Volume of distribution and clearance of peptide-based nanofiber after convection-enhanced delivery

Abstract

OBJECTIVE Drug clearance may be a limiting factor in the clinical application of convection-enhanced delivery (CED). Peptide-based nanofibers (NFPs) have a high aspect ratio, and NFPs loaded with drugs could potentially maintain effective drug concentrations for an extended period sufficient for cancer therapy. The objective of this study was to assess the volume of distribution (Vd) and clearance of variable lengths of NFPs when administered using CED. METHODS NFPs composed of multiple methoxypolyethylene glycol (mPEG)-conjugated constructs (mPEG-KLDLKLDLKLDL-K( FITC)-CONH, for which FITC is fluorescein isothiocyanate) were assembled in an aqueous buffer. The NFPs were approximately 5 nm in width and were formulated into different lengths: 100 nm (NFP-100), 400 nm (NFP-400), and 1000 nm (NFP-1000). The NFP surface was covalently conjugated with multiple Cy5.5 fluorophores as the optical reporters to track the post-CED distribution. Forty-two 6- to 8-week-old Ntv-a;p53 mice underwent CED to the striatum. Animals were killed immediately, 24 hours or 72 hours after CED. The brains were extracted and sectioned for assessing NFP Vd to volume of infusion (Vi) ratio, and clearance using fluorescence microscopy. RESULTS CED of NFPs was well tolerated by all the animals. The average Vd/Vi ratios for NFP-100, NFP-400, NFP-1000, and unconjugated positive control (free Cy5.5) were 1.87, 2.47, 1.07, and 3.0, respectively, which were statistically different (p = 0.003). The percentages remaining of the original infusion volume at 24 hours for NFP-100, -400, and -1000 were 40%, 90%, and 74%, respectively. The percentages remaining at 72 hours for NFP-100, -400, and -1000 were 15%, 30%, and 46%, respectively. Unconjugated Cy5.5 was not detected at 24 or 72 hours after CED. CONCLUSIONS CED of NFPs is feasible with Vd/Vi ratios and clearance rates comparable to other nanocarriers. Of the 3 NFPs, NFP-400 appears to provide the best distribution and slowest clearance after 24 hours. NFP provides a dynamic theranostic platform, with the potential to deliver clinically efficacious drug payload to brain tumor after CED.

Nanoparticle Brain Delivery: A Guide to Verification Methods

“…Half-life was 111 min 0.39 [87] Rat brain containing the region of CED of 175 nm carboplatin-labeled fluorescein-PLGA NPs was homogenized and platinum determined by ICP-MS 18 [88] The hemisphere that received CED of 60-100 nm radiosensitizer (VE822)-loaded PEG-conjugated, poly(u-pentadecalactone-co-p-dioxanone) NPs, of varying PEG polymer ratios, was analyzed by LC-MS for VE822. Half-life was 12 h, 2 and 5 days 46, 61 and 68 [89] Fluorescence images of mice brain sections were obtained after intrastriatal CED of Cy5.5 fluorophore-labeled peptide-based nanofibers (5-nm width, 100, 400 and 1000 nm length) 20, 25 and 29 [29] MRI imaging was conducted for 48 h after CED of 54-nm iron oxide chitosan-PEG NPs modified with a glioma-targeting ligand to mice-bearing brain tumors. Signals near the point source of the infusion of NP without and with ligand were used to calculate the MRT similar to the BBB, creating the BCSFB between blood and CSF.…”

“…It is most commonly used to treat glioblastoma multiforme, a brain cancer that has a poor prognosis [26][27][28]. Small molecules are cleared within 72 h [29], whereas some NPs have been found to persist for much longer (Table 1 & Supplementary Figure 1).…”

Catheter placement selection for convection-enhanced delivery of therapeutic agents to brain tumors

“…Previously, research groups defined therapeutic value using the ratio between specific therapy volume of distribution (V d ) and volume of infusion (V i ), which is the therapy plus carrier fluid 22,[35][36][37] . In vivo rodent and nonhuman primates' experiments allowed these researchers to determine V d by using image processing to measure the distribution of the specific therapy in the brain.…”

“…The aim of this study is to assess therapy distribution in the tumor based on catheter placement location. Measurement of the volume distribution was a predictor of therapy effectiveness [19][20][21][22][23] .…”

Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience

“…Co-infused agents, albeit effective at approximating distributive features at time 0, are not reliable longitudinally [ 73 ]. For this reason, theranostics, agents with both imaging and therapeutic properties, are being developed for CED, based either on modifications of small molecules [ 79 , 94 , 95 ] or relying on larger carriers [ 49 , 75 , 96 , 97 ]. Albeit promising, these agents are yet to be translated to the clinic successfully; their use, however, will guide dosing in early phase clinical trials to maximize therapeutic potential.…”