Engineering Exosome for Ovarian Cancer Targeting Therapy

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

Investigators

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Abstract

Despite various therapeutic developments, ovarian cancer is still one of the most lethal diseases in women. In 2018, almost 22,000 women in the US were diagnosed with ovarian cancer. Over 14,000 women died from it due to a relative lack of targeted agents leading to systemic toxicity, multidrug resistance (MDR) and ultimately to insufficient therapeutic efficacy and metastasis. Thus, ovarian cancer treatment with optimized targeting toward the tumor could produce a clinical advantage. Multiple lines of evidence and several clinical trials solidified the idea that extracellular vesicles, called “exosomes,” can be a potential cancer-targeting solution due to their small size (40~150 nm), biocompatibility, and therapeutic encapsulation and delivery. It is important to note that the surface modification of exosomes could enhance their therapeutic role as a drug delivery system, specifically targeting ovarian cancer and improving therapeutic outcomes. Currently, there are two major methods of exosome surface modification to endow their active targeting efficacy: 1) genetically engineered mother cells to embed targeting proteins and 2) chemical conjugation of a targeting ligand on the exosome. However, both methods require extensive amounts of time and labor to optimize for a feasible clinical application. Thus, alternative methods of exosome surface modification must be developed. In this proposal, we aim to develop an innovative exosome surface-modification method composed of anchor-spacer-ligand (ASL). Lipophilic near-infrared dyes as Anchors will be incorporated into the exosome membrane and produce their nanoconfinement mediated multifold thermal energy. It could inhibit tumor growth and trigger drug release, as evidenced by our preliminary data. Spacers will prevent exosome aggregation and systemic excretion. As targeting Ligands, we will use antibody candidates derived from the injection of ovarian cancer exosome into the animal because they could specifically bind to the exosomes and their mother ovarian cancer cells. Our preliminary data showed that preferential delivery of a drug (doxorubicin) to αvβ3 integrin overexpressing ovarian cancer cells and consequent cell killing efficacy by ASL exosomes coated by RGD peptide that specifically interaction at αvβ3 integrin. Another preliminary study demonstrated that a newly synthesized co-modulator that simultaneously depletes glutathione (MDR contributor) and vascular endothelial growth factor (VEGF: metastasis contributor) inhibits both MDR and metastasis of ovarian cancer. Therefore, the strategy of combining all of the above advantages into an exosome will make an innovative therapeutic platform to treat ovarian cancer, and to our knowledge, it is the first integrated strategy of this type. To achieve this goal, we will prepare a series of anchor-spacerligand conjugates and co-modulators and then integrate them to formulate and optimize co-modulator encapsulating ASL exosomes (cAExs) for enhanced targeting efficacy and sufficient therapeutic effects against ovarian cancer. The consequent ability to control ovarian cancer is essential in order to achieve the long-term goal to decrease the mortality of ovarian cancer using optimized cAExs. The overall objective is to develop, validate, and optimize the in vitro and in vivo therapeutic efficacy of cAExs. The central hypothesis of this proposal is that cAExs can deliver sufficient insults to reduce MDR and metastasis of ovarian cancer specifically. Four Aims are listed below: Aim 1. To design and optimize co-modulator ASL exosomes (cAExs) for their in vitro tumor targeting therapy. Aim 2. To establish in vivo therapeutic dose and the systemic fate of cAExs and validate their in vivo therapeutic outcome of MDR and metastasis inhibition using murine models. Aim 3. To validate MDR and metastasis inhibition of the final cAEx using clinically relevant patient-derived xenografted (PDX) ovarian cancer mice model. At the completion of the proposed research, it is our expectation to have identified optimal conditions for the use of cAEx as a targeted therapy for ovarian cancer. Thus, we anticipate demonstrating both in vitro and in vivo therapeutic efficacy of our engineered exosome-based therapy. The proposed research will have a significant positive impact because its success benefits not only ovarian cancer but also other cancer patients by reducing metastasis and MDR.