Trends in basic science research in interventional radiology: NANOTECHNOLOGY, STEM CELL, RNAi, AND RADIOGENOMICS

Nanotechnology for systemic and local drug delivery

Nanoparticles for drug delivery are engineered systems in the nanometer size range, and drugs can be attached to the surface of such particles or entrapped or encapsulated within them. The advantages associated with nanoparticle use lie in its ability to increase drug efficiency and improve the therapeutic index of currently available drugs, reducing drug toxicity to improve side-effect profiles, ^, and controlled release to achieve therapeutic levels for an extended period of time. They can also improve drug stability and solubility and allow targeted drug delivery. The potential to accommodate multiple types of drug molecules may allow for the development of systems for combined therapeutic and imaging applications. ^, The need for targeted drug delivery is particularly evident in interventional oncology, where it would be preferable for tumor to be exposed to high drug concentrations, while reducing systemic toxicity. As nanoparticles are able to pass through the fenestrations of the highly permeable tumor vasculature and are limited by tumor lymphatic systems, preferential collection of nanoparticles within the tumor interstitium may be achieved, and has been termed the enhanced permeability and retention (EPR) effect. ^{, ,}

The development of controlled or triggered intratumoral drug release in systemic chemotherapy is desirable as it can result in optimum drug delivery for longer periods, thus increasing efficacy of treatment. Such targeting has extended beyond the use of the passive EPR effect, and active targeting based on molecular recognition of tumor has been described. In terms of local drug delivery, direct intratumoral injection of chemotherapy-loaded nanoparticles in tumor-bearing mouse models has been observed to increase efficiency in impeding tumor development. Local intratumoral injection of radiosensitizers to enhance radiotherapy such as gadolinium has similarly shown promise in inhibiting tumor growth and increasing life expectancy. In the area of local thrombolysis of particular relevance to IR, nanoparticles modified with streptokinase and targeted to fibrin have been described. ^, Marsh et al. developed fibrin-targeted nanoparticles surface conjugated to streptokinase in vitro and found that they were able to lyse 90% of clots within 60 minutes of exposure, with substantially more potent fibrinolytic activity and the same degree of thrombolysis as a 1000–fold greater dose of free streptokinase.

Ultrasound-mediated drug delivery

When used in combination with systemically administered encapsulated therapies such as drug-loaded microbubbles or nanoparticles, locally applied ultrasound has been shown to enhance drug transport through tissues and across cell membranes. ^, As a drug delivery method, it is noninvasive and may be controlled and focused locally, thereby limiting the drug interactions to the target tissue and sparing surrounding normal tissues from unwanted side effects. An added major advantage is the targeting of deep tissues and the ability to be used through intraluminal, endoscopic, or percutaneous means to reach almost any site. Dayton et al. found in an in vitro study that ultrasonography, in combination with nanodroplets carrying the cytotoxic drug paclitaxel, resulted in significant cell death. In vivo studies using low-frequency ultrasonographic and polymeric micelles and liposomes encapsulating doxorubicin or fluorouracil have found statistically significant decreases in tumor size and increased effects of drug on tumor growth. Rapoport et al. described the potential for multifunctional nanoparticles to function both as drug carriers and ultrasound contrast agents for enhanced visualization. Long-lasting contrast provided enhanced tumor visualization in conjunction with ultrasonography-mediated enhanced release of encapsulated doxorubicin and intracellular uptake of drug from nanoparticles.

Nanotechnology and thermal therapy

The use of thermal therapeutics such as radiofrequency ablation has become established clinical practice for certain tumors including solitary renal masses. The minimally invasive nature of thermotherapy allows for treatment of tumors in sites where surgical resection is clinically impractical. However, this requires sufficient depth and penetration of tissues by the heating element. Current heating techniques do not discriminate between tumor and normal tissue, giving rise to potential damage to surrounding structures. In addition, heating tissue to different degrees has different effects—hyperthermia (40°C–42°C) may render cells more susceptible to the cytotoxic effects of chemotherapy or radiation and can induce some degree of apoptosis, ^, whereas thermal ablation (>46°C) has a direct cytotoxic effect on cells, and can be used as a monotherapy for destruction of tumor cells. A combination of hyperthermic effect of thermal ablation and use of nano-carrier of cytotoxic drugs may have enhanced therapeutic effects on the locoregional treatment of solid tumors, including hepatocellular carcinoma (HCC).

Magnetic thermotherapy

The capacity of magnetic nanoparticles to absorb energy from an alternating magnetic field and convert it to heat, forms the basis of magnetic thermotherapy. The feasibility of this technique has been demonstrated in patients with locally recurrent prostate cancer. ^, Iron oxide nanoparticles in suspension were injected transperineally into the prostate gland of patients under transrectal ultrasound, and an alternating magnetic field was applied. Because of retention of particles within the gland, serial heat treatments could be performed after a single injection, with the achievement of hyperthermic temperatures achieved at relatively low field strengths. The technique could potentially be used as a combination therapy along with irradiation and implantation of iodine-125 ( I) seeds, as the thermal dose achieved during the study would prove effective in such a setting. The intraarterial route has also been examined as a means for selective magnetic hyperthermia of tumors. In a rabbit model for renal carcinoma, Takamatsu et al. investigated the possibility of intraarterial selective hyperthermia using a transcatheter arterial embolization technique with a mixture of commercially available nano-sized magnetic particles (Ferucarbotran) and the embolic material lipiodol. Injection of this mixture into the renal artery under fluoroscopic guidance and exposure to an alternating-current magnetic field increased intratumoral temperatures to 45°C, which were sufficient for hyperthermia but not ablation. However, given the relative hypovascularity of the tumor, the authors hypothesized that much stronger selective hyperthermia might be achievable in a hypervascular tumor such as HCC.

