Ultrasound mediated delivery of drugs and genes to solid tumors

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Abstract

It has long been shown that therapeutic ultrasound can be used effectively to ablate solid tumors, and a variety of cancers are presently being treated in the clinic using these types of ultrasound exposures. There is, however, an ever-increasing body of preclinical literature that demonstrates how ultrasound energy can also be used non-destructively for increasing the efficacy of drugs and genes for improving cancer treatment. In this review, a summary of the most important ultrasound mechanisms will be given with a detailed description of how each one can be employed for a variety of applications. This includes the manner by which acoustic energy deposition can be used to create changes in tissue permeability for enhancing the delivery of conventional agents, as well as for deploying and activating drugs and genes via specially tailored vehicles and formulations.

Introduction

Human endeavor has made great strides in the treatment of cancer. Whereas a century ago the chances of someone surviving cancer was zero, today two out of every three people diagnosed will still be alive five years later. Although the ‘cure’ for cancer has been far more elusive than once hoped, treatment continues to improve, evident by the ever increasing number of survivors. In the last decade, for example, we have experienced a 10% decline in the number of cancer deaths [1].

Improved cancer treatment is in part linked to the increase in understanding of cellular, genetic and molecular mechanisms, which provide targets for interventions to prevent, detect, eliminate and control the disease [1]. After surgical removal and/or sterilization by radiation of a primary tumor, management of the residual disease is typically carried out using a variety of systemic therapies [2], [3]. However, in order for these therapies to be successful, there are two requirements that must be satisfied. First, the particular agent being used must be effective in the in vivo, orthotopic microenvironment of the tumor being treated (not just in cell culture). Secondly, optimal quantities of the agent must reach all cells of the targeted tumor [2].

In the United States, the large majority of deaths due to cancer is the result of solid tumors [4]. For most advanced cancers, chemotherapy remains the treatment of choice. However, chemotherapy is rarely curative, especially for solid tumors [5]. Although these anticancer agents are effective for killing tumor cells in monolayers grown in culture, they are unable to reach all tumor cells that are able to regenerate the tumors in vivo [3]. A number of factors has been identified in the microenvironment of solid tumors that are responsible for non-uniform and insufficient levels of anti-cancer agents being delivered. These occur due to abnormalities in both the vasculature and the extracellular matrix and lead to deficiencies in transvascular and interstitial transport, respectively [6], which ultimately affect the bioavailability and efficacy of chemotherapeutic agents [7].

Compared to normal tissues, blood vessels in tumors are leaky, possessing large gaps between endothelial cells [8]. The vasculature is also chaotic in regards to spatial distribution, microvessel length and diameter [6], and it can be tortuous and saccular, possessing haphazard interconnections, which renders the vessels functionally abnormal [9]. Proliferating tumor cells can also generate solid pressure on blood vessels that will further impair blood flow [9]. Another important characteristic of the tumor microenvironment is the combination of a leaky vasculature and a lack of functional lymphatics, which can create increased interstitial fluid pressures compared to normal tissues. These high pressures are found just past the periphery of solid tumors, being approximately the same as the microvascular pressure. As a result, extravasation of large convection-dependent agents can be severely limited [10]. In tumors, the plasma to interstitial gradient of oncotic pressure is also generally reduced, being yet another factor that can contribute to less than optimal delivery of therapeutic agents [11].

Another often overlooked factor for insufficient delivery of anti-cancer agents to tumor cells is the increase in mean distance between tumor cells and the blood vessels that they supply. Whereas the well-organized, normal tissues of the human body enable most cells to be within a few cell diameters of a blood vessel, this is often not the case in solid tumors. Relatively higher cell proliferation rates in tumors, compared to normal tissues, can result in tumor cells forcing vessels apart, leading to a reduction in vascular density. As a result, populations of cells are created that can be more than 100 µm from blood vessels, a problem that may further be exacerbated by the already poor organization of the tumor vasculature. This phenomenon can lead to limited access of drugs to those distant tumor cells. It can also reduce the delivery of oxygen and create conditions of hypoxia (leading to reduced efficacy of radiation therapy) and the build up of metabolic products (e.g. carbonic and lactic acid), lowering the extracellular pH and potentially affecting the cellular uptake of some drugs [3].

