Protein-protein interactions (PPIs) dictate most biological processes, including those responsible for carcinogenesis. Targeted therapeutics acting on these oncogenic PPIs have naturally become the focus of novel drug discovery. Currently,one small molecule PPI inhibitor, Venetoclax (AbbVie) is FDA approved to treat a number of hematologic malignancies through its inhibition of an antiapoptotic protein, BCL-2. However, considering that there are ~650,000 human PPI s as potential targets, the development of other PPI inhibiting drugs has been lagging due to the off-target and delivery issues. For example, a PPI inhibitor, ABT-263, although possessing potent nanomolar binding affinity to BCL-2, can lead to sever thrombocytopenia when administered systemically, which is due to the off-target BCL-XL inhibition in platelets. This is limiting its therapeutic index. We have developed a nanocarrier system, targeted polymersome (PSOM) nanoparticle, made of biocompatible poly(ethylene glycol)-disulfide-poly(propylene sulfide) (PEG-SS-PPS) with surface conjugated anti-CD19 F(ab) antibody fragments (aCD19 Fabs) as targeting motif to B cell lymphoma. PSOMs are fabricated by flash nanoprecipitation (FNP) and extrusion resulting in uniform vesicular morphology and size distribution (~130 nm in diameter). Moreover, ABT-263 was successfully encapsulated by PSOM at an efficiency over 90%, which increases the solubility of the lipophilic ABT-263 to over 10mM in PBS. From <i>in vivo</i> platelet-counting experiment, the intravenous administration of PSOM encapsulated ABT-263, in contrast to orally administered non-encapsulated drug, led to the mitigated thrombocytopenia in mice. Importantly, flow cytometric analyses on a panel of human CD19 positive diffuse large B cell lymphoma cell lines demonstrated specific uptake of aCD19-PSOM nanoparticles. We believe the results indicate the great promise of <i>in vivo</i> targeted delivery of ABT-263 by PSOM to B cell lymphoma.

Polymersome encapsulation of a lipophilic protein: Protein interaction inhibitor to achieve increased solubility and therapeutic index

ACS Spring Meeting 2021

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