Distribution of polymer nanoparticles by convection-enhanced delivery to brain tumors

Abstract

Glioblastoma multiforme (GBM) is a fatal brain tumor characterized by infiltration beyond the margins of the main tumor mass and local recurrence after surgery. The blood-brain barrier (BBB) poses the most significant hurdle to brain tumor treatment. Convection-enhanced delivery (CED) allows for local administration of agents, overcoming the restrictions of the BBB. Recently, polymer nanoparticles have been demonstrated to penetrate readily through the healthy brain when delivered by CED, and size has been shown to be a critical factor for nanoparticle penetration. Because these brain-penetrating nanoparticles (BPNPs) have high potential for treatment of intracranial tumors since they offer the potential for cell targeting and controlled drug release after administration, here we investigated the intratumoral CED infusions of PLGA BPNPs in animals bearing either U87 or RG2 intracranial tumors. We demonstrate that the overall volume of distribution of these BPNPs was similar to that observed in healthy brains; however, the presence of tumors resulted in asymmetric and heterogeneous distribution patterns, with substantial leakage into the peritumoral tissue. Together, our results suggest that CED of BPNPs should be optimized by accounting for tumor geometry, in terms of location, size and presence of necrotic regions, to determine the ideal infusion site and parameters for individual tumors.

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…The 7C1 delivery system ensures dual strength in direct delivery to the tumor cellular core (where the great majority of BTICs reside) and vasculature-associated invasive niches (11,(44)(45)(46)(47) (where residual resistant populations of BTICs accumulate after a standard therapy regimen). Additionally, we maintained continuous focused delivery via a CED brain-infusion catheter that is undergoing clinical trials for both malignant brain tumors and neurodegenerative diseases (71)(72)(73)(74). These combined considerations minimize the issues frequently associated with nanomedicine in regards to off-target delivery, imbalanced biodistribution, and the potential for systemic toxicity when high systemic dosing is required to achieve a detectable presence in brain tumor.…”

ITPP Treatment of RG2 Glioblastoma in a Rat Model

“…There are studies reporting polymer nanoparticles penetrating the BBB in healthy brain when delivered by convection-enhanced delivery, and nanoparticle size has been shown to be a critical factor for penetration (13).…”

Nanoparticular Drug Delivery Systems in the Treatment Central Nervous System Diseases: Review

“…Bununla birlikte polimer nanoparçacıkları, lipozomlara nazaran ajanlardan sürekli salımın daha kolay kontrol edilmesine ve sentetik polimer kimyasında izin verilen tasarımda daha çok yönlülüğe izin vermektedir. 49 Yapılan bir çalışmada, CED sonrası polimer beyin penetrating nanoparticle: beyin penetre edici nanopartikül [brain penetrating nanoparticle (BPNP)] dağılımı üzerinde bir tümör kütlesi varlığı araştırılmıştır. BPNP'lerin intratümöral infüzyonu-nun, tümör varlığına rağmen normal beyindeki gibi benzer bir hacim dağılımı ürettiği gözlenmiştir.…”

“…Bununla birlikte, BPNP'lerin hem tümör infüzyonu alanında anizotropik dağılım gösterdiği hem de RG2 ve U87 tümörlerinde tümöre sınırlı giriş sergilediği gözlenmiştir ve homojen dağılım ve tümör kütle-sine tam olarak girilebilmesi için yeni stratejilere duyulan ihtiyacı ortaya koymaktadır. 49 …”