(214d) Design, Synthesis & Biocompatibility Evaluation of Nano Dendrimer “Paint-Brush” Conjugates for Drug Delivery in Cancer Cells

Statistical figures outline the five-year survival rate for all cancers diagnosed between 1996 and 2002 as 66%, which depicts a marked rise from the 51% that survived in 1975-1977 (1). However, cancer still remains the second leading cause of death in the United States, following heart disease. An American Cancer Society report estimated that in 2007, there will be over 1.4 million new cancer cases and over half a million cancer deaths in the United States (1). The National Institutes of Health had estimated the overall costs of cancer treatment in 2006 to be at $206.3 billion even with a declining death rate in the last decade (1). Moreover, any use of traditional biomolecules as a treatment strategy would only elevate the treatment costs to higher levels. Though significant oncology drug discoveries have been made during the past 30 years, conventional chemotherapeutic agents exhibit poor specificity in reaching the tumor site and are often restricted by toxicity factors. The lack of a uniform biodistribution leads to harmful side-effects to healthy tissues and the need for administration of a larger than necessary drug dosage; with a higher repetitive rate so as to elicit a satisfactory pharmacological response.

Wide interest in cancer nanotherapy has led to the development of nanoparticle based “smart drugs” that have not only improved pharmacological and therapeutic properties of anticancer drugs, but also offer a less invasive alternative enhancing the patient's life expectancy and quality of life as well. Dendrimers, due to their unique architecture and exciting macromolecular characteristics are currently used extensively in research of nanoparticles for targeted and controlled drug delivery. The research objective is to design, synthesize and examine the biocompatibility of a novel nanoparticle based “Paint-Brush” like multi-hydroxyl capped poly (ethylene glycol) (PEG) conjugate using the dendron – bishomotris that may have a potential use in targeted cancer nanotherapy.

Characterization of the conjugates suggested that the synthesis was successful; resulting in the formation of nanoparticle “Paint-Brush” conjugates. A controlled level of release occurred at pH 7.4 for conjugates bearing the model anticancer drug while a remarkable burst of release was induced at pH 5.5, which corresponds to the endosomal pH within cancer cells. The cytotoxicity of human epithelial carcinoma cells (HeLa S3) exposed to these nano-scaled dendrimer conjugates has been examined using a LIVE/DEAD® cell assay and the results clearly demonstrate reduced levels of toxicity thus asserting the conjugate's suitability as a drug delivery vector. The uniqueness in the model envisioned lies in the fact that the structure can be exploited in more than one way to develop novel hybrids that may have the ability to carry antibodies; enzymes or even additional PEG linkages that may enhance the system's biocompatibility alongwith its purpose as a targeted drug delivery system for malignancies.

References: 1) Cancer Facts and Figures 2007, American Cancer Society, Atlanta, 2007