Convection Enhanced Delivery of Macromolecules for Brain Tumors

Mehta, Ankit I.; Choi, Bryan D.; Ajay, Divya; Raghavan, Raghu; Brady, Martin; Friedman, Allan H.; Pastan, Ira; Bigner, Darell D.; Sampson, John H.

doi:10.2174/157016312803305951

Cited by 33 publications

(31 citation statements)

References 49 publications

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“…The equations are of reaction- advection type, which has been much less studied mathematically. CED of antibodies (without consideration of conjugation to radionuclides and the absorbed dose resulting therefrom) has been performed, as have been such infusions of large proteins for radiotherapeutic purposes (Luther et al 2008, Mehta et al 2012). …”

Section: Methodsmentioning

confidence: 99%

“…In separate work we are creating the requisite devices to ensure uniform infusions into the margins from within the cavity at a flow rate that reaches the outer margin 2 cm away from the cavity wall (as shown in the blown up version top center in figure 1). We should point out that current practice in clinical trials is not to employ such infusions, but rather, generally utilizes several catheters placed directly into the peritumoral interstitium (the tissue in the margins) (Mehta et al 2012). We return to this point in Discussion (second paragraph).…”

Section: Methodsmentioning

confidence: 99%

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A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers

Raghavan¹,

Howell

Zalutsky

2017

Biomed. Phys. Eng. Express

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Radionuclides conjugated to molecules that bind specifically to cancer cells are of great interest as a means to increase the specificity of radiotherapy. Currently, the methods to disseminate these targeted radiotherapeutics have been either systemic delivery or by bolus injection into the tumor or tumor resection cavity. Herein we model a potentially more efficient method of delivery, namely pressure-driven fluid flow, called convection-enhanced delivery (CED), where a device infuses the molecules in solution (or suspension) directly into the tissue of interest. In particular, we focus on the setting of primary brain cancer after debulking surgery, where the tissue margins surrounding the surgical resection cavity are infiltrated with tumor cells and the most frequent sites of tumor recurrence. We develop the combination of fluid flow, chemical kinetics, and radiation dose models needed to examine such protocols. We focus on Auger electron-emitting radionuclides (e.g. 67Ga, 77Br, 111In, 125I, 123I, 193mPt, 195mPt) whose short range makes them ideal for targeted therapy in this setting of small foci of tumor spread within normal tissue. By solving these model equations, we confirm that a CED protocol is promising in allowing sufficient absorbed dose to destroy cancer cells with minimal absorbed dose to normal cells at clinically feasible activity levels. We also show that Auger emitters are ideal for this purpose while the longer range alpha particle emitters fail to meet criteria for effective therapy (as neither would energetic beta particle emitters). The model is used with simplified assumptions on the geometry and homogeneity of brain tissue to allow semi-analytic solutions to be displayed, and with the purpose of a first examination of this new delivery protocol proposed for radionuclide therapy. However, we emphasize that it is immediately extensible to personalized therapy treatment planning as we have previously shown for conventional CED, at the price of requiring a fully numerical computerized approach.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers

Raghavan¹,

Howell

Zalutsky

2017

Biomed. Phys. Eng. Express

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“…CED for cancer therapy is an approach that uses the direct injection of agents into solid tumors under convective force [127, 128]. CED is performed by using image-guidance to place a catheter directly into solid tumor parenchyma while therapeutic agents are infused through the catheter under constant pressure.…”

Section: Current Strategiesmentioning

confidence: 99%

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

Goins

Phillips

Bao

2016

Expert Opinion on Drug Delivery

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Introduction A major limitation of current liposomal cancer therapies is the inability of liposome therapeutics to penetrate throughout the entire tumor mass. This inhomogeneous distribution of liposome therapeutics within the tumor has been linked to treatment failure and drug resistance. Both liposome particle transport properties and tumor microenvironment characteristics contribute to this challenge in cancer therapy. This limitation is relevant to both intravenously and intratumorally administered liposome therapeutics. Areas covered Strategies to improve the intratumoral distribution of liposome therapeutics are described. Combination therapies of intravenous liposome therapeutics with pharmacologic agents modulating abnormal tumor vasculature, interstitial fluid pressure, extracellular matrix components, and tumor associated macrophages are discussed. Combination therapies using external stimuli (hyperthermia, radiofrequency ablation, magnetic field, radiation, and ultrasound) with intravenous liposome therapeutics are discussed. Intratumoral convection-enhanced delivery (CED) of liposomal therapeutics is reviewed. Expert opinion Optimization of the combination therapies and drug delivery protocols are necessary. Further research should be conducted in appropriate cancer types with consideration of physiochemical features of liposomes and their timing sequence. More investigation of the role of tumor associated macrophages in intratumoral distribution is warranted. Intratumoral infusion of liposomes using CED is a promising approach to improve their distribution within the tumor mass.

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“…In addition, CED causes minimal structural damage to the brain, with the exception of the catheter track, which is why a small catheter should be used. Convectionenhanced drug delivery has many possible clinical applications and can be used in the clinical treatment of neurological diseases such as malignant brain tumors (25)(26)(27)(28)(29)(30)(31), neurodegenerative disorders (32)(33)(34), epilepsy (19), and stroke (24,35). CED has recently been shown as a feasible method of intracerebral drug delivery, which appears to be safe, and has been used in both preclinical and clinical studies (36)(37)(38).…”

Section: Convection-enhanced Drug Deliverymentioning

confidence: 99%

Novel Central Nervous System Drug Delivery Systems

et al. 2014

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For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood-brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood-brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection-enhanced infusion, and ultrasound-mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.

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Convection Enhanced Delivery of Macromolecules for Brain Tumors

Cited by 33 publications

References 49 publications

A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers

A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

Novel Central Nervous System Drug Delivery Systems

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