Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy

• Published in: Nature communications 2020-11, Vol.11 (1), p.5687-15, Article 5687
• Main Authors: Gregory, Jason V., Kadiyala, Padma, Doherty, Robert, Cadena, Melissa, Habeel, Samer, Ruoslahti, Erkki, Lowenstein, Pedro R., Castro, Maria G., Lahann, Joerg
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 147/135; 42; 42/89; 59; 631/61/350/354; 631/61/54/152; 631/61/54/989; 631/67/1922; 692/4028/67/1922; Albumin; Animals; Blood-Brain Barrier; Brain cancer; Brain Neoplasms - drug therapy; Brain tumors; Cell Line, Tumor; Drug delivery; Drug Delivery Systems; Gene Silencing; Glioblastoma; Glioblastoma - drug therapy; Human serum albumin; Humanities and Social Sciences; Humans; Immune system; Immunological memory; Immunology; Intravenous administration; Invasiveness; Mice; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Particulates; Peptides; Polymerization; Proteins; Radiation; Radiation standards; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Serum albumin; siRNA; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Survival; Transcription activation; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19225-7

Glioblastoma (GBM), the most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in part, due to the absence of effective drug delivery strategies. Intravenous injection is the least invasive drug 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 (STAT3 i ) 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, STAT3 i SPNPs result in tumor regression and long-term survival in 87.5% of GBM-bearing mice and prime the immune system to develop anti-GBM immunological memory. The lack of effective drug delivery strategies has impaired the therapeutic progress in the treatment of glioblastoma (GBM). Here, the authors engineer synthetic protein nanoparticle based on polymerized human serum albumin equipped with the cell-penetrating peptide iRGD to deliver siRNA against STAT3 and report improved survival in a mouse model of GBM.