| The renin-angiotensin (Ang) system (RAS) is an enzymatic cascade that controls many body functions. It consists of classical and protective arms counteracting each other. Chronic imbalances of them are seen in different pathophysiological conditions. As part of the protective arm, Ang-(1-7) is extensively known or its beneficial actions in different body systems, including anti-inflammation, and anti-proliferation. However, enzymatic instability and short half-life, leading to its low bioavailability, hamper Ang-(1-7) beneficial effects. To address this shortcoming, we have employed a bisphosphonate (BP) conjugation strategy by conjugating Ang-(1-7) to a non-nitrogenated BP moiety through a polyethylene glycol (PEG) linker (Ang. Conj.). We hypothesize that formation of the Ang. Conj. can improve its stability which can present with an improved pharmacokinetic, and longer half-life. Therefore, it will outperform the native Ang-(1-7) peptide in different diseases. Our objectives were to show Ang. Conj. is capable of reducing signs and symptoms of inflammation in models of arthritis and cancers. Several methods were designed to test these hypotheses. chromatography method was used to quantify Ang-(1-7) and Ang. Conj. and to study Ang. Conj. stability, and pharmacokinetic, and pharmacodynamic. Fluorescent spectrometry was used to compare the hydroxy apatite binding of Ang. Conj. and compare it to the native peptide in vitro. MTT assays were done to measure the cancer cell viability. To perform the animal study of RA, Sprague-Dawley rats were treated with vehicle or test articles. Body weights and arthritis indices were measured during the study and nitric oxide colorimetric assay, and the RAS components in tissues were analyzed. Our results suggest that Ang. Conj. has more bioavailability and bone targeting capacity compared to native Ang-(1-7). Moreover, administration of Ang. Conj. decreased edema, weight loss, and nitrite/nitrate, and it balanced the RAS components' levels in an RA rat model and SS model in mice. We concluded that inflammatory diseases have detrimental effects on the RAS. We highlight the feasibility of a novel class of bone-targeting peptides for RA and other inflammatory conditions and prolonging the half-life of Ang-(1-7), enhances its therapeutic effects. Our approach represents a novel therapeutic opportunity for using natural peptides in inflammatory conditions. |