All-stage precisional glioma targeted therapy enabled by a well-designed D-peptide.

Uncontrollable cell proliferation and irreversible neurological damage make glioma one of the most deadly diseases in clinic. Besides the multiple biological barriers, glioma stem cells (GSCs) that are responsible for the maintenance and recurrence of tumor tissues also hinder the therapeutic efficacy of chemotherapy. Therefore, all-stage precisional glioma targeted therapy regimens that could efficiently deliver drugs to glioma cells and GSCs after overcoming multiple barriers have received increasing scrutiny. Methods: A polymeric micelle-based drug delivery system was developed by modifying a "Y-shaped" well-designed ligand of both GRP78 protein and quorum sensing receptor to achieve all-stage precisional glioma targeting, then we evaluated the targeting ability and barrier penetration ability both in vitro and in vivo. In order to achieve all-stage precisional therapy, we need kill both GSCs and glioma related cells. Parthenolide (PTL) has been investigated for its selective toxicity to glioma stem cells while Paclitaxel (PTX) and Temozolomide (TMZ) are widely used in experimental and clinical therapy of glioma respectively. So the in vivo anti-glioma effect of combination therapy was evaluated by Kaplan-Meier survival analysis and immunohistochemical (IHC) examination of tumor tissues. Results: The "Y-shaped" well-designed peptide, termed DWVAP, exhibited excellent glioma (and GSCs) homing and barrier penetration ability. When modified on micelle surface, DWVAP peptide significantly enhanced accumulation of micelles in brain and glioma. In addition, DWVAP micelles showed no immunogenicity and cytotoxicity, which could guarantee their safety when used in vivo. Treatment of glioma-bearing mice with PTL loaded DWVAP modified PEG-PLA micelles plus PTX loaded DWVAP modified PEG-PLA micelles or PTL loaded DWVAP modified PEG-PLA micelles plus TMZ showed improved anti-tumor efficacy in comparison to PTL and PTX loaded unmodified micelles or PTL loaded unmodified micelles plus TMZ. Conclusion: Combination of all-stage targeting strategy and concomitant use of chemotherapeutics and stem cell inhibitors could achieve precise targeted therapy for glioma.

EGFR/EGFRvIII Dual-Targeting Peptide-Mediated Drug Delivery for Enhanced Glioma Therapy.

Tumor-homing peptides have been widely used to mediate active targeted drug delivery. l-AE is a reported targeting peptide demonstrating high binding affinity to epidermal growth factor receptor (EGFR) and mutation variant III (EGFRvIII) overexpressed on neovasculature, vasculogenic mimicry, tumor cells, and tumor stem cells. To improve its proteolytic stability, a d-peptide ligand (termed d-AE, the enantiomer of l-AE) was developed. d-AE was confirmed to bind receptors EGFR and EGFRvIII with targeting capability comparable to l-AE. In vivo biodistribution demonstrated the superiority of d-AE in prolonged circulation and enhanced intratumoral accumulation. Furthermore, stabilized peptide modification endowed micelles higher transcytosis efficiency and penetrating capability on blood-brain tumor barrier/U87 tumor spheroids coculture model. When paclitaxel (PTX) was loaded, d-AE-micelle/PTX demonstrated excellent antitumor effect in comparison to Taxol, micelle/PTX, and l-AE-micelle/PTX. These findings indicated that the multitargeted drug delivery system enabled by d-AE ligand provides a promising way for glioma therapy.

d-Retroenantiomer of Quorum-Sensing Peptide-Modified Polymeric Micelles for Brain Tumor-Targeted Drug Delivery.

Compared to that of other tumors, various barriers, such as the blood-brain barrier (BBB), enzymatic barriers, and the blood-brain tumor barrier, severely impede the successful treatment of gliomas. Peptide ligands were frequently used as targeting moieties to mediate brain tumor-targeted drug delivery. LWSW (SYPGWSW) is a recently reported quorum-sensing (QS) peptide that is able to efficiently cross the BBB. Even though linear LWSW traverses the BBB in vitro, its in vivo targeting ability has been greatly impaired due to proteolysis. Here, we developed a stable peptide, DWSW (DWDSDWDGDPDYDS), using the retro-inverso isomerization technique to achieve an enhanced antiglioma effect. In vitro studies have demonstrated that both the LWSW and DWSW peptides possessed excellent tumor-homing properties and barrier-penetration abilities, whereas DWSW exhibited exceptional stability in serum and maintained its targeting ability after serum preincubation. In vivo, DWSW-modified probes and micelles accumulated more efficiently in the glioma region in comparison with LWSW-modified probes and micelles because of full resistance to proteolysis in blood circulation. As expected, DWSW-modified paclitaxel (PTX)-loaded micelles (DWSW Micelle/PTX) exhibited the longest median survival time among glioma-bearing nude mice. Our results suggested that the QS peptide appears to be a promising targeting moiety, with potential applications in glioma-targeted drug delivery.

GRP78 enabled micelle-based glioma targeted drug delivery.

GRP78, a specific cancer cell-surface marker, is implicated in cancer cells proliferation, apoptosis resistance, metastasis and drug resistance. l-VAP (SNTRVAP) is a tumor homing peptide exhibiting high binding affinity in vitro to GRP78 protein overexpressed on glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Even though short peptides are often non-immunogenic and demonstrate high affinity to tumor cells, their targeting efficacy is always undermined by rapid blood clearance and enzymatic degradation. In the present study, two d peptides RI-VAP (retro inverso isomer of l-VAP) and d-VAP (retro isomer of l-VAP) were developed by structure-guided peptide design and retro-inverso isomerization technique for glioma targeting. RI-VAP and d-VAP were predicted to bind their receptor GRP78 protein with similar binding affinity, which was experimentally confirmed. The results of in vivo imaging demonstrated that RI-VAP and d-VAP had remarkably advantage over l-VAP for tumor accumulation. In addition, RI-VAP and d-VAP modified paclitaxel-loaded polymeric micelle had better anti-tumor efficacy in comparison to taxol, paclitaxel-loaded plain micelles and l-VAP modified micelles. Overall, the VAP modified micelles suggested in the present study could effectively achieve glioma-targeted drug delivery, validating the potential of the stable VAP peptides in improving the therapeutic efficacy of paclitaxel for glioma.