Randall Toy

Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles

Recent advances in nanoparticle technology have enabled the fabrication of nanoparticle classes with unique sizes, shapes and materials, which in turn has facilitated major advancements in the field of nanomedicine. More specifically, in the last decade, nanoscientists have recognized that nanomedicine exhibits a highly engineerable nature that makes it a mainstream scientific discipline that is governed by its own distinctive principles in terms of interactions with cells and intravascular, transvascular and interstitial transport. This review focuses on the recent developments and understanding of the relationship between the shape of a nanoparticle and its navigation through different biological processes. It also seeks to illustrate that the shape of a nanoparticle can govern its in vivo journey and destination, dictating its biodistribution, intravascular and transvascular transport, and, ultimately, targeting of difficult to reach cancer sites.

Enhanced Delivery of Chemotherapy to Tumors Using a Multicomponent Nanochain with Radio-Frequency-Tunable Drug Release

While nanoparticles maximize the amount of chemotherapeutic drug in tumors relative to normal tissues, nanoparticle-based drugs are not accessible to the majority of cancer cells because nanoparticles display patchy, near-perivascular accumulation in tumors. To overcome the limitations of current drugs in their molecular or nanoparticle form, we developed a nanoparticle based on multicomponent nanochains to deliver drug to the majority of cancer cells throughout a tumor while reducing off-target delivery. The nanoparticle is composed of three magnetic nanospheres and one doxorubicin-loaded liposome assembled in a 100 nm long chain. These nanoparticles display prolonged blood circulation and significant intratumoral deposition in tumor models in rodents. Furthermore, the magnetic particles of the chains serve as a mechanical transducer to transfer radio frequency energy to the drug-loaded liposome. The defects on the liposomal walls trigger the release of free drug capable of spreading throughout the entire tumor, which results in a widespread anticancer effect.

The effects of particle size, density and shape on margination of nanoparticles in microcirculation

In the recent past, remarkable advances in nanotechnology have generated nanoparticles of different shapes and sizes, which have been shown to exhibit unique properties suitable for biomedical applications such as cancer therapy and imaging. Obviously, all nanoparticles are not made equal. This becomes evident when we consider their transport behavior under blood flow in microcirculation. In this work, we evaluated the effect of critical physical characteristics such as the particle shape, size and density on a nanoparticles tendency to marginate towards the vessel walls in microcirculation using an in vitro model. The wall deposition of nanoparticles was tested in a fibronectin-coated microfluidic channel at a physiologically relevant flow rate. Different classes of nanoparticles (liposome, metal particles) of different sizes (60-130 nm), densities (1-19 g ml(-1)) and shapes (sphere, rod) displayed significantly different deposition as a result of different margination rates. The smaller-sized and the oblate-shaped particles displayed a favorable behavior as indicated by their higher margination rates. Notably, the particle density showed an even more essential role, as it was observed that the lighter particles marginated significantly more. Since nanoparticles must escape the flow in order to approach the vascular bed and subsequently extravascular components for meaningful interactions, the design of nanoparticles strongly affects their margination, a key factor for their ultimate in vivo effectiveness.

Targeted nanotechnology for cancer imaging.

Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.

Multimodal In Vivo Imaging Exposes the Voyage of Nanoparticles in Tumor Microcirculation

Tumors present numerous biobarriers to the successful delivery of nanoparticles. Decreased blood flow and high interstitial pressure in tumors dictate the degree of resistance to extravasation of nanoparticles. To understand how a nanoparticle can overcome these biobarriers, we developed a multimodal in vivo imaging methodology, which enabled the noninvasive measurement of microvascular parameters and deposition of nanoparticles at the microscopic scale. To monitor the spatiotemporal progression of tumor vasculature and its vascular permeability to nanoparticles at the microcapillary level, we developed a quantitative in vivo imaging method using an iodinated liposomal contrast agent and a micro-CT. Following perfusion CT for quantitative assessment of blood flow, small animal fluorescence molecular tomography was used to image the in vivo fate of cocktails containing liposomes of different sizes labeled with different NIR fluorophores. The animal studies showed that the deposition of liposomes depended on local blood flow. Considering tumor regions of different blood flow, the deposition of liposomes followed a size-dependent pattern. In general, the larger liposomes effectively extravasated in fast flow regions, while smaller liposomes performed better in slow flow regions. We also evaluated whether the tumor retention of nanoparticles is dictated by targeting them to a receptor overexpressed by the cancer cells. Targeting of 100 nm liposomes showed no benefits at any flow rate. However, active targeting of 30 nm liposomes substantially increased their deposition in slow flow tumor regions (∼12-fold increase), which suggested that targeting prevented the washout of the smaller nanoparticles from the tumor interstitium back to blood circulation.

Treatment of invasive brain tumors using a chain-like nanoparticle

Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment.

Treatment of cancer micrometastasis using a multicomponent chain-like nanoparticle

While potent cytotoxic agents are available to oncologists, the clinical utility of these agents is limited due to their non-specific distribution in the body and toxicity to normal tissues leading to use of suboptimal doses for eradication of metastatic disease. Furthermore, treatment of micrometastases is impeded by several biobarriers, including their small size and high dispersion to organs, making them nearly inaccessible to drugs. To circumvent these limitations in treating metastatic disease, we developed a multicomponent, flexible chain-like nanoparticle (termed nanochain) that possesses a unique ability to gain access to and be deposited at micrometastatic sites. Moreover, coupling nanochain particles to radiofrequency (RF)-triggered cargo delivery facilitated widespread delivery of drug into hard-to-reach cancer cells. Collectively, these features synergistically facilitate effective treatment and ultimately eradication of micrometastatic disease using a low dose of a cytotoxic drug.

Triggered chemotherapeutic drug release from multi-component nanochains mediated by a local magnetic field

Therapeutic efficacy was evaluated by comparing survival times of treated animals with untreated animals and control groups. The mean survival time for animals receiving a single treatment of Drug-NC followed by RF exposure was 25.1 days, compared to 15.2 days for untreated and control groups. A two-cycle treatment prolonged survival to an average of 46 days. Significant cell death was observed in the Drug-NC+RF group in histological sections of the tumors, while nearly no cell death was observed in any of the control groups. The iron oxide nanoparticles used in the chain are an effective tool for converting magnetic energy into mechanical energy. The current application makes use of restricted Brownian motion of the nanoparticles in the nanochain. The movement of the iron oxide chain is restricted due to bonding, preventing true rotation to align with the field.2 We believe the result is a mechanical “vibration” that causes imperfections in the liposome though which the drug is able to escape. To investigate this hypothesis, drug release was measured from several concentrations of Drug-NC exposed to the same magnetic field, and all samples exhibited the same release rate, suggesting that a high concentration of iron oxide nanoparticles is not necessary for drug release. Further, no global heating was observed, and the possibility of local heating was excluded through linking a fluorophore (Alexa 488) to the iron oxide chain of the Drug-NC particle.3 Multiple Drug-NC suspensions were exposed to direct heating (ΔT=0-9°C), causing a measureable decrease in fluorescence intensity. However, when the suspensions were only exposed to RF, no change in fluorescence intensity was observed.