue, disease, and drug payload, the demand for more effective yet highly biocompatible nanomaterial-based drugs is increasing. While therapeutically improved and safe materials have been introduced in nanomedicine platforms, issues related to their degradation rates and bio-distribution still exist, thus making their successful translation for human use very challenging. Researchers are constantly improving upon novel nanomaterials that are safer and more effective not only as therapeutic agents but as diagnostic tools as well, making the research in the field of nanomedicine ever more fascinating. In this review stress has been made on the evolution of nanomaterials that have been approved for clinical applications by the United States Food and Drug Administration Agency (FDA).