Toxicity evaluation of prolonged convection-enhanced delivery of small-molecule kinase inhibitors in naïve rat brainstem

Ho, Sharon L.; Singh, Ranjodh; Zhou, Zhiping; Lavi, Ehud; Souweidane, Mark M.

doi:10.1007/s00381-014-2568-3

Cited by 7 publications

(2 citation statements)

References 19 publications

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“…Our group first established the feasibility of this delivery route in the brainstem in small animals for potential clinical application in 2002 [ 22 ]. Subsequently, the safety of inert agents, characteristics of distribution and toxicity of potential therapeutic agents in the brainstem of small animals and non-human primates have been studied [ 23 - 28 ]. These studies showed that CED does not cause clinically relevant mechanical injury to the brainstem and this approach has a promising therapeutic application in humans.…”

Section: Convection-enhanced Deliverymentioning

confidence: 99%

Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment

Zhou

Singh²,

Souweidane³

2017

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Convection-enhanced delivery (CED) is a technique designed to deliver drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier (BBB), one of the major hurdles in delivering drugs to the brain, has made it a promising drug delivery method for the treatment of primary brain tumors. A number of clinical trials utilizing CED of various therapeutic agents have been conducted to treat patients with supratentorial high-grade gliomas. Significant responses have been observed in certain patients in all of these trials. However, the insufficient ability to monitor drug distribution and pharmacokinetics hampers CED from achieving its potentials on a larger scale. Brainstem CED for diffuse intrinsic pontine glioma (DIPG) treatment is appealing because this tumor is compact and has no definitive treatment. The safety of brainstem CED has been established in small and large animals, and recently in early stage clinical trials. There are a few current clinical trials of brainstem CED in treating DIPG patients using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG treatment will come from several directions including: choosing the right agents for infusion; developing better agents and regimen for DIPG infusion; improving instruments and technique for easier and accurate surgical targeting and for allowing multisession or prolonged infusion to implement optimal time sequence; and better understanding and control of drug distribution, clearance and time sequence. CED-based therapies for DIPG will continue to evolve with new understanding of the technique and the disease.

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Section: Convection-enhanced Deliverymentioning

confidence: 99%

Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment

Zhou

Singh²,

Souweidane³

2017

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“…Previously, our group has published research on the feasibility and safety of prolonged CED in naïve animal brainstem. 21,35 Other experimental studies have also shown long-ABBREVIATIONS CED = convection-enhanced delivery; DIPG = diffuse intrinsic pontine glioma; FITC = fluorescein isothiocyanate; mPEG = methoxypolyethylene glycol; NFP = peptide-based nanofiber; PBS = phosphate-buffered saline; PFA = paraformaldehyde; PLGA = poly(lactic-co-glycolic acid); TEM = transmission electron microscopy; Vd = volume of distribution; Vi = volume of infusion.…”

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confidence: 99%

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

Singh

Bellat

Wang

et al. 2018

Journal of Neurosurgery

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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.

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Future Therapies for Malignant Brainstem Tumors

Zhou

Souweidane

2020

Brainstem Tumors

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Toxicity evaluation of prolonged convection-enhanced delivery of small-molecule kinase inhibitors in naïve rat brainstem

Cited by 7 publications

References 19 publications

Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment

Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment

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

Future Therapies for Malignant Brainstem Tumors

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