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Chapter 7
Future Embolic Therapies
Rajan Gupta and Louis Lucas
This chapter will consider potential future developments for embolotherapy. These
could take the form of the following:
• Novel agents: these are covered in the other chapters in this section and include
permanent embolic agents, particulate agents, and liquids. It is clear that there
will be developments in all these areas which will
◦ Improve the safety and efficacy of temporary and permanent vascular
occlusion.
◦ Increase the ability to deliver drugs to a target site as “magic bullets.”
• Novel technologies: these might not be limited to embolization with the objective
of vascular occlusion but rather to deliver therapeutic vectors which will modify
or even cure disease processes. These are some of the most exciting potential
avenues for interventional therapy. Examples include the following:
◦ Gene therapy
◦ Nanotechnology
◦ Cellular infusion
Gene Therapy
The first clinical trials using gene therapy were in 1988 and evaluated the use of gene
transfer to treat severe combined immunodeficiency (SCID). The fact that it is not
widely practiced indicates that the obvious theoretical advantages may be difficult to
achieve in practice. Gene therapy holds significant promise but many hurdles must
be overcome before its widespread use in clinical practice hence this remains a
highly theoretical and experimental field. Technical issues are not the only problem;
there are significant emotive ethical issues which need to be overcome before gene
therapy can become accepted.
Transcatheter Embolization and Therapy,
Techniques in Interventional Radiology, DOI 10.1007/978-1-84800-897-7_7,
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Springer-Verlag London Limited 2010
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70 R. Gupta and L. Lucas
Mode of Action
Gene therapy involves either the modulation of existing genes or the transfer
of foreign genetic material into patient’s cells and tissues. The net result is
modified protein expression (the gene product) with the purpose of treating disease. An obvious barrier to success is the limited effectiveness for multigene
disorders!
Challenges lie ahead in terms of controlling the expression of any modified or
induced genes in particular:
• Sustained production of the gene product, e.g., “cures” for systemic diseases
such as cystic fibrosis. For this to occur, genes need to be integrated into
viable long-term cell populations and expressed through subsequent generations
of cells.
• Limiting expression of the gene product. Concern regarding the risk of tumorge-
nesis, uncontrolled gene expression is after all a cause of proliferation of cancer
cells, e.g., use of vascular endothelial growth factor (VEGF) to promote neovascularization in patients with peripheral ischemia can lead to development of
angiomas rather than useful collaterals.
• Cell survival. Populations of injected cells might ultimately be able to
replace organ transplant for certain conditions. Unfortunately foreign cells
are immunogenic and likely to be rejected unless the patient is treated with
immunosuppressants.
◦ This has been the case in attempts to cure diabetes mellitus using islet-cell
therapy and liver-cell therapy to treat acute liver failure.
◦ Use of modified cells derived form the patient in a manner akin to autologous
marrow transplant would avoid this.
Mechanisms of Gene Transfer/Modulation
Two principal methods exist.
1. Transfer of foreign genetic material in order to replace deficient or faulty
genes via
• Genetically altered cells.
• Viral and plasmid vectors. Viruses were first used because they have adapted
the unique ability to insert their own genetic material into host DNA for
replication.
2. Modulation of expression of existing genes using
• Growth factors.
• Nanotechnology.
7 Future Embolic Therapies 71
Potential Roles for Interventional Radiology
• Direct injection of vectors into tumor or tissues.
• Selective intra-arterial or intravenous injection of altered cells or vectors
◦ Early experiments in treating familial hypercholesterolemia consisted of har-
vesting a patient’s liver tissue, genetically altering the cells outside the body,
and infusing them back into the portal vein. Unfortunately, this trial was limited
by negligible clinical effect.
• Use of embolic agents to enhance the potency of the gene therapy
◦ Lipiodol administered with vectors has been shown to improve efficiency of
cancer selective gene transfer in both rabbit and rat models.
◦ This effect is thought to be related to prolonged dwell time of the vector in the
neoplastic tissue.
◦ Injection of adenoviral human hepatocyte growth factor soaked in
gelatin sponge particles has also been shown to improve gene transfer.
Prolonged dwell time and time-dependent decrease in Kupffer cell activity are thought to be possible mechanisms of action by gelatin sponge
administration.
