A polymeric temozolomide nanocomposite against orthotopic glioblastoma xenograft: tumor-specific homing directed by nestin

• Published in: Nanoscale 2017-08, Vol.9 (30), p.10919-10932
• Main Authors: Prabhu, Suma, Goda, Jayant Sastri, Mutalik, Srinivas, Mohanty, Bhabani Shankar, Chaudhari, Pradip, Rai, Sharada, Udupa, Nayanabhirama, Rao, Bola Sadashiva Satish
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier; Brain Neoplasms - drug therapy; Cell Line, Tumor; Dacarbazine; Ferric Compounds; Glioblastoma - drug therapy; Heterografts; Humans; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Nanocomposites - chemistry; Nanoparticles; Nestin - metabolism; Temozolomide - chemistry; Xenograft Model Antitumor Assays
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/c7nr00305f

The development of effective therapeutic strategies for glioblastoma faces challenges such as modulating the blood brain barrier (BBB) for drug influx and selectively targeting tumor cells. Nanocarrier drug delivery strategies are functionalized to enhance vascular permeability. We engineered superparamagnetic iron oxide nanoparticle (SPION) based polymeric nanocomposites (84.37 ± 12.37 nm / 101.56 ± 7.42 nm) embedding temozolomide (TMZ) targeted against glioblastoma by tagging an antibody against nestin, a stem cell marker, and transferrin / polysorbate-80 to permeate the BBB. The targeting and therapeutic efficacy of the nanocomposite resulted in enhanced permeability across the BBB in an orthotopic glioblastoma xenograft model. Sustained release of TMZ from the nanocomposite contributed to enhanced tumor cell death while sparing normal brain cells as evidenced through micro SPECT/CT analysis. The functionalized nanocomposites showed significant reductions in tumor volume compared to pure TMZ, as substantiated by reduced proliferation markers such as proliferating cell nuclear antigen (PCNA) and Ki-67. We report here a novel targeted TMZ delivery strategy using a potent homing moiety, nestin, tagged to a polymeric nanocomposite to target glioblastoma. In addition to tumor targeting, this study constitutes a broad horizon for enhanced therapeutic efficacy with further scope for capitalizing on the magnetic properties of SPION for targeted killing of cancer cells while sparing normal tissues.