3D Printed Absorber for Capturing Chemotherapy Drugs before They Spread through the Body.

Despite efforts to develop increasingly targeted and personalized cancer therapeutics, dosing of drugs in cancer chemotherapy is limited by systemic toxic side effects. We have designed, built, and deployed porous absorbers for capturing chemotherapy drugs from the bloodstream after these drugs have had their effect on a tumor, but before they are released into the body where they can cause hazardous side effects. The support structure of the absorbers was built using 3D printing technology. This structure was coated with a nanostructured block copolymer with outer blocks that anchor the polymer chains to the 3D printed support structure and a middle block that has an affinity for the drug. The middle block is polystyrenesulfonate which binds to doxorubicin, a widely used and effective chemotherapy drug with significant toxic side effects. The absorbers are designed for deployment during chemotherapy using minimally invasive image-guided endovascular surgical procedures. We show that the introduction of the absorbers into the blood of swine models enables the capture of 64 ± 6% of the administered drug (doxorubicin) without any immediate adverse effects. Problems related to blood clots, vein wall dissection, and other biocompatibility issues were not observed. This development represents a significant step forward in minimizing toxic side effects of chemotherapy.

Endovascular Ion Exchange Chemofiltration Device Reduces Off-Target Doxorubicin Exposure in a Hepatic Intra-arterial Chemotherapy Model.

Purpose: To determine if endovascular chemofiltration with an ionic device (ChemoFilter [CF]) can be used to reduce systemic exposure and off-target biodistribution of doxorubicin (DOX) during hepatic intra-arterial chemotherapy (IAC) in a preclinical model. Materials and Methods: Hepatic IAC infusions were performed in six pigs with normal livers. Animals underwent two 10-minute intra-arterial infusions of DOX (200 mg) into the common hepatic artery. Both the treatment group and the control group received initial IAC at 0 minutes and a second dose at 200 minutes. Prior to the second dose, CF devices were deployed in and adjacent to the hepatic venous outflow tract of treatment animals. Systemic exposure to DOX was monitored via blood samples taken during IAC procedures. After euthanasia, organ tissue DOX concentrations were analyzed. Alterations in systemic DOX exposure and biodistribution were compared by using one-tailed t tests. Results: CF devices were well tolerated, and no hemodynamic, thrombotic, or immunologic complications were observed. Animals treated with a CF device had a significant reduction in systemic exposure when compared with systemic exposure in the control group (P <.009). Treatment with a CF device caused a significant decrease in peak DOX concentration (31%, P <.01) and increased the time to maximum concentration (P <.03). Tissue analysis was used to confirm significant reduction in DOX accumulation in the heart and kidneys (P <.001 and P <.022, respectively). Mean tissue concentrations in the heart, kidneys, and liver of animals treated with CF compared with those in control animals were 14.2 µg/g ± 1.9 (standard deviation) versus 26.0 µg/g ± 1.8, 46.4 µg/g ± 4.6 versus 172.6 µg/g ± 40.2, and 217.0 µg/g ± 5.1 versus 236.8 µg/g ± 9.0, respectively. Fluorescence imaging was used to confirm in vivo DOX binding to CF devices. Conclusion: Reduced systemic exposure and heart bioaccumulation of DOX during local-regional chemotherapy to the liver can be achieved through in situ adsorption by minimally invasive image-guided CF devices.© RSNA, 2019.

Phase Behavior of Mixtures of Block Copolymers and a Lithium Salt.

We present experimental results on the phase behavior of block copolymer/salt mixtures over a wide range of copolymer compositions, molecular weights, and salt concentrations. The experimental system comprises polystyrene- block-poly(ethylene oxide) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) salt. It is well established that LiTFSI interacts favorably with poly(ethylene oxide) relative to polystyrene. The relationship between chain length and copolymer composition at fixed temperature is U-shaped, as seen in experiments on conventional block copolymers and as anticipated from the standard self-consistent field theory (SCFT) of block copolymer melts. The phase behavior can be explained in terms of an effective Flory-Huggins interaction parameter between the polystyrene monomers and poly(ethylene oxide) monomers complexed with the salt, χeff, which increases linearly with salt concentration. The phase behavior of salt-containing block copolymers, plotted on a segregation strength versus copolymer composition plot, is similar to that of conventional (uncharged) block copolymer melts, when the parameter χeff replaces χ in segregation strength.

