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Functional Polymers for Nanomedicine
By Youqing Shen The Royal Society of Chemistry
Copyright © 2013 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-620-6
CHAPTER 1
Targeted Drug Delivery in Oncology: Current Paradigm and Challenges
DARREN LARS STIRLAND AND YOU HAN BAE
1.1 Targeted Drug Delivery
Targeted drug delivery seeks to improve the therapeutic index, that is, lower the toxicity but increase the efficacy of a drug. Some designs try to minimize side effects to allow a higher dose and increased therapeutic effects. Other designs focus on increasing efficacy to require less drug that could cause side effects. The methods of targeted drug delivery often control both when and where the drug is effective. If the drug could be presented only to the disease in the body, then there would be no side effects and efficacy would be improved with high concentrations in the target area. In this chapter, we focus on the topic of targeted drug delivery in cancer therapy. Research has been ongoing for years to accumulate a significant amount of knowledge into the field and fill the literature with the term "targeted drug delivery." Some have very aggressive claims of succeeding at targeted drug delivery and others, perhaps more accurately, state a goal of improving targeted drug delivery. While clear delineations of what targeted drug delivery is and is not would help, there are challenges with the current state of targeted drug delivery that extend beyond defining the term. These challenges are present in both the carrier and the target. Carrier technology has improved greatly, yet still has trouble delivering drug to the target. The target, cancer in the clinical setting, is still resisting treatment. The challenges associated with this problem need to be addressed in order to move forward. The systems may be targeted by design, but they are not hitting the target fully and exclusively.
1.1.1 Origins of Targeted Drug Delivery
The current paradigm of targeted drug delivery is linked to its origins, which are tied to chemotherapy and immunology. Paul Ehrlich was a pioneer in chemotherapy and is known for the metaphor of a magic bullet. The vision of the magic bullet was inspired from his ability to selectively stain bacteria cultures. He reasoned a toxic molecule could be tied to the stains to selectively kill only that target. Targeted drug delivery has been guided by Ehrlich's vision, particularly in the field of cancer therapy. In the context of cancer and chemotherapy, a magic bullet carrying an anticancer drug is administered to the patient to provide exclusive delivery to the cancer. In contemplating the metaphor of a magic bullet, perhaps the body's immune system fits best. It has both mobility and specificity. Immune cells can follow chemical gradients and have specificity with antibodies and cell receptors. Ehrlich himself stated that cancer would be more prevalent if not for the immune system.
1.1.2 Progress in Targeted Drug Delivery
Advances in immunology and the advent of monoclonal antibodies have become an important part of pursuing the vision of a magic bullet. With immunostaining, the targeting application seems flawless and provides motivation for application in cancer therapy. In targeted drug delivery there is a targeting aspect and a therapeutic aspect. Sometimes these monoclonal antibodies can provide a therapeutic effect on their own. However, monoclonal antibodies and other targeting designs are usually incorporated in a variety of therapeutic carriers, such as microemulsions, inorganic nanoparticles, viruses, and polymers. Liposomes are composed of lipids which assemble into vesicles with a bilayer capable of carrying drug molecules. Gold and iron oxide nanoparticles are among the more popular inorganic molecules used. Viral carriers, made by modifying existing viruses or by using certain aspects from them, have also been used in targeted drug delivery of chemotherapeutics. All of these have dimensions on the scale of nanometers and can be described as nanoparticles. While colloidal chemistry and even targeted drug delivery have a long history, nanotechnology and its application in nanomedicine are quickly becoming popular topics. Polymer therapeutics is another major trend in research that seeks after the properties of a magic bullet. Helmut Ringsdorf suggested a standard model that could be used to improve targeted drug delivery by focusing on different components of the polymer to give abilities for imaging, targeting, and drug loading. The Ringsdorf model has been an inspiration for many polymer designs in drug delivery for cancer therapy. It has led to a trend of polymer therapeutics, with researchers devising various ways to give properties to polymers. The versatility in chemistry and molecular architecture is one of the advantages of polymers in targeted drug delivery. With polymer therapeutics and the newly emerging field of nanomedicine, the possibilities are only limited by one's imagination.
