Medicine


One of major medical challenges is cancer. Cancer is a disease where cell growth is out of control. In addition to surgery and radiation treatment, chemotherapy relies on chemical agents that aim to slow down the abnormal cell growth and limit tumor spread. Yet, typical chemoagents cannot differentiate tumor cells from healthy ones, resulting in collateral damages to normal organs and tissues. Common side effects include fatigue (mainly due to the temporary drop in bone marrow function), sores, numbness, diarrhea, hair loss, and organ failure. Requirement of high doses due to the poor solubility worsens the side effects. Treatment gets more complicated due to the fact that many anticancer drugs are poorly soluble in water. Take paclitaxel as the example. Its solubility is less than 1 microgram per mL. As a comparison, acetaminophen (the active compound in Tylenol) has a solubility of 14 mg/mL in water. The FDA-approved Taxol formulation uses special solvents to dissolve the drug for intravenous delivery. Due to the solubility limitation and adverse effects of excipient, Cremophor EL, in the formulation, Taxol is typically administered through infusion for many hours. Because of the inherently poor solubility, therapeutic effects are hindered.

These limitations prompt extensive studies to design better delivery systems for poorly water-soluble chemoagents such as paclitaxel. Because many drugs are difficult to ionize, pH alteration or salt formation cannot be employed. Chemical modification to form prodrugs is promising, but a prodrug may be less cytotoxic and inclined to be degraded in the plasma. Pegylation is under investigation as PEG shows great solubilizing capacities as well as the “stealth” from the immune system. Physical approaches include using cosolvents, emulsions, micelles, liposomes, and micro-/nano-particles. Most of these approaches are liquid-based and thus inherently suffer the drawbacks of liquid-based dosage forms, such as instability, in vivo uncertainty, and manufacture cost. Using dried micro-/nano-particles for drug delivery does not increase the solubility of a drug significantly (unless smaller than a dozen of nanometers), although size reduction does increase the dissolution rate to some extent.

Formulating a poorly soluble drug as the amorphous state improves its dissolution rate. Compared with the crystalline form, the amorphous state has higher internal energy and higher (apparent) solubility due to loosely packing, unsaturated binding, and lacking of long-range order. Using amorphous materials for drug delivery becomes very attractive, particularly for oral drug delivery. Nevertheless, the amorphous state is thermodynamically unstable and can transform into a more stable crystalline form. Amorphous drugs are typically dispersed into a polymer matrix forming a solid dispersion. Such a solid dispersion system is prepared by hot melt – dissolving the drug into a melted polymer solution followed by rapid cooling – or by solvent evaporation – dissolving the drug and polymer in a common solvent followed by evaporation of the solvent). Mobility of drug molecules is hindered by the interactions between drug molecules and polymers. The chance of re-crystallization is kinetically reduced. Still, a solid dispersion system may eventually undergo phase transition and crystallize with or without help of temperature oscillation, moisture contact, or other conditions under which polymer chains fail to prevent the nucleation and crystal growth. Should crystallization occur during the preparation, storage, or administration stage, bioavailability of the drug will be significantly deteriorated.

For cancer therapy, targeted delivery has always been actively pursued. Ideally, a delivery system should spare healthy tissues and organs and only act on tumor and cancer cells. No such a system exists today and perhaps will never be made. To encourage more drug molecules reach a solid tumor, a delivery system is often formulated as nanosized particles. Tumor-targeting ligands or antibodies that are conjugated to a delivery system are thought to prompt cancer cell uptake of the drug-conjugate. Still, no more than a few percent of drug molecules get accumulated in tumor. More importantly, when tumor becomes metastasized, current chemotherapy regiments offer little help.

A stable, effective, and safer delivery platform for chemotherapeutic compounds, such as paclitaxel, remains to be developed.