Nanocomposite Carriers for Transarterial Chemoembolization of Liver Cancer

Abstract: The efficacy of conventional transarterial chemoembolization (TACE) approaches in liver cancer treatment is limited by the lack of effective drug carriers and/or the inability to monitor drug delivery to the targeted tumor tissues. Recent years have seen rapid advances in drug carriers for TACE. Bioabsorbable and MRI- or CT-visible microspheres that are trackable in vivo have been developed as a form of nanocomposite. Herein, we review notable progress in nanocomposite microsphere drug carriers available for TACE.  

Key words: transarterial chemoembolization, nanocomposite, microspheres, hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world¹ and the fourth leading cause of cancer death in the United States.² Developed countries have had an 80% increase in HCC incidence over the last 15 years.³ Resection and transplantation are the sole potentially curative treatments for HCC, but only 10% to 15% of patients are candidates.⁴ With the exception of recently introduced sorafenib multikinase inhibitors,⁵ systemic hormonal/chemotherapies and molecularly targeted therapies have offered no survival benefit.^6-8 Regional ablative therapies can be effective for small lesions but offer limited benefit for tumors >3 cm or in the cases of multifocal disease.^9,10 Image-guided catheter-directed therapies, such as transarterial chemoembolization (TACE), rely on differences in the blood supply between HCC and normal liver tissues. Hepatic arteries supply ~90% of blood flow to HCC but only ~25% of flow to normal liver.¹¹ TACE involves infusion of chemotherapeutic drugs (i.e. doxorubicin [DOX]) emulsified in lipiodol (embolic oil).^12-14 In a 2002 trial in Spain, a significant improvement in survival was achieved with TACE compared to best supportive care (P=.009);¹⁵ similar survival benefits were achieved for TACE in a 2002 Asian RCT,¹⁴ however, it is important to note that the overall survival benefit afforded by current liver-directed transcatheter approaches remains relatively modest. Improved therapeutic options for the treatment of advanced HCC are needed. 

Conventional Transarterial Chemoembolization 

During the early stages of HCC development in patients with poor liver function, liver transplantation is the preferred option. However, the gap between organ supply and demand may require a long lag of time prior to organ availability for an individual patient. Under these circumstances, other systemic or regional therapies are often employed.¹⁶ However, most systemic and regional therapies offer palliation only, rather than cure. Liver tumors derive their blood supply mainly from the hepatic artery, whereas the portal venous system serves as the main blood supply to normal liver tissues.¹¹ Local delivery affords significant reductions in systemic toxicity. Transarterial chemoembolization has been used as a palliative treatment for patients with unresectable HCC. It is one of the main catheter-based therapies for unresectable liver cancer. These procedures have been used for more than 30 years. Conventional TACE (C-TACE) is performed by infusing a mixture of drugs within ethiodized oil and embolic materials into the hepatic artery feeding the tumor(s). However, C-TACE offers only modest improvements in long-term patient survival over best supportive care.^17,18 The efficacy of C-TACE approaches may be limited by the lack of effective drugs drug carriers^19,20 and/or the inability to track and confirm drug delivery to the targeted tumor tissues.

Drug-Eluting Bead Trans­arterial Chemoembolization

In order to overcome the limitations of prior generation chemotherapies, drug-eluting beads (DEB) were recently developed for transcatheter delivery to HCC (drug-eluting bead TACE [DEB-TACE]). DC Bead microspheres (BTG), nonbiodegradable PVA microspheres with a sulfonic acid component, have been used to deliver DOX or irinotecan.^21,22 HepaSphere/QuadraSphere microspheres (Merit Medical), nonabsorbable acrylic copolymer microspheres, have been used for DOX drug delivery with embolization.²³ This new type of TACE procedure involves infusion of these DEBs into tumor-feeding arteries, thus permitting a somewhat more sustained drug release into the tumor blood vessels. However, despite encouraging safety profiles, these DEBs (typically used to deliver conventional doxorubicin chemotherapy) have yet to demonstrate significant improvements in treatment outcomes compared to C-TACE approaches. A combination of modern multifunctional drug carriers with high-efficiency drugs for catheter-directed procedures may be critically needed to improve therapeutic outcomes. High doses of drugs can be loaded onto drug carriers in a reproducible manner for controlled elution over an extended period of time (current DEB microspheres offer only a rapid-burst release profile). Development of new materials that are bioabsorbable, can load more than one drug type, and are visible on magnetic resonance imaging (MRI) or computed tomography (CT) will facilitate improved outcomes.