Comparative PubMed searches show an exponential increase in the number of articles related to polymer therapeutics and nanomedicine. Companies are willing to invest large amounts for research and development of these products because of their potential to return large profits. Review articles list various targeted drug delivery approaches that are in clinical trials, which include polymer–drug conjugates, monoclonal therapeutics, some that specialize in multidrug resistance, and those classified as nanoparticle-based therapeutics.
1.2 Current Paradigm
The current paradigm associated with targeted drug delivery shapes the design of the drug carriers. Currently, there are certain properties thought to maximize drug delivery to the tumor. First, a stable carrier for the drug can help reduce side effects and increase the therapeutic effect. A stable carrier will mean that the drug is protected from the body and that normal (nontargeted) tissues are protected from the drug. Second, the carrier will accumulate in the tumor via the enhanced permeability and retention (EPR) effect. Third, the carrier can target the tumor based on both environmental and cellular components.
In order to arrive at the tumor, the drug needs a stable carrier. The majority of anticancer drugs are hydrophobic and do not dissolve in aqueous solutions. The first requirement of a stable carrier is simply the ability to carry the drug. As the carriers transport the drug, they need to form a stable barrier between the drug and the body. Protecting the body from the drug requires that the drug not interact with nontargeted cells, tissues, or organs. Protecting the drug from the body provides long circulation in the bloodstream. Increasing the blood circulation half-life of the carrier can increase chances of interactions with the target. To achieve long blood circulation, it needs to avoid interaction with the reticuloendothelial system (RES), also known as the mononuclear phagocyte system (MPS). Cell uptake by the MPS will decrease the efficacy of the treatment. There should also be protection against blood-borne proteins that would lead to inactivation, destabilization, or opsonization. The carrier should also be designed to limit accumulation in the kidney, liver, spleen, and other non-targeted organs. Administration of the chemotherapeutic agent Taxol® is a good example of the need for good carriers. Taxol® consists of paclitaxel solubilized in Cremephor EL®, which is a highly toxic mixture of castor oil and ethanol. This excipient can cause hypersensitivity reactions in patients undergoing chemotherapy and can be a treatment limiting problem. Furthermore, the active pharmaceutical ingredient, paclitaxel, is known to cause dose limiting neurotoxicity at high doses. If stability and long circulation are achieved, it will be able to travel through the body and eventually reach the site of the tumor. Here, carrier technology can encourage treatment preferentially to the tumor by using environmental characteristics or cellular components, such as surface proteins, as targets.
The carrier can target environmental characteristics of the tumor. Some of the environmental characteristics provide a means for passive accumulation via the EPR effect. The EPR effect is possible because of two hallmarks of cancer: unchecked growth and continued angiogenesis. Continuous growth of the tumor leads to a chaotic tumor environment, with cells in hypoxic regions producing angiogenic factors which stimulate the production of new blood vessels. These new blood vessels are poorly formed and have gaps or fenestrations in the endothelium that allow passage of macromolecules into the tumor from the blood. Increased mass transport from the blood vessels is beneficial for a tumor that is starved of nutrients. Therapies can take advantage of this hyperpermeability that allows nanoparticles to accumulate in the tumor where this leakiness occurs. Furthermore, retention in the tumor is aided by the lack of functional lymphatics that would normally drain the tissue.
Once in the tumor environment, molecular targeting is a method used to provide treatment preferentially to tumors. Some cancer cell types overexpress certain surface markers. These markers are present in other cells, but can be much more abundant in some tumors. Overexpression of folate receptor and human epidermal growth factor receptor 2 (HER2) have been shown to be a predictor of poor prognosis of breast cancers. These and other over-expressed proteins have become a target implemented into the designs of drug carrier technologies. Alternatively, some carriers use a membrane penetration mechanism, such as the TAT peptide, to increase cell internalization in a nonspecific way. While techniques not relying on protein expression can increase efficacy, methods must be used to block activity outside the tumor environment. To achieve this, the carrier's actions can designed to be triggered by environmental characteristics of the tumor. Some drug carriers use pH-sensitive groups to provide a triggered action in the acidic environment. The low pH is a result of metabolism in hypoxic conditions that exist in the core of most solid tumors. As not all tumors possess a markedly low pH, it has been shown that a glucose infusion in nondiabetic patients can lower the pH in tumors. It also might be possible to use the high concentration of matrix metalloproteinases (MMPs) in the extracellular matrix (ECM) of tumors for triggering an active form of the carrier.