Radiofrequency ablation

Studies in the use of RFA in combination with chemotherapy for malignant tumors have shown improved efficacy as compared to either treatment alone. ^, Intravenous administration of a single dose of adjuvant liposomal doxorubicin in the rat breast cancer model increased the extent of coagulation necrosis induced with RFA compared with RFA alone. Similar increases in tumor destruction have been seen in the use of liposomal doxorubicin in combination with RFA in a variety of focal hepatic tumors. Ahmed et al. studied the independent effects of three different chemotherapeutic agents, nanoparticle size, and liposomal circulation time on the same combinational RFA therapy in a rat breast tumor model. It was found that all combinations of RFA with liposomal chemotherapy resulted in significantly greater tumor necrosis than RFA alone. The extent of tumor destruction was greatly influenced by nanoparticle size, with liposomes 100 nm in diameter achieving optimal results. In addition, the use of a pegylated liposomal preparation with prolonged circulation time was demonstrated to significantly influence intratumoral drug accumulation and coagulation necrosis. Thus, increasing drug circulation time and modifying nanoparticle properties may further enhance the efficacy of existing RFA and chemotherapeutic combinations.

Nanotechnology in vascular interventions

Conventional drug-eluting stents function via disruption and delay of the natural healing response and limiting the growth of neointima, making late in-stent thrombosis a major concern particularly in more complex lesions such as those in peripheral arterial disease. Thus, the development of endovascular stents with improved clinical characteristics remains imperative. Nanoparticle-eluting stents have been described and could provide a novel platform for delivery of therapeutic agents to the vessel wall. By utilizing electrodeposition coating to create a thin, uniform layer of biodegradable polymeric nanoparticles on stent surfaces, multiple agents within various nanoparticles may be delivered using a single stent. Intracellular uptake of nanoparticles and retention within the cytoplasm or extracellular space may allow for sustained drug delivery within cells. Such a stent has been tested in a porcine coronary artery model, where it demonstrated good biocompatibility and efficient drug delivery, and could potentially be used in the delivery of proteins or genes that inhibit inflammation, smooth muscle cell proliferation, and thrombosis. Polymer-based drug-eluting stents remain in contact with the arterial wall indefinitely, and the polymer is thought to induce local inflammation and potentially lead to late stent thrombosis and restenosis. ^, This could potentially be solved by the development of a biocompatible, noninflammatory medium for drug delivery to replace the standard polymer, and one study has demonstrated the efficacy and biocompatibility of a paclitaxel-eluting porous carbon-carbon nanoparticle-coated nonpolymeric cobalt chromium stent in a porcine model.

The use of local and systemic intraarterial drug-laden nanoparticles has been reported to have good outcomes in tumor treatment. ^, Concurrent use of balloon angioplasty has been demonstrated to cause a marked increase in vascular permeability, thereby allowing nanoparticles to selectively enter the arterial wall at specific sites. Doxorubicin-encapsulated nanoparticles administered intravenously have been shown to accumulate at sites of balloon stretch injury, with resultant inhibition of vascular smooth muscle proliferation and dose-dependent suppression of neointimal growth. Such an effect was not observed with administration of doxorubicin alone, and the approach shows potential for increased penetration and localization of therapy. Combining ionic or antibody targeting with local delivery of drug-laden nanoparticles to the vessel wall may deliver sufficient drug concentrations to prevent restenosis while avoiding systemic toxicity. ^, A study involving the modification of nanoparticles for a resultant positive surface charge has demonstrated enhanced local uptake of such nanoparticles into the arterial wall, possibly because of increased ionic interactions with the negatively charged glycosaminoglycan-rich arterial wall. In addition, in vitro studies by Lanza et al. showed that tissue factor-targeted perfluorocarbon nanoparticles containing doxorubicin or paclitaxel significantly inhibited the proliferation of vascular smooth muscle cells in culture, with the functionalized nanoparticles showing enhanced potency compared with nontargeted nanoparticles or free drug. In addition, these nanoparticles could be formulated with gadolinium and were readily detectable on T1–weighted spin echo imaging, whereas quantification of the nanoparticles was possible using 19F spectroscopy. It follows that targeted therapeutic nanoparticles could potentially provide visualizable and quantifiable therapy to prevent restenosis ( Figure 6-2 ).

Nanotechnology in implantable devices and hemostasis

The use of nanoparticles loaded with dexamethasone as a drug-delivery coating for implantable devices has been shown to reduce local postimplantation inflammatory response and may potentially improve biocompatibility. Several studies have examined the surface modification of nanoparticles with heparin without loss of the anticoagulant properties of heparin, and delivery of such nanoparticles has demonstrated prolonged clotting time of more than 200 seconds, as compared to 16.5 seconds with unmodified nanoparticles. Such an approach could potentially be used in the coating of interventional vascular devices, and hydrophilic surface modification of silicon catheters using a polymeric phospholipid monolayer has been shown to cause decreased platelet adhesion. The potential for nanotechnology to improve hemostasis has been shown through the development of a novel self-assembling peptide that establishes a nanofiber barrier when applied and achieves local hemostasis within 15 seconds, allowing the sealing of wounds in any wet ionic environment in the body. Its efficacy in achieving rapid hemostasis in brain, spinal cord, liver, skin, and even transection of the femoral artery has been demonstrated in a rat model such that bleeding could be stopped without the use of any conventional hemostatic methods such as pressure or cauterization. Additionally, the nontoxic, nonimmunogenic solution is also broken down into amino acids to serve as building blocks for tissue repair.