Self-assembled angiopep-2 modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles delivery TMZ for glioma synergistic TMZ and RT therapy

Abstract

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH 2 s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.

Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model

“…Based on this sequence, short peptides (Angiopeps ~2,3 kDa) which penetrate the BBB ten times more efficiently than BPTI were created [ 65 ]. The possibilities of their use in the composition of complex nanoparticles for the delivery of chemotherapeutic drugs to brain tumors are currently being investigated [ 66 , 67 , 68 ]. The indicated C-terminal fragment of BPTI or Angiopep-2 shares ~50% of identity with the corresponding fragment of Kunitz-type peptides from sea anemone H. crispa .…”

Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma

“…Zong et al developed angiopep-2 (A2) modified lipid-poly NP for TMZ delivery to achieve synergistic effects against glioma. The NP were injected in tail vein to subsequently penetrate the BBB and enter the glioma tumor due to the EPR effect and active target [ 71 ]. In this study, mice with xenograft glioma were divided into seven groups ( n = 10).…”

“…With this design, the in vitro and in vivo results demonstrated that these A2- P(MIs)25/TMZ can efficiently target glioma to increase the concentration of TMZ (hypoxic cell radiosensitizers). Additionally, the therapeutic studies showed that A2-P(MIs)25/TMZ can effectively inhibit the growth of glioma cells and significantly improve mice survival time without adverse effects [ 71 ].…”

Nanomedicine Revisited: Next Generation Therapies for Brain Cancer

“…Examples specific to GBM include targeting moieties that bind to cellular receptors such as Tf‐R, EGFR, Fn14 protein (Fn14), and the lipoprotein receptor protein (LRP‐1). [ 80,85,93,99–101 ] Groups have shown that nanoparticles with targeting moieties binding to these ligands exhibit significant increase in specificity and uptake by GBM cells ≈13‐fold (Tf‐R), ≈1.4‐fold (EGFR), ≈3.5‐fold (Fn14), and ≈2.3‐fold (LRP‐1) when compared to controls without the moiety. [ 85,99–101 ] It is important to note that this variation between targeting ligands may be due to the preclinical model used and mode of nanoparticle delivery (systemic vs local), but regardless, improved targeting is evident and can be further optimized with combinations of moieties.…”