Systemic Brain Tumor Delivery of Synthetic Protein Nanoparticles for Glioblastoma Therapy

Abstract

Glioblastoma multiforme (GBM), the most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in parts, due to the absence of effective drug delivery strategies. Intravenous injection is the least invasive delivery route to the brain, but has been severely limited by the blood-brain barrier (BBB). Inspired by the capacity of natural proteins and viral particulates to cross the BBB, we engineered a synthetic protein nanoparticle (SPNP) based on polymerized human serum albumin (HSA) equipped with the cell-penetrating peptide iRGD. SPNPs containing siRNA against Signal Transducer and Activation of Transcription 3 factor (STAT3i) result in in vitro and in vivo downregulation of STAT3, a central hub associated with GBM progression. When combined with the standard of care, ionized radiation, STAT3i SPNPs result in tumor regression and long-term survival in 87.5% of GBM bearing mice and primes the immune system to develop anti-GBM immunological memory.

Electrokinetic characterization of synthetic protein nanoparticles

“…SPNPs were synthesized using a modification of the well-established EHD co-jetting technique [ 51 – 53 ]. Generally, SPNPs are generated by dissolving a protein of interest and a copolymer of choice into a co-solvent system of water and an organic solvent, such as ethanol or ethylene glycol [ 16 ]. The mixture is then ejected through a small-gauge needle towards a collecting surface.…”

“…To address this issue, we have adapted electrohydrodynamic (EHD) co-jetting techniques, previously established by the Lahann lab, to create single-compartment and anisotropic (i.e., multicompartmental) synthetic protein nanoparticles (SPNPs and ASPNPs, respectively), which can be easily made from a variety of proteins [ 13 – 15 ]. A recent publication demonstrated how this versatile technique can be used to create particles with a significant therapeutic potential, in particular to treat glioblastoma [ 16 ]. To translate the promising benefits of these particles into the clinic, specific characterization techniques for anisotropic particles need to be developed.…”

Multifunctional Synthetic Protein Nanoparticles via Reactive Electrojetting

“…A small library of commercially available macromers was selected to investigate different sol/gel transitions. The first two macromers, 2 KDa O,O′-bis[2-(N-succinimidylsuccinylamino)ethyl]polyethylene glycol (PEG-NHS) and 4,7,10,13,16,19,22,25,32,35,38,41,44,47,50,53-hexadecaoxa-28,29-dithiahexapentacontanedioic acid di-N-succinimidyl ester (PEG-NHS-S), react the macromers' ester functional groups with the proteins' amine groups. This reaction completes after SPNPs are deposited by EHD jetting onto the collecting surface and then placed at 37 °C for 7 days.…”

Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development

“…We have recently demonstrated that local treatment of glioma with sHDL-mimicking nanodiscs By the modification of the NPs with various coating materials, efficient delivery of molecules can be achieved [258,259]. One such modification, tumor-penetrating peptide, iRGD has been shown to facilitate the NP transport and CNS penetration [260][261][262]. We recently demonstrated that albumin NPs loaded with siRNA against signal and transducer of activation 3 (STAT3) transcription factor (which inhibits immune functions upon activation), and iRGD penetrate the BBB and that, when administered in combination with SOC, extend MS of mice bearing glioma and elicit robust antiglioma immune response [262].…”

“…For example, nanoparticles injected i.v. composed of albumin, a siRNA against STAT3 and the tumor penetrating peptide iRGD, showed effective brain tumor delivery and a significant survival benefit in an aggressive glioma model [262]. It would be interesting to test the efficacy of these particles for the delivery of immune-stimulatory agents in the clinical setting.…”