Sulfonated Amphiphilic Poly(α)glutamate Amine-A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors.

Adva Krivitsky,Vadim Krivitsky,Eilam Yeini,Paula Ofek,Sahar Israeli Dangoor,Ronit Satchi-Fainaro,Sabina Pozzi,Sapir Golan,Asaf Madi,Tal Zur,Nitzan Albeck,Evgeny Pisarevsky

doi:10.3390/pharmaceutics13122199

Abstract

Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O6-methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of canonical genes related to cell proliferation and tumor progression, such as Polo-like kinase 1 (Plk1). Hereby, we attempt to sensitize resistant GB cells using our established amphiphilic poly(α)glutamate (APA): small interfering RNA (siRNA) polyplexes, targeting Plk1. Furthermore, we improved brain-targeting by decorating our nanocarrier with sulfonate groups. Our sulfonated nanocarrier showed superior selectivity towards P-selectin (SELP), a transmembrane glycoprotein overexpressed in GB and angiogenic brain endothelial cells. Self-assembled polyplexes of sulfonated APA and siPlk1 internalized into GB cells and into our unique 3-dimensional (3D) GB spheroids inducing specific gene silencing. Moreover, our RNAi nanotherapy efficiently reduced the cell viability of both chemo-sensitive and chemo-resistant GB cells. Our developed sulfonated amphiphilic poly(α)glutamate nanocarrier has the potential to target siRNA to GB brain tumors. Our findings may strengthen the therapeutic applications of siRNA for chemo-resistant GB tumors, or as a combination therapy for chemo-sensitive GB tumors.

Highlights

684 GB patients (25% long term and 25% short term survivors) revealed that high expression of both methylguanine-DNA methyltransferase (MGMT) and Polo-like kinase 1 (Plk1) significantly correlated with short-term survival, while low expression of both proteins significantly correlated with long-term survival of GB patients (Figure 1A)
The obtained results confirmed that in comparison to parental U251, TMZ-R cells express significantly higher levels of MGMT, while Plk10 s expression remained unchanged following the acquirement of TMZ resistance
We concluded that the inhibition of Plk1 could be an additional and attractive strategy to use in combination with TMZ in order to improve the survival of GB patients, whether sensitive or resistant to chemotherapy

Summary

Introduction

Glioblastoma (GB) is the most common and the deadliest type of malignant primary brain tumor in adults, with an annual age-adjusted incidence rate of 4.4 per 100,000 population. GB patient prognosis is extremely poor, with a 5-year survival rate of only 5.5% [1]. The current treatment regimen includes maximal surgical resection, followed by radiation and chemotherapy with alkylating agents, such as temozolomide (TMZ) [2]. This regimen increases patients’ median survival of 3 to 14 months [3,4]. Recurrence developed in more than 90% of patients within several years, and often displays enhanced resistance to initial chemotherapy treatment [5].

Methods

Results

Conclusion