Poly (Amido Amine) dendrimers: role of architectural features on biodistribution and oral absorption enhancement

Most of the chemotherapeutics used in the clinic indiscriminately act on healthy proliferating cells along with malignant cells resulting in nonspecific toxicities, a narrow therapeutic index and reduced patient quality of life. Most of such agents are also limited by very low aqueous solubility. One strategy to overcome these challenges is to use biocompatible, water-soluble polymeric carriers to deliver chemotherapeutics with higher selectivity to sites of action (tumors), resulting in a better safety profile, increased maximum tolerated dose, and potentially better efficacy. Poly(amido amine) or PAMAM dendrimers are a class of branched polymers being extensively investigated for their potential as carriers for the delivery of anticancer agents. Their commercial availability, well-defined physicochemical and architectural features, ease of surface functionalization and encapsulation make PAMAM dendrimers useful for the delivery of chemotherapeutics. This dissertation focusses on two aspects of PAMAM dendrimers as drug carriers. The influence of PAMAM's molecular architecture on biodistribution and pharmacokinetics is compared with traditionally used and clinically investigated linear polymers at various molecular weights. Architecture of the polymer affected its hydrodynamic size at different molecular weights. A difference in accumulation of polymers of varying architecture in nonspecific elimination organs (kidney, liver) as well as site-specific organs (tumor) was observed. Variation in polymer architecture also resulted in a decrease in blood clearance with increase in hydrodynamic size and affinity to passively target the tumor by the enhanced permeability and retention effect when circulating in the blood. This dissertation also explored the use of PAMAM dendrimers for oral delivery of chemotherapeutics. By virtue of their unique three-dimensional architecture, PAMAM dendrimers are known to encapsulate, complex and solubilize hydrophobic drugs, modify epithelial tight junctions and act as drug carriers for oral delivery. It was observed that co-administration with dendrimers increased oral bioavailability of camptothecin, a schedule-dependent drug limited in oral use by low and variable absorption. Results suggest that this increase in absorption was not due to epithelial tight junction modulation and that drug inclusion in PAMAM interior controlled solubilization in gastric conditions and increased oral bioavailability.