Activation of RNA interference (RNAi), a sequence-specific gene silencing mechanism, by synthetic small interfering (si)RNAs holds great promise as a novel therapeutic approach. siRNAs now represent the most promising type of RNAi-based therapeutics currently advancing in preclinical and clinical trials. Specifically, using siRNAs to suppress gene expression of specific molecule in hematologic cells would not only facilitates our understanding of the mechanism of disease, but could also help us develop RNAi-based and mechanism- oriented medicine to treat incurable blood cancers (e.g., multiple myeloma). However, blood cancers are among the most difficult targets for siRNA delivery, as they are resistant to conventional transfection reagents, and disperse in the body, making it hard to successfully localize or passively deliver via systemic administration. This is further compounded by the lack of systemically applicable technologies for selectively targeting siRNAs to blood cancers. In order to realize RNAi-based cancer treatment, the development of robust siRNA delivery technologies is imperative. Indeed, they must enable effective and specific gene silencing in target cells while mitigating off-target effects. We have addressed this specific problem by developing integrin-targeted stabilized nanoparticles (I-tsNP): nano-sized stabilized neutral liposomes that encapsulate siRNAs and that are selectively directed to blood cancer cells via surface-attached monoclonal antibodies (mAbs) to leukocyte integrins (e.g., alphaLbeta2 [LFA-1] and beta7 integrins). We have demonstrated in our preliminary data that siRNA delivery with I-tsNP induced potent gene silencing selectively in hematologic cells in vivo. We now intend to further validate and enhance the ability of I-tsNP to deliver siRNAs to blood cancers for in vivo applications.
Aim 1 is to test the hypothesis that I-tsNP serves as the optimal siRNA delivery technology to hematologic cells, thereby facilitating the validation of drug targets in vivo. To establish the groundwork for performing siRNA-based drug target validation in mice, we will define the in vivo delivery and safety profiles of I-tsNP that targets hematologic cell-specific integrins.
Aim 2 is to validate the hypothesis that siRNA delivery by I-tsNP induces therapeutic gene silencing in blood cancers using multiple myeloma (MM) as a model. Encapsulating, into the nanoparticles, the siRNAs to established MM drug targets (e.g., AKT, HSP90, or HDAC6), we will validate I-tsNP in a highly clinically relevant xenograft model bearing human MM cell in human bone marrow microenvironment (i.e., SCID-hu MM model).
Aim 3 is to substantiate the hypothesis that high-affinity conformation of the integrin LFA-1 can be used for selectively targeting siRNAs to MM cells. Using mAb AL-57 that preferentially binds to the high-affinity LFA-1, we will study the ability of I-tsNP to selectively deliver siRNAs in vivo to MM cells that express aberrantly activated LFA-1. I-tsNP, as proposed in these contexts, should help establish a siRNA delivery platform technology that will realize RNAi-based medicine for blood cancers.

Public Health Relevance

Since the discovery of RNA interference (RNAi) in worms in 1998 that earned the Nobel Prize in 2006, the race continues in the effort to realize RNAi-based medicine for a new treatment of many diseases including incurable blood cancers (e.g., multiple myeloma). The major challenge for the realization of RNAi-based medicine is, however, to direct intact RNAs to the right tissues in the body and then successfully escort them into cells. We tackle this specific problem by developing integrin-targeted stabilized nanoparticles (I-tsNP): a novel nanoscale delivery vehicle to target therapeutic RNAs to blood cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA139444-08
Application #
8204874
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2010-03-10
Project End
2012-09-30
Budget Start
2012-05-02
Budget End
2012-09-30
Support Year
8
Fiscal Year
2012
Total Cost
$439,110
Indirect Cost
$230,010
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
City
Boston
State
MA
Country
United States
Zip Code
02115
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