Additional factors in the extracellular matrix (ECM) of tumors can limit interstitial transport and, as a result, further prevent sufficient and uniform distribution of anti-cancer agents; especially large agents such as viral vectors [6]. The ECM is made up of a matrix of proteoglycans, collagens, and additional molecules, which are produced and assembled by stromal and tumor cells [12]. McGuire et al. [13] showed that greater collagen content in the ECM required higher infusion pressure to initiate flow in the tumor interstitium. Netti et al. [14] demonstrated the inverse relationship between tumor content of fibrillar collagen and interstitial diffusion of large macromolecules. Collagen in the ECM can physically obstruct transport, where the sizes of viral vectors, for example, can be larger than the space between the fibers [6]. The effects of collagen on reducing interstitial transport were established by treatment with collagenase to chemically disrupt the fibers and increase interstitial transport of antibodies [14] and oncolytic viruses [15]. Collagen fibers also bind and stabilize glycosaminoglycan and hyaluronic acid, which can affect interstitial transport by creating resistance to water and solute transport [14]. Dreher et al. [16] demonstrated the manner by which the size of agents may effect drug delivery to tumors, where increasing the molecular weight of macromolecules was found to increase their plasma half-life; however it decreased vascular permeability for reduced extravasation, as well as penetration into tumor tissue from the vessel wall.

The tumor microenvironment poses a formidable obstacle to enabling uniform and adequate delivery of anticancer agents. If delivered successfully, anticancer agents could substantially improve the treatment of solid tumors. Considerable effort, therefore, has gone into finding ways to modify the tumor microenvironment for this purpose. McKee et al. [15] recently showed using human melanoma xenografts in mice that improved interstitial distribution of oncolytic virus obtained by co-injecting collagenase could also improve growth inhibition of the tumors compared to the virus on its own. Krol et al. [17] on the other hand showed that reducing the number of viable cells could also increase the available fraction of drugs. Other strategies that are being developed for enhancing local drug delivery involve external sources of energy in combination with specially designed carriers to respond to that energy for local drug release [18]. Hyperthermia mediated liposomal drug delivery, for example, is one such strategy that has shown much promise for enhancing local drug deployment while minimizing drug distribution outside targeted tissues [19]. In this review, strategies based on combining non-invasive and non-destructive therapeutic ultrasound exposures with anti-cancer agents will be described by specifically using representative publications from the literature that best exemplify these strategies. In some of these, the exposures are used in a unique fashion with specially tailored agents to improve localized deposition. In others, direct effects are created in the tissues to reduce transport barriers as a way to improve the delivery of more conventional agents whose efficacy is limited because of dose limiting toxicity.

Section snippets

Diagnostic US versus therapeutic US

Using ultrasound for therapeutic purposes dates back to more than half a century ago, even predating the use of ultrasound for diagnostic imaging [20]. Therapeutic ultrasound is generally described as the use of ultrasound for applications other than imaging or diagnostics [21]. In diagnostic ultrasound, energy deposition in tissues is meant to be minimal in order not to produce biological effects. On the other hand, applications of therapeutic ultrasound are based on depositing ultrasound

Heat

Among all the ultrasound mechanisms for producing bio-effects, the generation of heat in tissues due to ultrasound exposure is probably the best known and understood. Heat generation results from the absorption of energy, where the volumetric rate of heat being created is directly proportional to the specific absorption coefficient of the tissue being treated and the intensity and the frequency of the ultrasound wave, and inversely proportional to the specific heat of that particular tissue [43]

Safety considerations

The evidence provided up until now has indicated that there are multiple ways that ultrasound can be used to enhance the delivery and activity of drugs and genes for improving the efficacy of cancer therapy. In order for these strategies to be considered, however, it is necessary that the proposed treatment itself does not worsen the clinical outcome. The large amount of data collected from preclinical studies to date has shown that the thermal dose created by pulsed-HIFU exposures (discussed

Conclusions

Since the first experiments were done using ultrasound exposures in biological tissue, an increasing body of knowledge has been acquired improving the understanding of the many ways that ultrasound energy can interact with tissues, therapeutic agents and carriers for enhancing the treatment of cancer and other diseases. (Fig. 2). Representative examples of these different types of treatments appear in Table 1. Together with advances in the technology of applying this energy and guiding and

Acknowledgements

The author would like to thank Ms Hilary Hancock for her editing contributions to this manuscript. This research was support in part by the NIH intramural program.

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    This review is part of the Advanced Drug Delivery Reviews theme issue on ʻʻUltrasound in Drug and Gene Delivery".

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