Multifunctional Nanocomposite Carriers 

Nanocomposites are multicomponent materials for which one of the phases has one, two, or three dimensions of less than 100 nanometers (nm). The mechanical, electrical, thermal, optical, electrochemical, and catalytic properties of the nanocomposite will differ markedly from that of the component materials. A combination of modern multifunctional nanocomposites with high-efficiency drugs may be critical to improve therapeutic outcomes following these catheter-directed procedures. Transcatheter delivery of multifunctional drug carriers should translate into reduced systemic drug exposures.^24,25 The development of multifunctional microsphere platforms with superior material properties and elution profiles should significantly improve treatment outcomes. Furthermore, there will be more opportunities for combining TACE with multimodal (MRI/CT/PET) imaging components and other therapeutics such as hyperthermia, immunotherapy, and photodynamic therapies in a single nanocomposite carrier. In this review, we provide a brief overview of the current status of developed nanocomposite microspheres suggesting future directions for the development of TACE procedures.

Controlled Drug-Eluting Nanocomposite for Transarterial Chemoembolization Applications

The use of chemotherapy has been attempted in patients with HCC. Unfortunately, chemotherapy with cytotoxic agents such as doxorubicin, cisplatin, or 5-fluorouracil have shown a relatively low response rate (<10%) without a clear benefit in overall survival.²⁶ Moreover, chemotherapy is poorly tolerated in HCC patients, especially because both cirrhosis and liver failure may have an unpredictable course. In addition, these drugs have a hepatic metabolism, making the toxicity of these drugs difficult to manage.²⁷ To achieve higher concentrations of cytotoxic drugs within the targeted liver tumors and to decrease systemic exposure compared to intravenously administered chemotherapy, TACE^13,28,29 is often used in patients with primary and secondary tumors of the liver for preferential drug delivery to these tumors.^14,30,31 Hepatic arteries supply ~90% of blood flow to primary liver tumors but only ~25% of flow to normal liver.¹¹ Among the agents tried for TACE, doxorubicin-based chemotherapeutic agents appear to offer the highest efficacy but with response rates of only 20% to 30% and a minimal impact upon survival. There is also no apparent benefit to chemotherapy in the adjuvant setting with a variety of hormonal and biologic agents.³² Recently, sorafenib has become a promising chemotherapeutic agent for the treatment of HCC in patients with preserved liver function.^33,34 However, the systemic exposure and a lack of tumor specificity of current chemotherapy can lead to severe side effects.³⁵ Clearly, improved drugs with superior tumoricidal impact and reduced toxicities are needed to more effectively treat those patients with advanced-stage HCC. 

Smart drug carriers with controlled drug elution capabilities offer the possibility to provide a controlled release of the chemotherapeutic agent into the tumor bed. The potential benefits of such a drug-delivery system are considerable, because a sustainable release of chemotherapy over time could have a greater impact upon tumor kill. In addition, because the amount of chemotherapy loaded into the drug-delivery carriers can be controlled, a more precise dose of chemotherapy can be delivered to the tumor. Recently, Kim et al developed DOX-loaded porous magnetic nanoclusters (DOX-pMNCs), which can be used with iodinated oil for TACE applications.³⁶ The high capacity and abundant active carboxylic groups on the pMNCs achieve high-drug loading efficiency and sustained drug release, along with magnetic properties resulting in high MRI T2-weighted image contrast. Each DOX-pMNC within iodinated oil, DOX-pMNCs, and DOX-alone within iodinated oil were tested with infusion via hepatic arteries to target liver tumors in a rabbit model. In vitro drug release tests, in vivo MRI, and histologic evaluations demonstrated that the long-term drug release and retention of DOX-pMNCs within iodinated oil induced significantly enhanced liver cancer cell death compared to conventional DOX/lipiodol preparation and/or DOX-pMNCs alone. Furthermore, combined pMNC and iodized oil allowed multimodal imaging of transcatheter intra-arterial delivery to liver tumors. The MR signal intensity of the tumor was maintained at significantly lower levels until day 14 after the intra-arterial delivery, which suggested an enhanced deposition of DOX-pMNCs in tumor tissues via codelivery with lipiodol. Prussian blue staining of tumor tissues histologically confirmed the retention of DOX-pMNCs (blue spots in the tumor vasculature). Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used to analyze therapeutic effects, and a significantly higher apoptosis rate (74.1%) was demonstrated for pMNC within lipiodol, while a control group showed a 61.8% of apoptosis rate (P<.05). 

