The targeted delivery of cancer drugs across the blood–brain barrier: chemical modifications of drugs or drug-nanoparticles?

One of the most challenging problems, if not the most challenging, in drug development is not to develop drugs to treat diseases of the central nervous system (CNS), but to manage to distribute them to the CNS across the blood–brain barrier (BBB) using transvascular routes following intravenous administration. The development of BBB targeting technologies is a very active field of research and development. One goal is to develop chemically modified derivatives of drugs or chemically modified nanoparticulate vectors of drugs, capable of crossing biological barriers, in particular the BBB. This manuscript will review the approaches that have been explored to achieve these goals, using chemical functionalization of drugs or of drug vector systems and endogenous transporters at the BBB.

Introduction

The treatment of brain cancers is limited by the inadequacy in delivering therapeutic agents in such a way that drug molecules reach the desired targets. In order to achieve efficient treatments of central nervous system (CNS) cancers, it is necessary to transport therapeutic agents across the specialized vascular system of the brain, the blood–brain barrier (BBB), which can present formidable challenges. These include the definition of the properties of the cerebral vascular system during cancer progression and the development of biotechnology to prepare biomarker-targeted delivery of multiple therapeutic agents, coupled to the possibility of avoiding various resistance mechanisms. A great deal of effort, therefore, is presently focused on improving CNS bioavailability, and tumors thereof, of therapeutic drugs that can be specifically targeted to diseased tissue, improving therapeutic opportunities, efficiency, and patient survival, while decreasing side-effects to normal cells.

The vast majority of presently used therapies for cancer capitalize on the faster rate of replication of tumor than normal cells. Most solid tumors also possess unique features and defects of their associated vasculature, such as extensive angiogenesis, defective vascular architecture, and increased vascular permeability, all of which can be used for delivering therapeutics. Devices, such as functionalized drug colloidal carriers, can take advantage of these features and act as vehicles to deliver, selectively and specifically, anti-cancer drugs to tissues, either using passive mechanisms relying on increased vascular permeability in a defined location, or using active targeting of chemically modified drugs or nanoparticles. Alternatively, direct modification and/or functionalization of drugs, involving the chemical conjugation of drugs to disease-targeting biological markers, can be used to achieve direct active targeting of drugs.

In this manuscript, the attempts that have been made to use either chemical modifications of drugs or the development of drug-nanoparticulate systems to reach these objectives will be reviewed and their advantages and drawbacks discussed, to define what should be the chemical, biophysical, and biological characteristics of an optimized system.