Microspheres and Regional Cancer Therapy

Neville Willmott, John M. Daly

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000142020
• Edition: 1
• Topic: Medicine
• Subtopic: Oncology

Microspheres and Regional Cancer Therapy takes an interdisciplinary approach to the subject of microspheres and regional cancer therapy. It synthesizes laboratory and clinical data to demonstrate the utility of microsphere-based strategies in the treatment of localized solid tumors (particularly in the liver) not amenable to surgery and as a component of strategies for treatment of disseminated disease. Using the same techniques that show the deficiencies of delivery strategies involving antibodies, liposomes, and synthetic polymers, clear evidence is presented describing how microspheres of appropriate size can be localized in solid tumor deposits in the liver with little exposure to other organs. To exploit this phenomenon, the extent and nature of the incorporation of active agents within microspheres is discussed in relation to release, pharmacokinetics, and tumor response achieved by intensification of therapy in the manner described. This book will benefit laboratory-based scientists and clinicians in pharmaceutics, pharmacology, physiology, surgical oncology, and nuclear medicine. In addition, cancer clinicians interested in the value of regional therapy will be able to evaluate the underlying theory and learn the necessary methodology.

Chapter 1

PHARMACEUTICAL AND METHODOLOGICAL ASPECTS OF MICROPARTICLES

Yan Chen, Mark A. Burton and Bruce N. Gray

TABLE OF CONTENTS

I. Introduction

II. Selection of Matrix/Wall Materials for Microparticles

A. Proteins

B. Polysaccharides

C. Synthetic Polymers

D. Glass and Ceramics

III. Techniques for Microparticle Preparation

A. Emulsion Stabilization

B. Solvent Evaporation

C. Coacervation or Phase Separation

1. Organic Phase Separation

2. Aqueous Phase Separation

D. Interfacial Polymerization

E. Emulsion/Dispersion Polymerization

F. Mechanical Processing

G. Other Techniques

IV. Characterization of Microparticles

A. Size

B. Drug Incorporation

1. Emulsion Stabilization

2. Solvent Evaporation

C. Drug Release Kinetics

D. Surface Properties

E. Biodegradability

V. Novel Strategies

References

I. INTRODUCTION

The past decade has seen a major effort to redefine the ability of cytotoxic drugs to cause tumor regression in terms of the total exposure of the tumor to the particular drug (defined as the area under the concentration-time curve) rather than the administered dose, which may be modified because of toxic side effects. This has helped to clarify some of the variation in response between individual patients when treated with cytotoxic chemotherapy. It is now apparent that in many of the earlier studies, patients, and hence their tumors, were not exposed to sufficiently high drug concentrations to cause meaningful tumor regression. Thus, the main requirements for effective cell killing are for the target cells to be exposed to a sufficiently high drug concentration for an adequate period of time to ensure irreversible changes that lead to cell death. The main dose-limiting factor for cytotoxic drugs is the tolerance of normal tissues. Systemically administered drugs will always cause damage to normal healthy tissues, although this varies between different agents. Therefore, it is not possible to simply use higher drug doses to achieve clinically useful destruction of the cells comprising a solid tumor.

Direct administration of cytotoxic agents into the environment of the tumor has the potential to increase target cell exposure while at the same time decreasing exposure of normal tissues. This principle has been widely applied by administering cytotoxic drugs either directly into tumors or into body cavities, such as the peritoneal or pleural space. Similarly, administration of cytotoxic drugs into the arterial blood supply of solid tumor-bearing organs will result in the target organ receiving a higher peak concentration of drug than when given systemically. This technique has been widely used for treating primary and secondary malignant tumors in liver, isolated limbs, and head and neck cancer. Although regional organ perfusion does increase peak drug concentrations to the target tissues, this exposure advantage is restricted to the first pass of blood through the perfused organ. That fraction of drug not removed on the first pass recirculates as if given systemically.

The greatest advantage would be obtained by a drug delivery system that not only enhanced delivery of the drug to the target organ but also prevented loss of the drug in the efferent venous drainage from that organ. Microspheres and microcapsules, collectively referred to as microparticles, have been described for delivery of active agents to target organs.¹ Due to their size they are trapped in the micro-vasculature of tissues, when administered via the regional artery, where they release their drug payload. The procedure is termed chemoembolization. Microspheres are monolithic and may contain dispersed drug molecules either in solution or solid form, whereas microcapsules consist of drug concentrated in a central core inside a polymer-rich wall or shell. Figure 1 illustrates the basic structures of these two microparticles, although variations have been described.²

Figure 1. A schematic representation of microspheres and microcapsules.

Administration of the drug microsphere system will effectively localize the drug to the target organ and the release profile of the drug from the system can be chosen to obtain a specified duration of exposure. The ability to design drug microsphere systems with a variety of release profiles has opened up a whole new area for cytotoxic drug delivery. There are certain basic requirements for this form of therapy to be effective. First, there is a need to localize sufficient quantities of the drug at the target site to have the desired cytotoxic effect. Second, there is a need to control the rate of delivery into the tumor milieu that will cause maximal cell destruction.

The use of targeted drug delivery by microspheres has particular attraction for treating tumors within isolated organs that have a single afferent arterial blood supply, such as the liver. Moreover, it is obviously of most value in those circumstances in which the tumor in the target organ is the sole site that requires treatment. It would thus have little application in treating patients with widespread cancer. However, there are many clinical situations in which tumor is localized to one area that cannot be eff...

Table of contents

• Cover
• Title Page
• Copyright Page
• Foreword
• Preface
• The Editors
• Contributors
• Acknowledgments
• Table of Contents
• Chapter 1 Pharmaceutical and Methodological Aspects of Microparticles
• Chapter 2 Blood Flow and its Modulation in Malignant Tumors
• Chapter 3 Microparticulate Carriers as a Therapeutic Option in Regional Cancer Therapy: Clinical Considerations
• Chapter 4 Magnetically Controlled Targeted Chemotherapy
• Chapter 5 Agents for Microsphere Incorporation: Physicochemical Considerations and Physiological Consequences of Particle Embolization
• Chapter 6 Drug Analysis of Protein Microspheres: From Pharmaceutical Preparation to In Vivo Fate
• Chapter 7 Regional Therapy of Liver Metastases: A Surgeon’s View
• Chapter 8 Evaluation of the Potential of Microspherical Systems for Regional Therapy in the Tumor-Bearing Liver and Kidney Using Techniques in Nuclear Medicine
• Chapter 9 Perspective on Microspheres in Regional Cancer Therapy
• Index