ABSTRACT
Peripheral arterial disease (PAD) is a severe impairment of arterial vessels resulting in obstruction of normal
blood flow in the legs, leading to acute or chronic lower limb ischemia and subsequently high morbidity and
mortality rates. Common treatments for PAD, such as medications and surgical revascularization, have several
limitations. For instance, medications used to lower cholesterol, reduce high blood pressure, control blood sugar,
prevent blood clots, and relieve symptoms like leg pains may delay onset. Still, they cannot treat the established
disease directly and often cause side effects, including bleeding, headache, and diarrhea. Meanwhile, many
elderly PAD patients cannot undergo surgical options. Therefore, it is vital to develop an alternative therapy to
treat PAD. Our long-term goal is to develop novel degradable dual-modal imaging nanoparticles (DINPs) to
precisely deliver therapeutic reagents that provide cell protection and facilitate the formation of blood vessels de
novo at ischemic sites while allowing detection of the NP location and monitoring of their therapeutic
effectiveness for PAD treatment. We have three specific aims: (1) To synthesize, characterize and optimize our
biodegradable dual-modal fluorescent/photoacoustic elastomers named biodegradable photoluminescent
polymers-aniline tetramers (BPLPAT), (2) To formulate and analyze DINPs made of optimized BPLPATs and
loaded with therapeutic reagents for facilitating cell protection and angiogenesis, and (3) To evaluate the
effectiveness of DINPs to treat PAD in vivo using animal models. Innovative aspects of this research are i) the
use of our novel BPLPAT material allowing both fluorescent and deep-tissue photoacoustic imaging opportunities
to detect the in vivo distribution of these NPs and evaluate their degradation assessment; ii) development of
DINPs based on recent advances in nanotechnology and tissue engineering providing a unique strategy to
deliver new therapeutic agents to the ischemic site in order to enhance cellular protection and promote
angiogenesis in situ under hypoxic conditions such as ischemic tissues. The rigor of prior research and
scientific feasibility of our developed DINPs are well-established as we have already demonstrated (1) their
detectability via both fluorescence and photoacoustic imaging, (2) the retention of DINPs loaded with therapeutic
agents at the ischemic zones, (3) the release of therapeutic compounds in a sustained manner, and (4) their
capacity to provide cell protection and promote angiogenesis to recover blood perfusion after ischemia. The
success of our research will provide a novel therapy for the effective treatment of PAD.