Magic Bullets: How Nanosized Drug Packages Can Bring Drugs More Selectively to Cancer
27 Nov, 2007 10:42 am
Anticancer agents such as paclitaxel and cisplatin display a very high therapeutic potency towards isolated cancer cells. However, the observed anti-tumour efficacy in patients is disappointing while the various detrimental side effects (e.g. anaemia, nausea and hair loss) limit the dose that can be administered. The reason for this decreased clinical performance is an unfavourable distribution of the drug over the body upon administration. The delivery of anticancer agents to tumours can be made more selectively if one takes a closer look at the structural properties of these malignities. Blood vessels in tumour tissue contain gaps (so-called leaky vasculature) whereas the local lymphatic system, responsible for drainage, is not functioning properly. Both aspects facilitate that structures with a size up to approximately 200 nm will accumulate in tumour tissue.
The entrapment of anticancer drugs in a nanosized carrier system aims at achieving a higher drug concentration in the tumour using its leaky vasculature, and prevents direct toxicity of the drugs towards blood components and hinders a rapid elimination. Once the target tissue is reached, the encapsulated drug is preferably released in a controlled manner to execute its therapeutic effect. A well known colloidal drug delivery carrier is a liposome, which is composed of lipids that form a hollow vesicular morphology and where hydrophilic drugs are dissolved in the aqueous core. Although a liposomal formulation increases the therapeutic efficacy as compared to free drug, the encapsulated drug is not released via predefined or controllable mechanisms and side effects are observed upon repeated administrations. Therefore, we continued the search to the ideal carrier that selectively transports encapsulated drug to diseased tissue for which we used a novel type of biodegradable polymeric micelle.
Biodegradable Polymeric Micelles
Polymeric micelles are globular nanoparticles composed of soap-like polymers, comprising a water soluble segment (most frequently polyethylene glycol (PEG)) and a water repellent segment connected to each other. In an aqueous environment, the water repellent chains assemble into a fatty core whereas the water soluble parts form the shell of the micelle. In our case, a special type of core-forming segment is used, namely lactic acid derivatives of polymethacrylamides which are so-called temperature sensitive polymers. That means that by simply heating an aqueous polymer solution, compact spherical nanoparticles smaller than 100 nanometer are spontaneously formed. A large variety of fat-soluble drugs are successfully enclosed in the core of these micelles. The encapsulated compounds are released after the lactic acid groups of the polymer have been split off by a process that takes place in wet conditions, causing the nanoparticles to fall apart eventually (see Figure 1, "Concept of stable biodegradable polymeric micelles as a controlled drug delivery system). The small size is advantageous for a prolonged circulation in the blood stream and tumour accumulation whereas the polymers composition tailors the ultimate destabilisation time of the micelles.
Stabilised Polymeric Micelles
After administration of drug-loaded micelles in the blood stream by injection, the formulation is diluted and various blood components can interact with the nanoparticles. Both mechanisms often provoke a too early destabilisation of the micelles and/or result in a preliminary release of the encapsulated drug. We solved this issue via a rational design, which is by fixation of the polymer chains within the micellar core (by a chemical process called core crosslinking). The stabilised micelles appear to have an excellent physical stability but are still fully biodegradable. The blood circulation time and distribution of the core crosslinked micelles throughout the body was evaluated in tumour-bearing mice and compared to non-stabilised nanostructures. After 6 hours, more than 50% of the stabilised micelles still resided in the blood whereas less than 5% of the non-crosslinked particles were recovered. After core crosslinking, the tumour accumulation of the micelles was 6-fold increased and these stabilised micelles were only marginally taken up by the liver or spleen. The increased life time in the blood circulation is essential to take maximal benefit of the leaky tumour vasculature. The circulation profile of the core crosslinked micelles is comparable with that of liposomes, but the biodistribution profile is clearly better.
Application of Polymeric Micelles and Current Developments
These biocompatible micelles with a unique, fully tuneable transient stability are very promising drug carriers. Attractive properties are the easy of formation, the stable encapsulation of high amounts of hydrophobic drugs, the tuneable and controlled destabilisation / release profile, the biocompatibility and the elimination profile. Especially the core crosslinked micelles display a very favourable blood circulation time and an enhanced tumour accumulation. This beneficial behaviour gives promise to improve the blood circulation profile of encapsulated anticancer drugs. Therefore, animal studies are planned in the near future to determine the biodistribution and therapeutic efficacy of drug-loaded stabilised micelles and their safety, which is required before the new formulations can be tested on real patients in a clinical setting. Additional innovations include the attachment of so-called targeting ligands (such as antibodies or small peptides), which promote active cellular uptake of the micelles, thus further enhancing the therapeutic efficacy of the micellar encapsulated drugs. The development of new components as building blocks for the nanoparticles will allow an even more accurate regulation of the specificity and drug release. Besides, the co-loading with a contrast agent enables the visualisation of the drug-loaded micelles on its way through the body.
In sum, the biodegradable polymeric micelles that have been developed in our laboratories have the potency to be developed into very advanced drug delivery systems in the near future, thereby increasing the therapeutic efficacy of anticancer agents while minimising their side effects.
Dr. Cristianne J.F. Rijcken, thesis. "Tuneable & degradable polymeric micelles for drug delivery: from synthesis to feasibility in vivo".
Correspondence: Ms. Dr. C.J.F. Rijcken, Department of Pharmaceutics, Utrecht University, 3584 CA Utrecht, The Netherlands.