Targeted Drug Delivery Systems

Polymeric micelles are an important class of targeted drug delivery systems that act as carriers of chemotherapeutic agents. A recent review summarized the research being carried out in the development and use of polymeric micelles and micelle-forming drug-polymer conjugates for cancer therapy.


A common problem in cancer treatment is the untargeted delivery of highly toxic drugs, which kills healthy cells in addition to cancer cells and results in serious side effects. Another notable problem that compounds the toxic side effects of these drugs is their insolubility in water and blood, which reduces their circulation time in the blood and necessitates the administration of larger and more frequent doses of the drug.

For the reasons cited above, a targeted drug delivery system that selectively delivers a drug to the tumor site and leaves healthy tissue unaffected is a prized goal for many researchers. A review published in AAPS PharmSciTech in 2014 provided a comprehensive overview of ongoing research in this area, some of which is summarized below.

Many chemotherapeutic drugs are insoluble in water and blood, which reduces their effective availability at the site of the tumor. However, these drugs are “oil-loving” or soluble in oils, fats, detergents, and compounds such as those found in cell membranes. This makes micelles prime candidates for carrying these drugs to specific sites in the body where drug action is required. Micelles are aggregates that are formed when molecules or chemical compounds that have both “water-loving” (called hydrophilic) and “water-repelling” (called hydrophobic) segments are added to water or water-based solutions. Detergents are examples of micelle forming compounds, and as for soap bubbles—yes, they are micelles. When added to water, the detergent molecules aggregate in a manner that allows their hydrophilic segments to interact with water while their hydrophobic or “oily segments” are buried in the interior of the aggregate. It is now easily seen how micelles can serve as carriers for “oil-loving” or hydrophobic drugs.

Polymeric micelles, commonly used as drug carriers, are generally formed from molecules called block co-polymers, which have very large hydrophilic and hydrophobic segments. The hydrophilic segments of polymeric micelles for drug delivery generally consist of polyethylene glycol (PEG) with a molecular weight of 2–15 kilodaltons. Their hydrophobic segments are prepared from polyesters such as poly(lactic acid) (PLA) and polyamides such as poly (L-lysine) (PLL) and poly (beta-amino ester). Genexol-PM is an example of a polymeric micelle formulation containing the antitumor drug paclitaxel that is available in the market for the treatment of breast cancer, non small cell lung cancer (NSCLC), and ovarian cancer. Additionally, its efficacy in treating gynaecologic cancer in combination with carboplatin is currently being tested in a phase I clinical trial.

Researchers have developed different types of polymeric micelles with an improved capacity to load drugs into the micelle interior. This was achieved by incorporating chemical groups that can interact with the drugs in the interior of the micelle. This strategy has been successfully used to create micelles with improved loading capacities for a number of drugs including doxorubicin, camptothecin, and paclitaxel. However, more tests for efficacy and safety need to be carried out before these formulations reach the clinical trial stage.

In a novel strategy, researchers are have tried to use micelle forming conjugates of hydrophobic drugs and hydrophilic polymers to load a second drug, which would be carried in the micelle interior. Loading of the antitumor drug cisplatin on the polyglutamic acid and paclitaxel conjugate (paclitaxel poliglumex) is an example of this strategy being successfully deployed to improve efficacy while lowering toxicity.

Another example is the PEG conjugate with vitamin E called D-α-tocopheryl polyethylene glycol (PEG) 1,000 succinate (TPGS). TPGS has been approved for use by the United States Food and Drug Administration as a pharmaceutical adjuvant. TPGS helps overcome multidrug resistance in cancer and increases the availability of orally taken cancer drugs at tumor sites. TPGS has been conjugated to doxorubicin, and this formulation is eliminated more slowly and has fewer side effects when administered in rats.

Similarly, embelin, a small molecule compound isolated from a Japanese herb, has been conjugated with PEG, and PEG-embelin formulations with paclitaxel have been shown to possess superior antitumor activity compared to taxol when administered to mice with breast or prostate cancer. Embelin is known to bind and inhibit a protein called XIAP, which is expressed in large quantities in tumor cells but not normal cells. Therefore, drug formulations containing embelin are expected to accumulate at tumor sites while avoiding healthy tissues, improving both drug efficacy and safety. In a similar vein, another small molecule compound called S-trans,trans-farnesylthiosalicylic acid, which binds to and inhibits the activity of the tumor-causing protein Ras, has been conjugated to PEG and when used in combination with paclitaxel shows significantly higher anticancer activity than taxol in mice with breast cancer.

In other experiments, researchers are attempting to conjugate PEG or other polymers to curcumin, a compound isolated from turmeric with known antitumor activity against melanomas and cancers of the prostate, colon, breast, liver, kidney, and lymphoid and myeloid tissues, to improve its solubility and availability at tumor sites. These are but a few examples. Further improvements in the methods of conjugating drugs to polymeric carriers and identifying new polymeric carriers that do not trigger allergic or hypersensitive responses are expected to pave the way for exciting new targeted drug delivery systems for treating cancer and other chronic diseases.



Written By: Usha B. Nair, Ph.D.

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