| Angiotensin 1-7 (Ang 1-7) is a biologically active heptapeptide of the renin-angiotensin
system (RAS) and has emerged as a promising therapeutic agent owing to its cardioprotective,
anti-inflammatory, anti-fibrotic, and anti-proliferative effects mediated through Mas receptor.
The clinical translation of Ang 1-7 has been limited by its rapid enzymatic degradation, leading
to very short plasma half-life. This dissertation addresses these pharmacokinetic barriers through
different strategies including novel analog synthesis, advanced formulations. Furthermore, it
explores the role of RAS peptides in breast cancer and evaluates their potential in clinical
biomarker discovery.
In the first aim, a previously synthesized bisphosphonate conjugated Ang 1-7 was
encapsulated into lipid nanoparticles (LNPs). Physicochemical characterization demonstrated
favorable particle size (<200 nm), high entrapment efficiency, and improved stability in
simulated gastric and intestinal fluids. A novel competitive chelator-based LC-MS/MS method
was developed and validated for quantification of Ang conj. in rat plasma. Pharmacokinetic (PK)
study revealed that LNP encapsulation, albeit with low bioavailability, promoted sustained
systemic exposure following oral administration with half-lives exceeding 22 hours. Ang conj.
alone demonstrated an improved intravenous (IV) half-life of approximately 8 hours.
In the second part of this study, a lipophilic Ang 1-7 analog, AngiLip, was synthesized
and formulated into PEGylated liposomes. AngiLip showed improved systemic stability with IV
and subcutaneous (SC) half-lives of 4.04 and 15.38 hours respectively. Oral bioavailability, however, remained low at 0.07%, highlighting persistent challenges of oral delivery and
identifying the need for further optimization.
Finally, a pilot case-control study was conducted to evaluate plasma RAS components
and cytokines in treatment-naïve breast cancer patients against healthy controls. Plasma ACE2
was found to be significantly elevated and Ang 1-7/Ang II ratio was reduced in breast cancer
patients. This indicated the shift of RAS balance towards classical axis. A multi-analyte logistic
regression model was developed incorporating ACE2, Ang 1-7, and Ang II, which achieved
excellent discriminatory performance (AUC = 0.9396, accuracy = 92.59%) outperforming any
single biomarker alone. Collectively this dissertation establishes a comprehensive framework for
translational development of Ang 1-7-based therapeutics and advances plasma RAS components
as a novel biomarker panel for breast cancer.
Keywords: Renin Angiotensin System, Angiotensin 1-7, ACE2, Lipid Nanoparticles, Drug
Delivery, Biomarkers |