Image-Guided Local Delivery Strategies Enhance Therapeutic Nanoparticle Uptake in Solid Tumors

Abstract

Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nano-ablation and nano-embolization. Nano-ablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nano-embolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intra-tumoral DOX-SPIO uptake, with limited off-target delivery in tumor bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.

MR Imaging Enables Measurement of Therapeutic Nanoparticle Uptake in Rat N1-S1 Liver Tumors after Nanoablation

“…These dosages were chosen to approximate clinically relevant doxorubicin concentrations from previous chemoembolization studies (23–25) and to be consistent with previous animal work on nanoablation (8), while attempting to create a range of concentrations for correlation analysis and to investigate a possible dose-response relationship.…”

“…Two minutes after DOX-SPIO injection, electroporation was applied to the tumor via a two-pronged electroporation tool (BTX, Holliston, MA) with two 0.4 mm-diameter needles separated by 1 cm, a configuration which has been shown to provide full coverage of the area between the electrodes (27). Eight 1300 V/cm pulses of 100 µs each with 100 ms between pulses were delivered with an ECM830 function generator (BTX, Holliston, MA) in accordance with previous work (8). The liver was then returned to the abdominal cavity, and the incision was closed via suture.…”

“…Nanoablation, which combines intravenous (IV) nanoparticle delivery with local reversible electroporation, is an innovative method to increase nanoparticle delivery (8). Unlike irreversible electroporation, which utilizes intense electrical pulses to induce cell death through permanent cell membrane defects, reversible electroporation employs a series of electric pulses that transiently increase the permeability of the targeted cells, resulting in selectively increased drug delivery (9–11).…”

“…Nanoablation differs from microwave ablation and radiofrequency ablation in that it does not induce necrosis through thermal measures (12). It is a versatile therapy with many applications, as it enhances uptake of superparamagnetic iron oxide nanoparticles (SPIOs) in both hepatic and non-hepatic tumors compared to standard IV dosing (8, 13). Additionally, local electroporation can be combined synergistically with selective intra-arterial nanoparticle delivery (8).…”

Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer

“…8,9 While adapting the therapeutic techniques of interventional radiology, MRI-guided nanoparticle delivery could enhance uptake of an intratumoral agent and limit its nonspecific delivery to the reticuloendothelial system. 10,11 In support of this concept, some studies have reported on application of MRI-guided intra-arterial 12 and intrabiliary 13 nanoparticles for the treatment of liver tumors. Cell-penetrating peptides (CPPs) are short 30-residue synthetic peptides and represent one of the most promising strategies for enhancing the permeability of therapeutic agents, despite the limitations of various biomolecules with regard to extracellular and intracellular diffusion.…”