Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex

Abstract

Treatment of glioblastoma (GBM) remains to be the most formidable challenge because of the hindrance of the blood-brain barrier (BBB) along with the poor drug penetration into the glioma parenchyma. Nanoparticulate drug delivery systems (DDS) utilizing transferrin (Tf) as the targeting ligand to target the glioma-associated transferrin receptor (TfR) had met the problem of loss of specificity in biological environment due to the high level of endogenous Tf. Here we conjugated CRT peptide, an iron-mimicry moiety targeting the whole complex of Tf/TfR, to poly(ethylene glycol)-poly(l-lactic-co-glycolic acid) nanoparticles (CRT-NP), to open a new route to overcome such obstacle. High cellular associations, advanced transport ability through the BBB model, and penetration in 3-dimensional C6 glioma spheroids in vitro had preliminarily proved the advantages of CRT-NP over Tf-nanoparticle conjugates (Tf-NP). Compared with Tf-NP, NP, and Taxol, paclitaxel-loaded CRT-NP (CRT-NP-PTX) displayed a superior antiproliferation effect on C6 glioma cells and stronger inhibitory effect on glioma spheroids. Favored pharmacokinetics behavior and enhanced accumulation in glioma foci was observed, together with a much deeper distribution pattern in glioma parenchyma compared with unmodified nanoparticles and Tf-NP. Eventually, mice treated with CRT-NP-PTX showed a remarkably prolonged median survival compared to those treated with Taxol, NP, or Tf-NP. In conclusion, the modification of CRT to nanoparticles holds great promise for enhancement of antiglioma therapy.

Overcoming blood brain barrier with a dual purpose Temozolomide loaded Lactoferrin nanoparticles for combating glioma (SERP-17-12433)

“…Receptors of Lf are known to be over-expressed in glioma cells and on brain endothelial cells 16–19 . Lf is known for its ability to cross BBB and this property has been extensively used for targeted delivery of several drugs to the brain 19, 20 . Our group has previously reported the benefits of delivering several drugs using Lf nanoparticles 21–23 .…”

Covalent nano delivery systems for selective imaging and treatment of brain tumors

“…Importantly, this ability can only be exploited because different physiological structures express distinctive biomarkers [199]: for instance, malignant endothelial cells overexpress the TfR, as they require a larger amount of iron [211, 212]. This overexpression allows NTs to actively bypass the strict constraints imposed by the BBB: by carrying transferrin-targeting moieties, such as transferrin peptides, NTs can target and bind to endogenous BBB TfRs [213]. Once the NTs engage their targeted receptors, they are shuttled into the tumor mass via receptor-mediated endothelial transcytosis [214].…”

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors

“…Hutchison invented p97-antibody conjugates and related compositions that could be used in the treatment of cancers such as Her2/neu-expressing and Her1/ EGFR-expressing cancers to inhibit, prevent, or delay the metastasis of an antibody-resistant cancer. [108] Kang et al [109] hypothesized that modification of calreticulin (CRT) peptide to poly(ethylene glycol)-poly(l-lactic-co-glycolic acid) (PEG-PLGA) nanoparticles would mediate drug transport across the BBB and enable deep penetration to the interior of the glioma by functionally mimicking iron. Their study proved that CRT-NP significantly improved the therapeutic efficacy of paclitaxel for the treatment of gliomas.…”

“…Their study proved that CRT-NP significantly improved the therapeutic efficacy of paclitaxel for the treatment of gliomas. [109] Toxins: targeting agents and a potential treatment Disintegrins, a group of snake venom toxins, have the potential to block cancer cell migration and invasion by interaction with integrins. [110] Contortrostatin, a snake venom disintegrin, was proven to inhibit tumor growth and angiogenesis and to prolong survival in a rodent glioma model by Pyrko et al [111] Similarly, scorpion venoms has been used in targeting brain tumors, in tumor painting, and in cell sensitization to chemotherapy.…”