• Use of embolization to induce cell replication enhancing gene therapy
◦ Gene therapy may be enhanced in replicating tissues. Several studies have
shown that partial portal vein embolization induces hepatocyte replication
in the nonembolized tissue (Chapter 41). In theory, genetic transfer may be
increased in the nonembolized tissue demonstrating higher cell turnover.
• Use of stents/coils as platforms to deliver or act as vectors
◦ Several investigations have shown that vectors can be attached to stents
or coils.
◦ Nanopatterning could be used to modify the surface of the implant into a bio-
logically active material capable of modifying cellular behavior. For example
the surface could be engineered to resemble a drug or cell receptor or gene
product.
◦ Many potential applications have been proposed, including inhibition of inti-
mal hyperplasia could prevent in-stent restenosis, and promotion of intimal
hyperplasia or enhanced matrix metalloproteinase inhibitors could promote
stabilization of coiled aneurysms.
• Use of gene therapy for vascular embolization
◦ In vivo mice models have induced selective tumor specific blood vessel coag-
ulation resulting in massive tumor necrosis. Therefore, gene therapy could be
used as a mechanism of vascular embolization.
72 R. Gupta and L. Lucas
Nanotechnology
Nanotechnology is an emerging highly multidisciplinary field based upon the construction of particles, devices or surfaces on the atomic or molecular level (generally
<500 nm, often smaller). For reference, a RBC diameter is 6000–8000 nm.
Nanopatterning has already been described above.
Nanoparticles
• It is important to emphasize that nanoparticles and nanocapsules are not generally
intended as embolic agents because they are too small to cause vessel occlusion.
Rather, they are engineered to make drugs more available and/or selective for
tumors, while at the same time decreasing systemic toxicity.
• Nanoparticles can be administered either intra-arterially or directly into a tumor
to maximize delivery to target tissues.
• It should be noted that the field of nanotechnology has markedly advanced the
development and manufacturing of embolic materials, particularly in regards to
the manufacturing of novel spherical and drug-eluting embolic devices.
• In the future, paramagnetic nanoparticles may be used for magnetic drug targeting and tumor imaging. Also, nanoparticles may be used as an adjunct in the
targeted thermal ablation of tumors.
Keypoints
Gene therapy and nanotechnology are likely to evolve in parallel with developments in embolic agents and have the potential to radically alter the types
of therapy provided by interventional radiology.
This will require interventional radiologists (IRs) to have a thorough
understanding of the disease processes which they are involved in treating.
The natural inventiveness of IRs will lend itself to expanding the range
of techniques and treatments in ways that will not occur to clinicians or
scientists.
Recommended Readings/References
Abrahams, JM et al. Endovascular microcoil gene delivery using immobilized anti-adenovirus
antibody for vector tethering. Stroke 2002;33: 1376–1382.
Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv
Rev 2002; 54: 631–651.
7 Future Embolic Therapies 73
Damascelli, B et al. Feasibility and efficacy of percutaneous transcatheter intraarterial chemother-
apy with paclitaxel in albumin nanoparticles for advanced squamous-cell carcinoma of the oral
cavity, oropharynx, and hypopharynx. J Vasc Interv Radiol 2007; 18: 1395–1403.
Gwinn, MR Nanoparticles: Health effects – pros and cons. Environ Health Perspect 2006; 114(12):
1818–1825.
Moghimi SM et al. Nanomedicine: Current status and future prospects. FASEB J 2005; 19: 311–
330.
Park et al. Vascular administration of adenoviral vector soaked in absorbable gelatin sponge parti-
cles (GSP) prolongs the transgene expression in hepatocytes. Cancer Gene Therapy 2005; 12:
116–121.
Service RF. Nanotechnology takes aim at cancer. Science 2005; 310: 1132–1134.
Shiba H. et al. Efficient and cancer-selective gene transfer to hepatocellular carcinoma in a rat using
adenovirus vector with iodized oil esters. Cancer Gene Therapy 2001 Oct; 8(10): 713–718.
Sinha R. Nanotechnology in cancer therapeutics: Bioconjugated nanoparticles for drug delivery.
Mol Cancer Therapy 2006; 5(8): 1909–1917.
Wickline S, Neubauer, A. Applications of nanotechnology to atherosclerosis, thrombosis, and
vascular biology. Arterioscler Thromb Vasc Biol 2006; 26: 435–441.
