Development of Nanoparticles with High Drug Loading Capacity and Stability
Many anti-cancer drugs are poorly water-soluble and show undesirable pharmacokinetics and low bioavailability. Nanoparticles (NP) are used as delivery vehicles to improve bioavailability and biodistribution of such drugs. For clinical translation of an NP product, it is critical that the NP carry a large amount of drug and maintain good stability during circulation. A typical drug loading capacity of current NP formulations is less than 20% of the total mass, which is concerning from the standpoint of safety and administration convenience. Current NP formulations are also limited in retaining a drug during circulation and release the drug prematurely before they reach target tissues. These challenges are responsible at least partly for recent failure of leading NP products in clinical trials.Given these challenges, I have focused on developing a stable NP formulation with high drug loading capacity, drug-rich nanocores stabilized by interfacial assemblies of iron-tannic acid (pTA) and albumin. Tannic acid is a polyphenol of natural origin and can form coordination complexes with Fe3+ ions that stabilize the interface between drug rich core droplets and aqueous solution. The underlying hypotheses are that (i) NP core formed solely of drug will offer a high drug loading capacity and (ii) the strong interaction of TA with drug molecules will maintain the nanocore stability and avoid premature drug release. Carfilzomib (CFZ), an epoxyketone peptide and a second-generation proteasome inhibitor, the use of which is limited to multiple myeloma due to the low stability, was chosen as a model drug to encapsulate in the new NP formulation. The NP surface was further functionalized with albumin, quinic acid derivative and plasmid DNA based on their affinity for TA complex. With an additional albumin coating, CFZ nanocore (CFZ-pTA-alb) showed sustained drug release and metabolic stability. In murine syngeneic model of B16F10 melanoma, systemically administered CFZ-pTA-alb showed enhanced biodistribution and anti-tumor effect than commercial cyclodextrin-based CFZ (CFZ-CD). With localized intratumoral administration, CFZ-pTA-alb also outperformed CFZ-CD in antitumor efficacy, potentially by prolonged drug retention, reduced damage to tumor-infiltrating lymphocytes, and enhanced delivery of tumor antigens to DCs.
Egyptian Government, Ministry of Higher Education
NIH R01 EB017791
NIH R01 CA232419
- Doctor of Philosophy
- Industrial and Physical Pharmacy
- West Lafayette