In This Issue
Winter Bridge on Frontiers of Engineering
December 14, 2018 Volume 48 Issue 4

Developing Targeted Theranostic Nanoparticles: Challenges and Potential Solutions

Thursday, December 13, 2018

Author: Andrew Tsourkas

It has been nearly 50 years since President Richard Nixon declared “War on Cancer” with the National Cancer Act of 1971. Yet according to the Centers for Disease Control and Prevention[1] the cancer death rate has decreased by only about 20 percent since then, paling in comparison to the >65 percent reduction in the death rate for heart disease and stroke (Ma et al. 2015). The development and refinement of targeted theranostic nano-particles may advance progress on this front.

Introduction

The vast majority of cancer chemotherapeutics, which primarily consist of small-molecule drugs, have failed to make a major impact on the death rate for most cancer types. This can be at least partially attributed to the substantial risk of systemic toxicity, which limits the dose that can be safely administered. Because of the body’s rapid clearance of small-molecule drugs, high doses are needed to achieve a therapeutic effect, but since drugs perfuse both diseased and healthy tissue, there can be undesirable effects in the -latter. Small-molecule drugs are also often associated with broad mechanisms of action, which can disrupt unintended cellular pathways.

Initially, it was thought that nanoparticles would provide an immediate solution to all of these problems. Nanoparticles used in therapeutic applications are typically produced at sizes of 10–150 nm to ensure long circulation times after intravenous administration. In general, drugs of less than 10 nm are rapidly cleared by the kidneys, and nanoparticles larger than 150 nm are more efficiently cleared by phagocytic Kupffer cells in the liver. Nanoparticles are also designed to be biocompatible (so they do not elicit a significant immune response) and biodegradable (to ensure eventual excretion).

Imaging agents and therapeutic agents are used to facilitate the study and evaluation of nanoparticle pharmacokinetics. Nanoparticles prepared with both a therapeutic and diagnostic imaging agent are often referred to as “theranostic.”

Advantages and Challenges of Nanoparticle Drug Delivery

There were many reasons for the initial excitement surrounding nanoparticles as drug delivery vehicles. First, their circulation half-life in serum can be 10- to 100-fold longer than the small-molecule drugs that they carry (O’Brien et al. 2004), giving the drug more time to find its target and often allowing for the use of lower doses. Longer circulation times are also generally associated with reduced toxicity to organs involved in drug excretion (e.g., the kidney and liver), because of slower accumulation in these organs and a lower maximum drug concentration at any given time.

A second advantage of nanoparticles, compared with small-molecule drugs, is that they do not freely perfuse all tissues but are confined to blood vessels and tissues with highly permeable vasculature (i.e., the liver, spleen, and tumor). This results in a lower chance of toxicity to healthy organs. The best known example is the drug Doxorubicin: its cardiotoxicity is reduced 7-fold when packaged in a nanoparticle (O’Brien et al. 2004).

Third, nanoparticles can be used to solubilize drugs that are highly hydrophobic and cannot otherwise be administered to patients, thus increasing the number of drug candidates.

Despite the clear advantages of nanoparticles, -nanoparticle-based drug formulations have not consistently led to a significant improvement in patient survival compared with free drug. As a result, only six nanoparticles have FDA approval for the treatment of cancer (-Ventola 2017). There seem to be two primary (and related) reasons for the limited efficacy of nanoparticles: low levels of accumulation in tumors and limited penetration into tumor tissues.

A survey of the literature from the past 10 years found that, despite extended circulation time, only 0.7 percent (median) of an administered nanoparticle dose is found in solid tumors (Wilhelm et al. 2016). The accumulation is largely driven by the enhanced permeability and retention associated with the greater vascular permeability of tumors and poor lymphatic drainage.

Once nanoparticles cross the vascular wall, they need to penetrate a dense extracellular matrix in order to reach tumor cells. Unfortunately, nanoparticles typically travel just tens of microns over the course of days (Sykes et al. 2014; Wang et al. 2015).

Theranostic Targeting

Strategies are being explored to improve both the accumulation and penetration of nanoparticles in tumors. The most common approach to bolster the accumulation of nanoparticles in tumors involves functionalizing the nanoparticle surface with targeting ligands specific for a tumor biomarker. While targeting alone does not address the challenge of tumor penetration, the penetration has been shown to increase with repeated dosing.

The benefits of targeting probably stem from better retention of the nanoparticles in the tumor rather than a greater quantity of nanoparticles that reach the tumor. Targeting also likely improves the probability of nanoparticle binding and internalization by cancer cells (in relation to surrounding stromal cells), which can enhance drug efficacy. Moreover, the targeting agent may exhibit an additive, or even synergistic, therapeutic effect on target cells when combined with the chemo-therapeutic payload in the nanoparticle (Yang et al. 2007).