Chapter 8
Vascular Access, for Embolization: Techniques and Equipment
Nick Chalmers
A successful embolization procedure depends as much on achieving satisfactory
catheterization of the required vessels as on delivering an appropriate embolic
material. Successful catheterization depends on making the right decisions and on
manual dexterity.
Decisions regarding equipment principally concern the types of catheter/s and
guidewires required. The choice will be affected by many factors.
Catheter Choice
Several factors need to be considered in order to select the correct catheters for a
particular case. These include the following:
• The anatomy of the target vessel: this requires careful pre-procedural preparation
and review of all available imaging to determine the following:
• Exactly which vessels are to be catheterized?
• Factors likely to lead to difficulty during catheterization – angulation, tortuosity, stenosis, aneurismal dilatation, calcification?
• The shapes of catheters that are likely to succeed (Fig. 8.1); this is discussed
later.
• Other factors such the length, torque control, and trackability of the catheter.
• The optimal approach for the procedure.
• In the absence of any pre-procedural imaging, selection of access r oute and
equipment is a “best guess” based on previous experience.
• The need for diagnostic angiography: this will probably require a catheter with
end and sideholes. These catheters may be non-selective such as a pigtail catheter
or a selective shaped catheter. Embolization should be performed using an
endhole-only catheter. Catheters with sideholes should not be used for embolization, particularly with coils: one end of the coil may emerge through a sidehole
and the other through the endhole, making deployment impossible and requiring
removal of the catheter.
Transcatheter Embolization and Therapy,
Techniques in Interventional Radiology, DOI 10.1007/978-1-84800-897-7_8,
C
Springer-Verlag London Limited 2010
75
76 N. Chalmers
Fig. 8.1 Selective catheter shapes. This range of commonly used selective catheters will permit
the great majority of selective catheterizations: (a) Sos or USL, (b) Cobra, (c) multipurpose or
hockey-stick, (d) Sidewinder or Simmons 3
• The type of embolic agent to be used: the catheter must be compatible with the
embolic agent in terms of lumen diameter, length, and material.
• The catheter lumen must accommodate appropriate coil diameter and parti-
cle size.
• The catheter must be chemically compatible with the agent; this is most impor-
tant with liquid agents. For instance, lipiodol is used as an embolic agent in
liver tumor chemoembolization and can be used to opacify cyanoacrylate glue.
Lipiodol is made from poppy seed oil and has unpredictable effects on some
catheter hubs, taps, and syringes, which can become very brittle and may fragment during the procedure, necessitating exchange of the catheter (Fig. 8.2).
Onyx is suspended in DMSO which can also lead to catheter failure.
a
Fig. 8.2 Lipiodol effect on catheter hubs and taps. Fragmentation of the luer-lock hubs of a
catheter (a) and a three-way tap (b) due to contact with Lipiodol
b
8 Vascular Access, for Embolization: Techniques and Equipment 77
• Take care when using coils after other embolic agents, as any residual material
in the lumen of the catheter may cause the coils to lodge in the catheter.
• The need for a co-axial catheter system. Make sure that
• The chosen catheter/microcatheter will fit through your guiding catheter.
• The chosen catheter/microcatheter is long enough to reach the target through
the guiding catheter. This is a common source of frustration.
• Guidewires and coil pushers are long enough to reach the target and also to
allow catheter exchanges.
• The need for adjunctive measures:
• Procedures such as balloon occlusion will influence access and sheath size.
In practice, it is useful to have a mental list of the available options so that if
“Plan A” fails, one can move on to “Plan B” and so on.
Catheter Properties
A range of catheters with different properties is required. Remember, every operator
has their individual preference and there is usually more than one way of working. It
is important that you experiment with different approaches and become comfortable
with at least one.
Catheter Shapes and Technical Tips
The shape of the catheter (Fig. 8.1) is initially often a “best guess” based on anatomy
and operator’s experience.
Reverse Curve Catheters
The celiac axis and superior mesenteric artery (SMA) often have a markedly downward course with sharp angulation at their origin. To negotiate this from the femoral
artery requires a reverse curve catheter such as a sidewinder, a SosOmni or a visceral
curve.
Technical note: Forming a sidewinder catheter: The sidewinder catheter requires
a specific technique to reform its hook shape.
a. Advance the catheter over a guidewire up to the distal part of the aortic arch.
b. Pull back the guidewire into the shaft.
c. Simultaneously rotate and push the catheter from the groin until the tip doubles
back on the shaft.
d. Pull back the catheter carefully under fluoroscopic control.