Another potential use of nanocarriers for TACE will be nanocomposite microspheres. Recent studies importantly demonstrated that drug loading and release rates can be readily altered by adjusting nanoparticle contents during microspheres fabrication processes.³⁷ When the iron oxide nanoclusters are incorporated into polymeric microspheres (Figure 1), drug-release kinetics can be controlled. The concentration-dependent drug release kinetics of nanoclusters were clearly demonstrated for iron oxide nanoclusters embedded in alginate microspheres.³⁷ For microspheres without iron oxide nanoclusters, 76% of the drug was released within the first 8 hours. Co-encapsulating iron oxide nanoclusters significantly slowed release rates such that only 56%, 43%, and 36% of the drug was released within the first 8 hrs for microspheres including 1 wt%, 3 wt%, and 5 wt% iron oxide nanoclusters, respectively. When we extended the periods of drug release, the nanocomposite microspheres of 3 wt% and 5 wt% iron oxide nanoclusters released most of the drug (~95%) within 4 days and 9 days, respectively. The measured 3 nm to 5 nm pores in polymeric microspheres could be blocked by the incorporated iron oxide nanoclusters, resulting in slower diffusion of drugs. Furthermore, functional polyacrylic acid anionic polymer on the iron oxide nanoclusters also contributes to the improved drug loading efficiency and affected drug release kinetics. These promising results suggest that optimal compositions of various chemical surfaced nanoparticles within microspheres may be able to achieve patient-specific drug release kinetics for future translational TACE investigations. 

Nanocomposite Microspheres Visibly by Magnetic Resonance or Computed Tomographic Imaging

As previously described, C-TACE involves a sequential process of injecting an oily emulsion with a chemotherapeutic drug followed by an occluding material. Typically, the emulsifying agent is an iodinated oil such as lipiodol. The high iodine content renders the fluid radiopaque. Initially, it was assumed that the opaque oil was an indicative marker for the distribution of the delivered drug. To the contrary, studies have shown ethiodized oil content is a poor marker of local drug concentrations. These results found no significant correlation between calculated iodine content and measured chemotherapy level in the treated tumors, indicating that the degree of intratumoral oil deposition is a poor predictor of local drug delivery post TACE.³⁸ Design of a drug-eluting microsphere incorporating imaging agents would provide more accurate spatial localization of the drug-eluting carriers. Transarterial chemoembolization also requires intraprocedural imaging with x-ray-based digital subtraction angiography (DSA) for catheter guidance and monitoring of subsequent drug infusion and embolization procedures. There is an increasing interest in introducing MRI into the interventional radiology suite to offer the benefit of functional measurements to guide therapeutic endpoints.^39-41 However, current DEB technology, lipiodol oil, and the gel foams used in clinical settings are invisible with both imaging modalities; importantly, the delivery of DEBs is not directly monitored because they are not visible with x-ray or MRI modalities.⁴² A modern multifunctional drug carrier for image-guided catheter-directed procedures is critically needed to improve therapeutic outcomes. Incorporation of imaging agents into the drug source itself (i.e., radiopaque/magnetic microspheres) should offer several advantages over current embolization agents not visible with clinical imaging modalities.43-46 

Single MRI-visible nanocomposite microspheres were also tested for potential TACE applications. Iron oxide nanoclusters were successfully incorporated into biocompatible alginate microspheres during microfluidic processes. The fabricated nanocomposite microspheres showed strong MR visibility, demonstrating significant signal reductions in T2 and T2* images. During in vivo MR scans after intra-arterial infusion, delivered nanocomposite microspheres in liver tumors and peripheral tumor regions were well depicted on MRI (Figure 2). It was well correlated with histopathology data. Larson et al investigated the feasibility of sorafenib-eluting poly(D,L-lactide-co-glycolide) (PLG) microspheres for transcatheter delivery.^47,48 This biocompatible polymer is widely used to encapsulate therapeutic drugs for sustained delivery and is advantageous in that it can be formulated as an injectable particle that encapsulates both hydrophobic and hydrophilic components for localized drug delivery. Furthermore, PLG microspheres co-encapsulate a ferrofluid of iron-oxide nanoparticles, thus permitting MRI of intrahepatic biodistributions. 

