nanoparticle-delivery-an-oligonucleotide-payload-glioblastoma

Nanoparticle Delivery of an Oligonucleotide Payload in a Glioblastoma Multiforme Animal Model

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain malignancy for which there is no cure. The blood-brain barrier is a ...

Michigan State University

Paclitaxel (PTX) is a widely used chemotherapeutic agent in the clinic. However, its clinical benefit is limited due to its low water solubility, off-target toxicity, and for being a multidrug-resistant (MDR) substrate. To overcome these limitations in this study, a tumor-targeting peptide (CRGDK peptide, a ligand for NRP-1 receptor) conjugate of α-tocopheryl succinate (α-TOS) was synthesized and modified on PTX-loaded lipid aggregate (TL-PTX) to leverage the benefits of α-TOS, which include a) anti-cancer activity, b) increased PTX loading, and c) inhibition of MDR activity. Use of peptide conjugate of α-TOS (α-TOS-CRGDK) in lipid aggregate increased PTX entrapment efficiency by 20%, helped in NRP-1 specific cellular uptake and significantly enhanced apoptotic and cell killing activity (p <0.01) of PTX compared to control formulation (CL-PTX) by inhibiting MDR-activity in melanoma resulting in ∼70% increment in overall survival of melanoma tumor-bearing mice. In conclusion, CRGDK- α-TOS conjugate in association with PTX-loaded liposome provided a unique NRP-1 targeted, drug-resistant reversing anticancer regimen for treating aggressive melanoma.

Modification of α-Tocopherol Succinate with a Tumor-targeting Peptide Conjugate Enhances the Antitumor Efficacy of a Paclitaxel-loaded Lipid Aggregate.

 Recent studies have shown that miRNA-10b is highly expressed in high-grade glioblastoma multiforme (GBM), and its inhibition leads to deregulation of multiple pathways in tumorigenesis, resulting in repression of tumor growth and increased apoptosis. Thus, we hypothesized that suppressing miR-10b could enhance the cytotoxicity of conventional GBM chemotherapy with temozolomide (TMZ).  Inhibition of miR-10b in glioblastoma cells was achieved using an experimental therapeutic consisting of anti-miR10b antagomirs conjugated to iron oxide nanoparticles (termed MN-anti-miR10b). The nanoparticles serve as delivery vehicles for the antagomirs as well as imaging reporters guiding the delivery in future animal studies.  Treatment of U251 and LN229 human glioblastoma cells with MN-anti-miR10b led to inhibition of miR-10b accompanied by repression of growth and increase in apoptosis. We next explored whether MN-anti-miR10b could enhance the cytotoxic effect of TMZ. During these studies, we unexpectedly found that TMZ monotherapy increased miR-10b expression and changed the expression of corresponding miR-10b targets. This discovery led to the design of a sequence-dependent combination treatment, in which miR-10b inhibition and induction of apoptosis by MN-anti-miR10b was followed by a sub-therapeutic dose of TMZ, which caused cell cycle arrest and ultimately cell death. This combination was highly successful in significant enhancement of apoptosis and decrease in cell migration and invasiveness.  Considering the unexpected effects of TMZ on miR-10b expression and possible implications on its clinical application, we reasoned that comprehensive  studies were warranted before embarking on studies in animals. These intriguing findings serve as a solid foundation for future  studies and offer promise for the successful treatment of GBM.

Co-administration of temozolomide (TMZ) and the experimental therapeutic targeting miR-10b, profoundly affects the tumorigenic phenotype of human glioblastoma cells.

Approximately 10% of women suffer from endometriosis during their reproductive years. This disease is a chronic debilitating condition whose etiology for lesion implantation and survival heavily relies on adhesion and angiogenic factors. Currently, there are no clinically approved agents for its detection. In this study, we evaluated cRGD-peptide-conjugated nanoparticles (RGD-Cy5.5-MN) to detect lesions using magnetic resonance imaging (MRI) in a mouse model of endometriosis. We utilized a luciferase-expressing murine suture model of endometriosis. Imaging was performed before and after 24 h following the intravenous injection of RGD-Cy5.5-MN or control nanoparticles (Cy5.5-MN). Next, we performed biodistribution of RGD-Cy5.5-MN and correlative fluorescence microscopy of lesions stained for CD34. Tissue iron content was determined using inductively coupled plasma optical emission spectrometry (ICP-OES). Our results demonstrated that targeting endometriotic lesions with RGD-Cy5.5-MN resulted in a significantly higher delta T2* upon its accumulation compared to Cy5.5-MN. ICP-OES showed significantly higher iron content in the lesions of the animals in the experimental group compared to the lesions of the animals in the control group. Histology showed colocalization of Cy5.5 signal from RGD-Cy5.5-MN with CD34 in the lesions pointing to the targeted nature of the probe. This work offers initial proof-of-concept for targeting angiogenesis in endometriosis which can be useful for potential clinical diagnostic and therapeutic approaches for treating this disease.

Imaging of Endometriotic Lesions Using cRGD-MN Probe in a Mouse Model of Endometriosis.

Despite advances in breast cancer screening and treatment, prognosis for metastatic disease remains dismal at 30% five-year survival. This is due, in large, to the failure of current therapeutics to target properties unique to metastatic cells. One of the drivers of metastasis is miR-10b, a small noncoding RNA implicated in cancer cell invasion, migration, viability, and proliferation. We have developed a nanodrug, termed MN-anti-miR10b, that delivers anti-miR-10b antisense oligomers to cancer cells. In mouse models of metastatic triple-negative breast cancer, MN-anti-miR10b has been shown to prevent onset of metastasis and eliminate existing metastases in combination with chemotherapy, even after treatment has been stopped. Recent studies have implicated miR-10b in conferring stem cell-like properties onto cancer cells, such as chemoresistance. In this study, we show transcriptional evidence that inhibition of miR-10b with MN-anti-miR10b activates developmental processes in cancer cells and that stem-like cancer cells have increased miR-10b expression. We then demonstrate that treatment of breast cancer cells with MN-anti-miR10b reduces their stemness, confirming that these properties make metastatic cells susceptible to the nanodrug actions. Collectively, these findings indicate that inhibition of miR-10b functions to impair breast cancer cell stemness, positioning MN-anti-miR10b as an effective treatment option for stem-like breast cancer subtypes.

Article	Year
Modification of α-Tocopherol Succinate with a Tumor-targeting Peptide Conjugate Enhances the Antitumor Efficacy of a Paclitaxel-loaded Lipid Aggregate. Chemistry, an Asian journal\| PubMed ID: 36482874	2023
Co-administration of temozolomide (TMZ) and the experimental therapeutic targeting miR-10b, profoundly affects the tumorigenic phenotype of human glioblastoma cells. Frontiers in molecular biosciences\| PubMed ID: 37398551	2023
Imaging of Endometriotic Lesions Using cRGD-MN Probe in a Mouse Model of Endometriosis. Nanomaterials (Basel, Switzerland)\| PubMed ID: 38334590	2024
Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties. Oncotarget\| PubMed ID: 39189967	2024

Sujan K. Mondal

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