Solid-State Organic Chemistry at University of Kentucky

University of Kentucky | College of Pharmacy

Tonglei Li

analyze, compute & design
	solid-state organic/drug chemistry

Cancer is a disease where cell growth is out of control. In addition to surgery and radiation for cancer treatment, chemotherapy relies on chemical agents that can slow down abnormal cell growth and limit tumor spread. Similar to various anticancer agents with regard to drug development, paclitaxel is representative due to its significant therapeutic activity and is thereby widely used for cancer treatment. It is marketed by Bristol-Myers Squibb as Taxol. In 2001, sale of the drug was $1.4 billions. Yet, like many cytotoxic drugs, paclitaxel is poorly soluble in water (0.01 mg/ml). As a comparison, acetaminophen (the active 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 sides 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.

Extensive studies have been promoted to design effective delivery systems for the poorly water-soluble chemoagents like paclitaxel. Since many drugs are difficult to ionize, pH alteration or salt formation cannot be employed. Chemical modification to form prodrugs is promising but these prodrugs may be less cytotoxic activity and have an inclination to be catalyzed by human plasma. Pegylation is under investigation as PEG shows great solubilizing capacities for paclitaxel and some other drugs. Physical approaches, in general, 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, namely, stability, patient compliance, manufacture cost, etc. Using dried micro-/nano-particles for paclitaxel delivery may not increase the solubility if drug molecules exist as the crystalline form, although size reduction does increase the dissolution rate to some extent.

Moreoever, amorphous drugs have been widely used as a way to improve the solubility for delivery. Compared with the crystalline form, amorphous state has higher internal energy and higher solubility apparently due to the loosely packing, unsaturated binding, and lacking of the long-range order. Loosely packed molecules make using amorphous materials for drug delivery very attractive. However, amorphous state is thermodynamically unstable and may transform into a more stable crystalline form. To avoid the phase transformation, amorphous drugs are typically dispersed into a polymer matrix forming a solid solution, called solid dispersion. This solid dispersion system can be prepared by hot melt method (i.e., dissolving drug into a melt polymer solution followed by rapid cooling) or solvent evaporation method (i.e., dissolving drug and polymer in a common solvent followed by evaporation of the solvent). Mobility of drug molecules is hindered and confined by the interaction between drug molecules and polymers. The chance for re-crystallization of amorphous drugs may be significantly reduced.

Nevertheless, solid dispersion systems may still face stability problems. Over time, drug molecules may form aggregates and can 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. If crystallization occurs during preparation, storage, or release, bioavailability of the drug delivered will be significantly deteriorated.

In addition to poor solubility, another limitation of paclitaxel treatment is the severe side effects due to its cytotoxicity against healthy cells, which include fatigue (mainly due to the temporary drop in bone marrow function), sores, numbness, diarrhea, hair loss, etc. Requirement of high doses due to the poor solubility may worsen the side effects. To avoid the presence of the anticancer drug to the normal cells, ligand-conjugated polymeric carriers have been researched based on the fact that some receptors may be upregulated or only exist in cancer cells. Targeting these specific receptors, ligand molecules may cumulate the drug delivery system to the receptor-bearing cancer cells. Many targeted delivery systems have been developed and promising results have demonstrated the feasibility of using ligand-receptor binding mechanism to reduce side effects and improve treatment efficacy. Most of these systems are liposomes, microemulsions, and micelles. Since they are liquid-based, however, integration between the ligand-carrier and drug can be troublesome. Dissociation may not be uncommon.

Therefore, a stable and yet effective drug delivery platform of chemotherapeutic compounds like paclitaxel remains to be developed.

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