While a number of imaging approaches have been employed with PLG microspheres, MRI does not require exposure to ionizing radiation and provides excellent soft-tissue contrast for depicting tumor tissues. The PLG microspheres were tested for sorafenib elution properties and in vitro cell cytotoxicity after exposure to these microspheres. Then the in vivo therapeutic efficacy of these sorafenib-eluting PLG microspheres following transcatheter infusion was investigated in rodent HCC models. With the hydrophobic drug sorafenib dissolved along with the polymer in the organic phase, PLG was employed for microsphere fabrication. This approach enabled loading of sorafenib into a particle platform with high efficiencies. Hydrophobic drug loading in PLG is well studied, and in comparison to previous literature with sorafenib for other applications, the loading efficiency was comparable to studies performed by Butoescu et al⁴⁹ and greater than that observed in a sorafenib dextran/PLG nanoparticle study by Kim et al.⁵⁰ The relatively poor solubility of sorafenib dictated a need for relatively large volumes of DMSO during our current microsphere fabrication process; this fabrication process resulted in the fabrication of roughly 1 micron microspheres.

With further development of imageable microspheres, Kim et al fabricated drug-loaded dual MRI/CT visible microspheres that included both gold nanorods and magnetic clusters using continuous microfluidic methods (Figure 3). The drug-release profile and imaging properties of these MRI- or CT-visible nanocomposite microsphere drug carriers were first evaluated during in vitro and in vivo studies in orthotopic HCC rat models; these studies demonstrated potential for dual MRI/CT detection of these nanocomposite microspheres following intra-arterial infusion. The resulting hydrophilic, deformable, and nonaggregated microspheres were monodisperse and roughly 25 um in size. Sustained drug release and strong MRI T2 and CT contrast effects were achieved with the embedded magnetic nanoclusters and radiopaque gold nanorods. The intra-arterial infused microspheres could confirm subsequent distribution in the targeted liver tissues using MRI and CT.⁵¹ These dual-modality nanocomposite drug carriers should be ideal for selective intra-arterial catheter-directed administration to liver tumors while permitting MRI/CT visualization for patient-specific confirmation of tumor-targeted delivery. Multimodal MRI- or CT-visible microspheres would permit direct visualization of these drug carriers and delivery of the tumoricidal drugs. Monitoring the distribution of these drug-loaded microspheres is paramount to determining the success of a given procedure to permit physicians to either administer additional microspheres to achieve an optimal tumor dose or even reposition the catheter to ensure complete coverage of the targeted lesion.

Conclusion

Nanocomposite microspheres could become the most effective nonsurgical therapeutic tool for liver cancer. Combining new functional materials including nanoparticles allows the development of diverse nanocomposite carriers that overcome the disadvantages of conventional carriers used for TACE. Well-customized nanocomposites that utilize high-performance chemotherapeutic drugs, biocompatible polymers, and functional nanoagents will permit targeted and controlled drug delivery, real-time feedback with multimodal medical imaging, biodegradation, and further adjuvant therapeutics to improve outcomes following TACE. 

Editor’s note: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no financial relationships or conflicts of interest regarding the content herein.

Manuscript received May 31, 2016; manuscript accepted July 14, 2016. 

Address for correspondence: Dong-Hyun Kim, PhD, Department of Radiology, Northwestern University, 737 N. Michigan Ave., Suite 1600, Chicago, IL 60611, USA. Email: dhkim@northwestern.edu.

Suggested citation: Kim DH, Larson AC. Nanocomposite carriers for transarterial chemoembolization of liver cancer. Intervent Oncol 360. 2016;4(11):E173-E182.

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