Challenges and Solutions for Targeting Strategies

While targeting is widely considered to be beneficial, studies have shown that receptor targeting does not always make therapeutic nanoparticles more efficacious (Lee et al. 2010; McNeeley et al. 2007). It is now understood that many complicating factors can limit the success of targeted nanoparticles. Not surprisingly, poor tissue penetration remains a significant problem. Heterogeneous antigen expression and/or the loss of cell surface antigen expression during disease progression are also problematic.

Use of the Tumor Microenvironment

One strategy being tested to overcome the high variability and instability of cancer cells involves taking advantage of cues in the tumor microenvironment to promote nanoparticle retention in tumors. For example, numerous nanoparticles have been developed to be retained in tumors in response to the acidic tumor microenvironment, matrix-metalloproteinases, hypoxia, binding of stromal cells, and other factors common to most tumor types (Du et al. 2015). A variation on this approach involves using biological cues to generate smaller nanoparticles in the tumor environment so that they can diffuse more readily through the interstitium (Li et al. 2016; Wong et al. 2011).

While targeting strategies that take advantage of the tumor microenvironment have seemed encouraging in preclinical studies, no single approach can be used in all patients because of patient-to-patient variability. Progress toward personalized medicine is needed to determine which targeting strategies will be effective in individual patients.

External Stimuli

As an alternative to molecular and environmental signatures for targeting, externally administered -stimuli have been used to improve the accumulation and penetration of nanoparticles. Pharmacological stimuli have included enzymes to degrade the extracellular matrix (Parodi et al. 2014), inhibitors to limit matrix generation (Diop-Frimpong et al. 2011), and drugs to alter vascular permeability or blood flow (-Chauhan et al. 2012). Physical triggers include radiation (-Baumann et al. 2013; Koukourakis et al. 2000) and ultrasound (-Mullick Chowdhury et al. 2017; typically in combination with microbubbles). By increasing vascular and tumor permeability both approaches can dramatically improve nanoparticle delivery when timed appropriately.

Magnetic forces can also be used to boost the accumulation and penetration of nanoparticles in tumors. While this has been limited to superficial tissues (-Al-Jamal et al. 2016; Schleich et al. 2014) because of the rapid dropoff of the magnetic field gradient with distance from the magnet, proper configuration of multiple magnets can enhance the delivery of magnetic nano-particles into deep (permeable) tissues.

Physical triggers can also be used to promote the release of drugs from nanoparticles. The hypothesis is that once a drug is released it can more readily perfuse the tumor tissue. A second possibility is that the rapid release of a drug from intratumoral nanoparticles can yield a higher effective dose. Importantly, for this approach, drug release must be limited to the tumor and not be triggered in healthy organs. The most common physical trigger is light irradiation to promote drug release from light- or thermally responsive nano-particles (Linsley and Wu 2017), but its use is limited to superficial tumors.

Recent work shows that alternating magnetic fields can be used to spatially target the heating of magnetic nanoparticles and trigger drug release from thermally responsive nanoparticles (Tay et al. 2018).

A limitation of all physical triggers is that their effect is confined to the primary tumor. The use of external triggers will therefore need to be complemented with biological targeting strategies to ensure the elimination of metastatic niches.

Prospects

As advances continue in nanoparticle design efforts to overcome the many challenges of treating cancer, there has been a corresponding increase in nano-particle complexity and cost, and yet there are still very few examples of clinical benefit. Many failures stem from the inability to produce complex nanoparticles at large scale. Therefore, there seems to be movement toward simplifying nanoparticle designs to achieve high drug encapsulation efficiencies, high drug payloads, and high conjugation efficiencies with few (or no) purification steps required.

While progress toward effective treatments for cancer is taking longer than expected, researchers are beginning to understand the obstacles that have prevented nanoparticles from significantly reducing the cancer death rate. Innovative solutions are being identified that will one day allow nanoparticles to live up to the lofty expectations of them.

Acknowledgments

I thank Cameron Fletcher for her helpful comments and edits.

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[1]  Expected New Cancer Cases and Deaths in 2020, https://www.cdc.gov/cancer/dcpc/research/articles/cancer_ 2020.htm.

About the Author:Andrew Tsourkas is a professor in the Department of Bioengineering, co-director of the Center for Targeted Therapeutics and Trans-lational Nanomedicine, and director of the Chemical and Nanoparticle Synthesis Core Facility, all at the Uni-versity of Pennsylvania.