Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy

Abstract

Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy (RT). However, there is no effective drug delivery system to effectively overcome the blood—brain barrier (BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles (ch-K n (s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed on brain capillary endothelial cells (BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2 (MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-K n (s-s)R8-An micelles maintained a reasonable size (80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration (CMC) with positive surface charge, ranging from 15 to 40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro , improved uptake in glioma cells and good biocompatibility in vitro and in vivo . In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro . Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.

Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

“…This delivery system showed high gene transfection efficiency and improved uptake in glioma cells. The application of ch-K5(s-s) R8-An/Dbait with radiotherapy dramatically inhibited the tumor growth in vitro (Jiao et al, 2019). pH was the most common condition to trigger CPPs activation in tumor delivery, pH-responsive anionic materials were generally used in combination.…”

In vivo gene delivery mediated by non-viral vectors for cancer therapy

“…There are several various approaches to improve the transfection efficiency of non-viral carriers for brain delivery. For example, Jiao et al [221] designed a multifunctional cargo for gene delivery (Fig. 4).…”

“…They prepared a cholesterol coupled micelle containing lysine and arginine (ch-KnR8) with the particle size and zeta potential of 90-160 nm and +10-40 mV, respectively. The cargo showed high transfection efficacy and uptake in U251 cells and high accumulation in mice bearing glioma [221].…”

“…(B) Size distribution and TEM image of the micelles. (C) Real-time in vivo fluorescence imaging of U251 tumor-bearing nude mice intravenously administrated with PBS(I), YOYO-1(II), ch-K5(s-s)R8/pEGFP-YOYO-1(III), and ch-K5(s-s)R8-An/pEGFP-YOYO-1 (IV).Reprinted with permission from[221].…”

Sodium Tanshinone IIA Sulfonate Promotes Spinal Cord Injury Repair by Inhibiting BSCB Disruption In Vitro and In Vivo

“…The impermeability of the BSCB depends on the TJ and AJ proteins that are expressed by the SCMECs, and form a barrier which keeps solutes and cells from entering into the inner environment [14]. The activation of matrix metalloproteases (MMPs), especially MMP-9 and MMP-2, is the key pathological basis of BSCB disruption [15][16][17]. MMP9 causes proteolytic degradation of the BBB, and blocking MMP9 activity can attenuate vascular permeability [18].In fact, restoring BSCB integrity is the primary therapeutic approach for SCI.…”