Various strategies have been taken for cancer chemotherapy, however, treatment-related toxicity and immune response are still major issues due to the lack of targeted delivery to cancer cells. In particular, pediatric high grade gliomas (pHGGs) are currently often difficult to treat, largely due to locations of the disease. High levels of oncogenic miRNA (oncomiR) inhibit expression of tumor suppressor proteins, thus critically implicated in initiation and progression of pHGGs. Anti-miRNA can neutralize oncomiRNA that are aberrantly expressed in pHGG, and restore the expression of tumor suppressor proteins that inhibit tumor growth. However, cellular delivery of anti-miRNA is currently one of the largest challenges for advancement into the clinic. Peptide-mediated anti-miRNA delivery that efficiently and specifically targets cancer cells may offer a solution. Our innovative approach potentially overcomes these problems for the following reasons: 1) a novel non-toxic CPP, p28, selectively enters cancer cells; 2) p28 crosses the blood-brain barrier and can serve as a cancer-targeting delivery system when functional molecules are conjugated; 3) p28-conjugated with anti-miRNAs, which is highly specific to their targets, will be expected to specifically inhibit growth of pHGGs. Our supporting data suggest that p28 conjugated with anti-miR20 (anti-miR20-p28), the overexpressed oncomiR in pHGG compared to adult high-grade glioma (aHGG) and healthy brain tissue, preferentially and successfully delivers functional anti-miR20 into pHGGs. The overall goal of this proposal is to take a strategic approach to evaluate the effects of anti-miRNAs conjugated with non-toxic tumor-targeting peptide (p28) on pHGGs. If successful, our approaches may potentially overcome the major limitation of current anti-miRNA-based therapy and improve the treatment of childhood brain tumors without damaging healthy tissues.
(Relevance) Our novel cell-penetrating peptide (CPP) that crosses the blood brain barrier (BBB) and preferentially enters cancer cells can be an effective therapeutic agent for difficult to treat pediatric brain cancer cells that are aberrantly expressing oncomiRs. Anti-miRNA based agents show promising effect in vitro, but delivery of the anti-miRNAs to tumor in vivo has been challenging. Our approach potentially enables cellular delivery of such anti-miRNAs by using CPP (p28) as a carrier and overcomes the limitations of developing anti-miRNA-based agents for pediatric patients with brain cancer.