Reentrant phase behavior and coexistence in asymmetric block copolymer electrolytes.

It is known that the addition of salts to symmetric block copolymers leads to stabilization of ordered phases and an increase in domain spacing; both trends are consistent with an increase in the effective Flory-Huggins interaction parameter between the blocks, χ. In this work, we show that the addition of salt to a disordered asymmetric block copolymer first leads to the formation of coexisting ordered phases which give way to a reentrant disordered phase at a higher salt concentration. The coexisting phases are both body centered cubic (BCC) with different domain spacings, stabilized by partitioning of the salt. Further increase in salt concentration results in yet another disorder-to-order transition; hexagonally packed cylinders are obtained in the high salt concentration limit. The coexisting phases formed at intermediate salt concentration, elucidated by electron tomography, showed the absence of macroscopic regions with distinct BCC lattices. A different asymmetric block copolymer with composition in the vicinity of the sample described above only showed only a single disorder-to-order transition. However, the dependence of domain spacing on salt concentration was distinctly non-monotonic, and similar to that of the sample with the reentrant phase behavior. This dependence appears to be an announcement of reentrant phase transitions in asymmetric block copolymer electrolytes. These results cannot be mapped on to the traditional theory of block copolymer electrolyte self-assembly based on an effective χ.

In vitro clearance of doxorubicin with a DNA-based filtration device designed for intravascular use with intra-arterial chemotherapy.

To report a novel method using immobilized DNA within mesh to sequester drugs that have intrinsic DNA binding characteristics directly from flowing blood. DNA binding experiments were carried out in vitro with doxorubicin in saline (PBS solution), porcine serum, and porcine blood. Genomic DNA was used to identify the concentration of DNA that shows optimum binding clearance of doxorubicin from solution. Doxorubicin binding kinetics by DNA enclosed within porous mesh bags was evaluated. Flow model simulating blood flow in the inferior vena cava was used to determine in vitro binding kinetics between doxorubicin and DNA. The kinetics of doxorubicin binding to free DNA is dose-dependent and rapid, with 82-96 % decrease in drug concentration from physiologic solutions within 1 min of reaction time. DNA demonstrates faster binding kinetics by doxorubicin as compared to polystyrene resins that use an ion exchange mechanism. DNA contained within mesh yields an approximately 70 % decrease in doxorubicin concentration from solution within 5 min. In the IVC flow model, there is a 70 % drop in doxorubicin concentration at 60 min. A DNA-containing ChemoFilter device can rapidly clear clinical doses of doxorubicin from a flow model in simple and complex physiological solutions, thereby suggesting a novel approach to reduce the toxicity of DNA-binding drugs.

Block Copolymer Membranes for Efficient Capture of a Chemotherapy Drug.

We introduce the use of block copolymer membranes for an emerging application, "drug capture". The polymer is incorporated in a new class of biomedical devices, referred to as ChemoFilter, which is an image-guided temporarily deployable endovascular device designed to increase the efficacy of chemotherapy-based cancer treatment. We show that block copolymer membranes consisting of functional sulfonated polystyrene end blocks and a structural polyethylene middle block (S-SES) are capable of capturing doxorubicin, a chemotherapy drug. We focus on the relationship between morphology of the membrane in the ChemoFilter device and efficacy of doxorubicin capture measured in vitro. Using small-angle X-ray scattering and cryogenic scanning transmission electron microscopy, we discovered that rapid doxorubicin capture is associated with the presence of water-rich channels in the lamellar-forming S-SES membranes in aqueous environment.