In vivo evaluation of intracellular drug-nanocarriers infused into intracranial tumours by convection-enhanced delivery: distribution and radiosensitisation efficacy

Abstract

The objective of the present study was to investigate the interest of convection-enhanced delivery (CED) for the administration of a nanocarrier-based radiosensitizing chemotherapy in the rat brain. Pursuing on newly developed lipid nanocapsules (LNC) that can be internalised within brain tumour cells, we studied their intracerebral distribution when labelled with fluorescent Nile red (NR). As paclitaxel (Px) represents an interesting radiosensitiser, we also evaluated the potential radiosensitising effects of Px-loaded LNC administered through CED in the 9L intracranial rat glioblastoma model. The distribution study demonstrated that CED injection of NR-loaded LNC (NR-LNC) improved significantly the volume of distribution of NR when matched with simple injection (by about 150 fold). It also reveals that the LNC perfusion of a whole tumour forming area inside the CNS (6 days after implantation of 10(3) 9L cells) is achievable through CED injection, whilst preserving the ability of LNC to reach the intracellular space of encountered tumour cells. Having established an animal model of encephalic irradiation close to the clinic (18 Gray in three fractions of six Gray at days 8, 11 and 14 after 9L cell implantation) we proved the feasibility of the combination of CED for the administration of drug-loaded LNC with external beam therapy. Although a single CED injection of Px-LNC at low Px dose (375 mug/kg of bodyweight) gave the best median survival (twice that of untreated controls), it underlines the need for optimisation. Hence, the possibility of grafting recognition moieties onto the LNC surface combined to their biocompatibility must be beneficial.

Tumor eradication in rat glioma and bypass of immunosuppressive barriers using internal radiation with 188Re-lipid nanocapsules

“…Relative radioactivity was quantified using OptiQuant software and expressed as the mean radioactivity density (DLU/mm²). Results revealed the radioactivity content to be more 16 concentrated for the SI injection compared to the CED, with 64.54±1.99DLU/mm² and 23.24±2.68 DLU/mm², respectively (p=0.0006) (Figure 1e,g). 2a-b).…”

“…As simple stereotactic injections (SI) and convection-enhanced delivery (CED) lead to distinct LNC distribution volumes [16], these two LNC 188 Re-SSS infusion techniques were chosen to study the impact of the activity gradient.…”

Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors

“…This method, using an external pressure gradient inducing fluid convection in the brain via a surgically implanted catheter, allows greater volume distribution to be achieved in comparison to diffusion alone [13,14]. A combination of nanotechnology with the CED technique showed promising results in 9L experimental glioma in rats [15,16]. However, this approach presented some disadvantages such as long infusion times inducing infections, potential intracranial hypertensions and unpredictable drug distribution.…”

Nanoscale Materials for Tackling Brain Cancer: Recent Progress and Outlook

“…For example, convection enhanced delivery (CED) is a powerful method which allows the continuous delivery of therapeutic agents under positive pressure directly to the CNS while bypassing biological barriers through catheters implanted during surgery. Designed for the delivery of macromolecules which would otherwise not cross the blood-brain barrier into the parenchyma, [ 95 ] CED was successfully applied for nanoscale materials targeted to glioblastoma xenografted in experimental animals, such as 125 I-labeled EGF incorporating and heavily boronated compounds linked to a dendrimer scaffold for BNCT, [ 96 ] non-PEGylated liposomes loaded with MRI-enhancement and chemotherapy agents, [ 97 ] lipid "nanocapsules" labeled with a fl uorescent marker and loaded with the drug paclitaxel, [ 98 ] multifunctional dendriworms bearing siRNA cargo, [ 87 ] and MRI-contrast enhancing magnetic nanoparticles. [ 99 ] Although there are obstacles in application of PDT in CNS, abovementioned obligatory surgical procedure allows applying of light-based techniques for intraoperative (application of light to a surgery cavity) or postoperative (via implanted optical fi ber) adjuvant therapy.…”