Thus, the current paradigm is to have the carrier stably transport the drug while circulating through the bloodstream so that it can accumulate in the tumor, where a targeting mechanism will provide selective treatment. This paradigm has a plethora of opportunities for polymer therapeutics and nanomedicine. Designs can be custom tailored to fit certain aspects of the paradigm. What often happens is a therapeutic approach will focus on one specific aspect of the paradigm to increase efficacy. Unfortunately, this can result in shortcomings in other areas. Overall, there is still a low rate of clinical success for targeted drug delivery.
1.3 Challenges to Current Paradigm
Methods for targeted drug delivery have trouble showing that they are safe, effective, and better than what is currently used for treatment. Currently, ligand–receptor targeting drug carriers have challenges getting approved. For example, Mylotarg® is an antibody–drug conjugate that was approved for clinical use to treat leukemia. However, it has since been withdrawn due to poor results from a post-approval clinical trial, and continued post-marketing surveillance reveals lack of improved efficacy and unacceptable side effects. The antibody has no trouble binding to its target antigen of CD33, but lack of antigen exclusivity to the cancer and accumulation in the liver doomed this product. To make successful targeted drug delivery products, the assumptions underlying these magic bullets will have to be questioned.
For solid tumors, an additional barrier seems to be intratumoral distribution. Once the carrier reaches the site of the tumor, it might be tempting to assume it will then invariably reach and enter the cancer cells. However, there are various factors that prevent the nanoparticle from penetrating into the tumor core. Figure 1.1 shows how accumulation in the tumor is possible but also how penetration is limited. Tumors grown in window chambers show heterogeneous permeation and the accumulation of nanoparticles adjacent to the blood vessel. Other studies also show that the permeability varies and that liposomes do not diffuse far from blood vessels. Distribution beyond the vicinity of blood vessels is a challenge even for viruses and free drug molecules.
Challenges to successful targeted drug delivery come from carrier dependent factors and tumor dependent factors. Current targeted drug delivery formulations are not magic bullets. Biodistribution and the EPR effect depend on carrier characteristics and these carriers are not always well characterized or stable or safe. Also, if good results with a drug carrier are seen in a mouse model, the success does not translate into the clinical model. The tumor resists treatment from the environmental to the cellular level. Aspects of the paradigm need to be examined in order to see improvements. There have been critical examinations of targeted drug delivery for quite some time now, and certain challenges are beginning to be understood.
1.3.1 Challenges Present in the Carrier
In Ehrlich's day a "magic bullet" seemed an appropriate analogy for the vision he had. Present-day scientists sometimes interpret this analogy to something more akin to a homing missile. However, current targeting drug delivery designs are not target-seeking as they cannot sense the target from a distance and adjust their trajectory to home in on it. Furthermore, current designs are not capable of self-propulsion. Instead, they are opportunistic in that they rely on being carried to the target by convective blood flow and diffusion through tissues. There are also challenges associated with the characteristics of the carrier that can have an effect on its stability.
1.3.1.1 Challenges in Stability and Tumor Accumulation
As mentioned earlier, a carrier needs to be stable and this will have an effect on safety and efficacy. For example, while a strongly positively charged molecule aids in entering the cell, high doses of cationic carriers can be toxic. Essentially, the biocompatibility of the carrier is determined by the chemistry of the monomer and degradation products. Viruses also serve as effective carriers but have risks — one of which being an immune response against the viral components. Stability upon dilution in the blood may be challenged for some microemulsion carriers such as liposomes or micelles. Other potential problems that all carriers face when introduced into the blood include destabilization from high salt concentrations, adsorption of proteins, interactions with lipids, opsonization, and phagocytosis from cells. When the drug interacts with normal tissue because of the carrier's instability or is unable to reach targeted tissue because it lacks long circulation, the targeted drug delivery has failed. A common technique to increase circulation time is to add extremely hydrophilic poly(ethylene glycol) (PEG) to oppose adsorption or molecular interactions. PEG interacts with water to make it thermodynamically favorable for the PEG chains to extend and limit adsorption of proteins. However, long circulation is only relative and there can still be some uptake by the MPS and other organs as well as recognition from antibodies. This is evident when PEG only increases the blood circulation half-life of liposomes in blood by just hours.
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Excerpted from Functional Polymers for Nanomedicine by Youqing Shen. Copyright © 2013 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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