Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor

Abstract

(2016) Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor, Drug Delivery, 23:3, 771-776, DOI: 10.3109/10717544.2014 AbstractIn cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intratumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra-or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.

Deformational changes after convection-enhanced delivery in the pediatric brainstem

“…Preclinical studies using CED paved the way for clinical introduction. 2,4,7,10,11,14,[16][17][18][19][24][25][26] Limited clinical experience led to development of a systematic clinical trial aimed at assessing the tolerance of CED in the brainstem, which has now validated the infusion parameters and theoretical principles in children with DIPG. 20 Studies in nonhuman primates and canines with brain tumors employing CED in the supratentorial compartments have demonstrated detectable but transient regional increases in pressure with compression of the lateral ventricles.…”

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

“…BPNP penetration into the peritumoral space was observed in most tumors, providing for a high concentration of NPs at the tumor periphery ( Fig 4 and 6 ). Although accumulation of BPNP in the peritumoral region is probably beneficial to kill invasive satellite tumor cells which tend to promote tumor recurrence post-treatment [33], these results suggest that strategies are needed to improve the BPNP distribution in the tumor tissue and allow more complete coverage of the tumor mass. Finally, infusions into RG2 tumors with heavily necrotic cores demonstrated widespread distribution of NPs within the tumor interior ( Fig 5 and Supp Fig 5 ).…”

“…As a result, multiple injection sites are used to allow the full coverage of the desired volume of tissue, which is personalized to each patient. Similarly, infusion at multiple locations, strategically selected with respect to the tumor geometry, would produce more significant coverage of large tumors, and balance nanoparticle accumulation in the tumor periphery and core [33]. Recent mathematical models also provide some understanding of intratumoral and peritumoral transport of small molecules during CED [54], but these models must be refined in order to be applicable to the transport and distribution of infused nanoparticles.…”

Predicting and optimizing the territory of blood–brain barrier opening by superselective intra-arterial cerebral infusion under dynamic susceptibility contrast MRI guidance

“…6 Although osmotic BBBO was introduced over 40 years ago, 7 its variability and lack of techniques for non-invasive validation in real-time during the procedure have limited its utility and currently only a few trials have implemented this strategy. 8,9 Alternative new methods to overcome this barrier are currently being developed and include convection-enhanced delivery, 10 however drawbacks of this technique include peri-tumoral leakage 11 and the need for burr-hole placement. MRI guided high-intensity focused ultrasound (HIFU) is another strategy that utilizes acoustic ultrasound to induce mechanical stress and endothelial cell deformation to temporarily disrupt tight junctions, thereby increasing BBB permeability.…”