Nanoparticle and targeted systems for cancer therapy

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Abstract

This review explores recent work directed towards more targeted treatment of cancer, whether through more specific anti-cancer agents or through methods of delivery. These areas include delivery by avoiding the reticuloendothelial system, utilizing the enhanced permeability and retention effect and tumor-specific targeting. Treatment opportunities using antibody-targeted therapies are summarized. The ability to treat cancer by targeting delivery through angiogenesis is also discussed and antiangiogenic drugs in clinical trials are presented. Delivery methods that specifically use nanoparticles are also highlighted, including both degradable and nondegradable polymers.

Introduction

Current cancer therapy usually involves intrusive processes including application of catheters to allow chemotherapy, initial chemotherapy to shrink any cancer present, surgery to then remove the tumor(s) if possible, followed by more chemotherapy and radiation. The purpose of the chemotherapy and radiation is to kill the tumor cells as these cells are more susceptible to the actions of these drugs and methods because of their growth at a much faster rate than healthy cells, at least in adults. Research efforts to improve chemotherapy over the past 25 years have led to an improvement in patient survival but there is still a need for improvement. Current research areas include development of carriers to allow alternative dosing routes, new therapeutic targets such as blood vessels fueling tumor growth and targeted therapeutics that are more specific in their activity. Clinical trials have shown that patients are open to new therapeutic options and the goal of these new chemotherapeutics is to increase survival time and the quality of life for cancer patients.

In all cases, the effectiveness of the treatment is directly related to the treatment's ability to target and to kill the cancer cells while affecting as few healthy cells as possible. The degree of change in the patient's quality of life and eventual life expectancy is directly related to this targeting ability of the treatment. Most current cancer patients' only selectivity in their treatment is related to the inherent nature of the chemotherapeutic drugs to work on a particular type of cancer cell more intensely than on healthy cells. However, by administering bolus doses of these intense drugs systematically some side effects will always occur and sometimes are so intense that the patient must discontinue therapy before the drugs have a chance to eradicate the cancer [1]. Unfortunately, not all treatments, even if carried through to the oncologists specifications, are effective in killing the cancer before the cancer kills the patient. The advances in treatment of cancer are progressing quickly both in terms of new agents against cancer and new ways of delivering both old and new agents. Hopefully this progress can move us away from near-toxic doses of non-specific agents. This review will primarily address new methods for delivering therapies, both old and new, with a focus on nanoparticle formulations and ones that specifically target tumors.

A single cancerous cell surrounded by healthy tissue will replicate at a rate higher than the other cells, placing a strain on the nutrient supply and elimination of metabolic waste products. Once a small tumor mass has formed, the healthy tissue will not be able to compete with the cancer cells for the inadequate supply of nutrients from the blood stream. Tumor cells will displace healthy cells until the tumor reaches a diffusion-limited maximal size. While tumor cells will typically not initiate apoptosis in a low nutrient environment, they do require the normal building blocks of cell function like oxygen, glucose and amino acids. The vasculature was designed to supply the now extinct healthy tissue that did not place as high a demand for nutrients due to its slower growth rate.

Tumor cells will therefore continue dividing because they do so without regard to nutrient supply but also many tumor cells will perish because the amount of nutrients is insufficient. The tumor cells at the outer edge of a mass have the best access to nutrients while cells on the inside die creating a necrotic core within tumors that rely on diffusion to deliver nutrients and eliminate waste products. In essence, a steady state tumor size forms, as the rate of proliferation is equal to the rate of cell death until a better connection with the circulatory system is created. This diffusion-limited maximal size of most tumors is around 2 mm3 [2], [3]. To grow beyond this size, the tumor must recruit the formation of blood vessels to provide the nutrients necessary to fuel its continued expansion. An illustration of tumor development from a single cell to a diffusion-limited tumor is shown in Fig. 1. It is thought that there could be numerous tumors at this diffusion-limited maximal size throughout the body. Until the tumor can gain that access to the circulation it will remain at this size and the process can take years. The exact molecular mechanisms that initiate angiogenesis at a tumor site are not known and could be unique to site of origin but more information about what factors play a role in this process is being discovered. As more is known about the molecular mechanisms that stimulate angiogenesis, the factors involved present new therapeutic targets to prevent tumor development.

Section snippets

Achieving targeting by avoiding reticuloendothelial system (RES)

Nanoparticles will usually be taken up by the liver, spleen and other parts of the RES depending on their surface characteristics. Particles with more hydrophobic surfaces will preferentially be taken up by the liver, followed by the spleen and lungs [4]. Hydrophilic nanoparticles (35 nm diameter), such as those prepared from poly(vinyl pyrrolidone), show less than 1% uptake by the spleen and liver and 8 h after injection show 5–10% still circulating in the bloodstream. However, nanoparticles

Paclitaxel

Paclitaxel is a microtubule-stabilizing agent which promotes polymerization of tubululin causing cell death by disrupting the dynamics necessary for cell division. It has neoplastic activity especially against primary epithelial ovarian carcinoma, breast, colon, and non-small cell lung cancers. Paclitaxel is poorly soluble in aqueous solutions but soluble in many organic solvents such as alcohols. It therefore lends itself well to more advanced formulation strategies. The currently available

Targeting to specific organs or tumor types

One of the greatest challenges is defining the optimal targeting agent or agents to selectively and successfully transport nanoparticle systems to cancerous tissue. These strategies also then rely on the targeting agents' or ligands' capability to bind to the tumor cell surface in an appropriate manner to trigger receptor endocytosis. The therapeutic agents will thereby be delivered to the interior of the cancer cell.

Imaging for cancer

Many of the same techniques used to target delivery of drugs to cancerous tissues may also be used to target imaging agents. In fact, as targeted delivery systems approach the stage where they can be used clinically, primary assessment of the utility of a particular formulation in a particular patient may be made with imaging agents to verify that the delivery system goes primarily to the cancerous tissues before any drug regimen is begun.

Studies using vasoactive intestinal peptide (VIP), whose

Conclusions

Research activity aimed towards achieving specific and targeted delivery of anti-cancer agents has expanded tremendously in the last 5 years or so with new avenues of directing drugs to tumors as well as new types of drugs. The first of these creative treatment methods have made it to the clinic and hopefully are well on their way to improving the length and quality of life for cancer patients. However, there is a great deal more that can be done to treat and perhaps prevent advanced cancer by

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