<p>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. </p>
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 Fe<sup>3+</sup> 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.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8035925 |
| Date | 14 May 2019 |
| Creators | Maie Shaaban Taha (6630752) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Development_of_Nanoparticles_with_High_Drug_Loading_Capacity_and_Stability/8035925 |
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