78 N. Chalmers
Care must be taken to prevent selection of an arch branch during this maneuver.
Remember that it may be simpler and safer to approach from the arm than to
struggle to form a sidewinder catheter in a diseased aortic arch.
Double-curve catheters: less caudally angulated vessels such as the renal arteries
require a less angulated catheter, such as a cobra or renal double-curve shape. These
catheters do not have to be “formed” into shape.
Single-curve catheters: these are the simplest shapes to use and have a single
bend; they are excellent for engaging forward-facing vessels and are typified by the
multipurpose and Berenstein shapes.
Scenarios
It is impossible to cover every eventuality; however, some of the commonest
encountered during embolization are included below. Remember that selective
catheterization of youthful, elastic arteries is generally much easier than older, rigid,
and calcified vessels. Vessels in younger patients are, however, more prone to spasm.
A sharply angulated vessel will present little challenge when the arteries are healthy,
but may prove very difficult or even impossible to catheterize when the arteries are
diseased (especially if there is significant dilatation or stenosis).
Crossing the Aortic Bifurcation
The optimal catheter for crossing the aortic bifurcation will depend on the shape of
the bifurcation and the elasticity of the arteries. In young women undergoing uterine
artery embolization (UAE), the cobra or Roberts catheter is usually appropriate.
Most operators will start from a right femoral approach and first catheterize the
left uterine artery. In elderly patients or in patients who have undergone an aortobi-iliac/bifermoral bypass operation, a reverse curve catheter such as the SosOmni
may be necessary.
Catheterizing the ipsilateral internal iliac artery: during UAE the cobra catheter
can usually be used to select the ipsilateral internal iliac either in the normal fashion
or by forming a “Waltman Loop.” A Roberts catheter may also be used without
forming a loop. In other scenarios, the contralateral approach is usually simpler.
Technical Note: Waltman Loop Technique
• With the catheter tip in the left internal iliac, advance the stiff end of a
guidewire into the catheter as far as the aortic bifurcation.
• With the combination of a slight twist and a gentle push, the cobra catheter
will form a loop in the aorta.
8 Vascular Access, for Embolization: Techniques and Equipment 79
• Further pushing will advance the catheter tip into the lower abdominal
aorta. The catheter can then be pulled back and steered into the right
internal iliac artery.
Catheterizing the celiac axis and SMA using the sidewinder catheter: pull the
catheter back until the tip engages the vessel origin. If you engage non-target aortic
side branches, push the catheter back in to disengage and make small rotational
adjustments before pulling back again.
Selective catheterization of a celiac artery branch requires further manipulation.
• Continued traction on the hub will pull the tip of the sidewinder further into one
of the celiac branches, usually the splenic.
• In order to then catheterize the common hepatic artery
◦ Either pull the catheter back at the groin until the curve of the catheter is lost,
and so that the tip of the catheter is pulled back into the main celiac trunk.
Repeated small injections of contrast will enable this to be done with precision.
Remember that pulling back shortens the loop of the catheter and can lead to
instability. The common hepatic artery can then be selected with a steerable
guidewire (see below) and the catheter advanced into the hepatic artery by
pushing it forward over the wire.
◦ Or push the catheter back until the tip is in the celiac trunk, then use a wire to
select the hepatic artery. The catheter is then pulled down along with the wire
until the tip enters the hepatic artery.
Catheter Characteristics
Different stages in a procedure may require catheters with different mechanical
properties. For example, accessing a visceral vessel, particularly in the presence
of diseased or tortuous arteries, may require a catheter with a high degree of stiffness and torque control. However, advancing a catheter into a second- or third-order
branch for selective embolization may require a catheter with different properties:
flexibility, trackability, lubricity.
The handling properties of catheters vary considerably according to the
following:
• Diameter: the French gauge of the catheter is its outer circumference in millime-
ters (or approximately the diameter in millimeters multiplied by three).
• Construction: material, braiding, shape, and coating.
In general, larger gauge catheters have greater stiffness, pushability, and torque
control, whereas smaller gauge catheters will track over a guidewire into more tortuous anatomy. A 4 or 5Fr catheter is usually an appropriate first choice for selective
catheterization of first- and second-order branches of the aorta.