Importance of Delivery and Accessibility for Solid Tumor Treatment
The efforts to streamline the techniques involved in delivering cancer drugs into solid tumors have run along several lines. Among the leading candidates are improved approaches to radiation, cryotherapy, and ablation techniques.
For example, stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy, offers a successful clinical model for the development and widespread use of new radiation therapy technologies. Early research has shown increased rates of tumor control and even survival compared to conventional radiation therapy. That said, broad acceptance of SBRT by radiation oncologists has been hampered by concerns of toxicity from the very potent, focused beams of radiation delivered to extracranial tumors using one or more dose intervals, or fractions. However, many patients prefer this short treatment course—consisting of five or fewer outpatient sessions of less than 30–60 minutes each—over conventional radiation therapy, which requires six to eight weeks of daily treatments at much lower doses. Based on patient demand and early research that has shown increased rates of tumor control and even survival compared to conventional radiation therapy, SBRT is emerging as a standard of care for treating lung, liver, and spine tumors for many medically inoperable and surgically unapproachable cancer patients. SBRT is now being investigated for the treatment of primary tumors of the breast, prostate, pancreas, and kidney, and cancers that have metastasized to the bone and lymph nodes.
Meanwhile, cryotherapy is the use of extreme cold produced by liquid nitrogen (or argon gas) to destroy abnormal tissue. Cryosurgery can be used to treat external tumors, such as those on the skin. For external tumors, liquid nitrogen is applied directly to the cancer cells with a cotton swab or spraying device. Cryosurgery is also used to treat tumors inside the body (internal tumors and tumors in the bone). For internal tumors, liquid nitrogen or argon gas is circulated through a hollow instrument called a cryoprobe, which is placed in contact with the tumor.
Alternatively, other forms of tumor ablation might be used to treat solid tumors, such as a process involving destroying the tumor inside the body. Radioactive pellets, less than an inch in length and approximately the width of a pin, can be placed inside a tumor; afterwards, the pellet emits lethal radioactive atoms that irradiate the tumor from the inside out. As the tumor disintegrates, it starts to release antigens that trigger an immune response against the cancer cells. In some cases, the body also forms an immune memory against the recurrence of tumor cells. Another proposed ablation technique, “pulsed electric current ablation,” involves the insertion of electrodes into tumors, which then release extremely high-energy electrical currents. These currents create a physical reaction that eliminates the tumor cells.
At the same time, several innovative options exist for delivering drugs into tumors. These include emulsification, nanoparticles, liposomes, microspheres, micelles, and electroporation.
Anticancer agents are typically hydrophobic and unstable in water, making formulation development a major undertaking. For this reason emulsification, the semihomogeneous mixture of two immiscible liquids, is an attractive dosage form for anticancer drugs. Research continues on the development of injectable emulsion formulations, particularly those containing anticancer drugs; the major challenges to date have involved processing difficulties, the lack of physiologically safe ingredients, and thermodynamic instability of the emulsion system.
Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side effects. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles have showed some interesting capacity to reverse multiple-drug resistance, which is a major problem in chemotherapy.
Meanwhile, liposome-based chemotherapeutics used in the treatment of tumors can in principle enhance the therapeutic index of otherwise unencapsulated anticancer drugs. This is partially attributed to the fact that encapsulation of cytotoxic agents within liposomes allows for increased concentrations of the drug to be delivered to the tumor site. In addition, the presence of the phospholipid bilayer prevents the encapsulated active form of the drug from being broken down in the body prior to reaching tumor tissue and also serves to minimize exposure of the drug to healthy sensitive tissue.
Microsphere technology is another recent trend in cancer therapy. Radioactive polymer spheres can be designed to emit beta radiation. Physicians insert a catheter and can deliver millions of the microspheres directly to the tumor site. Microsphere technology is a promising method that can be used for site-specific action without causing significant side effects in normal cells.
Polymeric micelles are also used as drug delivery vehicles. They are prepared from certain amphiphilic co-polymers consisting of both hydrophilic and hydrophobic monomer units. They can be used to carry drugs that have poor solubility. Techniques have been developed that utilize reactive polymers along with a hydrophobic additive to produce a larger micelle, which creates a range of sizes.
Another promising approach to treating solid tumors targets the tumor itself without affecting any of the surrounding healthy tissue, ensuring that a drug or other therapeutic agent is immediately absorbed by the cancer cells. One such targeted therapy could harness a scientific phenomenon known as electroporation. Derived from the words “electric” and “pore,” this involves applying a brief electric field to a living cell. Doing this causes a temporary opening of pores in a cells membrane—pores that close again within minutes once the electric field is discontinued. By creating these membrane pores, the cell’s permeability is temporarily increased, and a drug or other agent injected into the area can flow into the cell by an increased factor of 1,000 or more. An apparatus could be constructed consisting of a generator that creates a pulsed electric field and using a handheld applicator with electrode needles at its tip; the cancer cells affected by this electric field would undergo electroporation.
Such technology has been conceived for use in two separate kinds of therapy: electrochemotherapy and electroimmunotherapy. In the former, an anticancer drug could be injected into a tumor that is electroporated; consequently, the quantity of drug required would be well below that needed in traditional chemotherapy. Meanwhile, the latter therapy would involve the use of a specific cytokine, a substance known to boost the human immune system against cancer cells, to stimulate an immune response producing both a local and a systemic effect against cancerous cells.