Dendritic polymers for the delivery of chemotherapeutic agents.

The use of polymers for delivery of chemotherapeutic drugs is extensively studied for their potential to improve drug solubility, reduce toxicity, and more effectively target tumor tissue than chemotherapeutic drugs alone.

PEGylated dendrimer carriers, molecules in which poly(ethylene glycol) chains have been attached to the periphery of a dendrimer core, are increasingly studied by researchers due to their numerous advantages over linear polymer drug carriers.

PEGylated dendrimers can be synthesized with simple, biodegradable chemistry while maintaining a high degree of controllable functionality and low polydispersity.

Due to their core-shell conformation, they are remarkably effective at carrying and protecting a drug cargo covalently attached to the dendrimer core.

Furthermore, the branched architecture of PEGylated dendrimers allows for increased blood circulation and tumor accumulation compared to linear polymers.

Chapter 1 presents an introduction to polymer drug carriers.

Macromolecules behave differently in vivo than small molecule drugs.

This chapter discusses how architectural features such as hydrodynamic volume, molecular conformation and 1 flexibility, and branching impact how a polymer may perform as a drug carrier.

The rationale for using PEGylated dendrimers as drug carriers is presented.

In Chapter 2, the synthesis and in vivo evaluation of two PEGylated dendrimer carriers is discussed.

One carrier is based on 2,2- bis(hydroxymethyl)propionic acid repeat units, forming ester bonds, and the other is based on lysine repeat units.

Although both carriers showed promising in vivo properties, the lysine dendrimer is chosen for further study due to synthetic concerns.

In Chapters 3 and 4, the versatility of the PEGylated poly(L-lysine) (PLL) dendrimer is tested by attaching the chemotherapeutic drugs doxorubicin (DOX) and camptothecin (CPT), respectively.

Attachment of each drug to the carrier significantly prolonged blood circulation time and tumor accumulation of the drug and reduced systemic toxicity.

Furthermore, both conjugates were tested in colon carcinoma models in mice and found to slow tumor growth and prolong mouse survival compared to the free drug.

Finally, Chapter 5 presents the initial work completed towards combination therapy with PEGylated PLL-DOX and -CPT conjugates.

Synergistic cell killing combinations of the drug conjugates were determined, and the toxicity of one drug combination evaluated in mice.