Cancer
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21618
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Browsing Cancer by Author "Dossou, Akpedje"
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Item Reconstituted high-density lipoprotein as a potential delivery vehicle for TAMs re-polarization agents(2019-03-05) Sabnis, Nirupama; Raut, Sangram; Lacko, Andras G.; Dossou, AkpedjePurpose: As part of the tumor microenvironment, tumor-associated macrophages (TAMs) form a functionally heterogeneous population where the pro-inflammatory M1 type macrophages exert anti-tumoral function by enabling the activation of cytotoxic immune cells while immunosuppressive M2 type macrophages support tumor progression, angiogenesis, immune system evasion and metastasis. However, TAMs display a high ratio of M2 to M1 macrophages, and this polarization is promoted by tumor secretions. Thus, their presence in tumor microenvironment is associated with poor prognosis. Because the reversal from M2 to M1 constitutes an attractive cancer immunotherapy strategy, there is a need for targeted selective delivery carriers for reversal agents to avoid off-target effects. Reconstituted high density lipoprotein (rHDL) nanoparticles (NPs) are biocompatible with various administration routes, and they have been confirmed to deliver their cargo to targeted cells via a scavenger receptor class B type 1 (SR-B1)-mediated uptake. In addition, Apolipoprotein A1 (ApoA1), one of the components of the rHDL NP, has been shown to promote a M2 to M1 reversal of TAMs. Hence, we propose that rHDL NPs are particularly appropriate to deliver specific re-polarizing agents to TAMS to achieve a predominately M1 type TAM population, and thus enhance the effectiveness of tumor immunotherapy. Methods: The rHDL NPs were prepared using egg yolk phosphatidylcholine, free cholesterol, cholesterol oleate and the ApoA1 protein. The size, polydispersity index and zeta potential of the NPs were assessed by dynamic light scattering. Transmission electron microscopy confirmed size and uniformity of the rHDL NP preparation. Raw 264.7 macrophages were polarized to M1, M2a and M2c by using respectively lipopolysaccharide + interferon-gamma, interleukin-4, and interleukin-10. Protein expression was confirmed via immunoblot. Results: The rHDL NPs show a sub-50 nm size and form a fairly homogeneous preparation. M2 type macrophages display a higher SR-B1 expression than the M1 type (Raw 264.7 macrophages). Conclusions: Findings of these and earlier studies show that the rHDL NPs may be particularly suited to deliver reversal (re-polarizing) agents to M2 macrophages.Item Translational research program utilizing the rHDL drug delivery platform.(2019-03-05) Lacko, Sangram; Sabnis, Nirupama; Mooberry, Linda; Nair, Maya; Dossou, Akpedje; Remaley, Alan; Dossou, Akpedje; Sood, Anil; McConathy, Walter; Lacko, Andras G.Translational research program utilizing the rHDL drug delivery platform. Sabnis N1, Raut S1, Mooberry L1, Nair M1, Nagarajan B1, Garud A1, Dossou A1, Remaley A2, Graham J3 , Sood AK4, McConathy WJ1, Lacko AG1. UNTHSC1, NIH/NHLBI2, Qana Therapeutics3, MD Anderson Cancer Center4. Purpose. Due to the off-target effects, frequently observed with cancer chemotherapy, we established the Lipoprotein Drug Delivery Research Laboratory nearly 20 years ago, to develop a tumor selective drug delivery model, applicable to the transport of drugs with poor solubility and bio-availability. Our purpose was to produce drug formulations with increased therapeutic efficacy, including low off target toxicity Methods We employed two formulations: Synthetic/reconstituted high density lipoprotein formulation (rHDL), resembling native (circulating) HDL, containing the main protein component of HDL, apolipoprotein A-I (apo A-I). rHDL formulation using a 37 amino acid peptide (a mimetic of apo A-I), conjugated to Myristic acid (MYR-5A). Results We developed nano-formulations containing drugs, including paclitaxel, valrubicin, fenretinide, and doxorubicin as well as as well as polynucleotide formulations containing siRNA, pDNA and morpholinos that have been found to be effective against several pre-clinical models of breast cancer, ovarian cancer, prostate cancer, neuroblastoma, Ewing sarcoma and other cancers. Currently we are working on developing novel rHDL formulations for immunotherapy. Our work resulted in over 30 publications in refereed journals, Funding, in excess of $1.5 million from Federal State and private sources, two issued and two pending patents and students graduating with here PhDs and four MSc degrees. Conclusions Currently, both our issued patents are licensed to biotech companies who are actively pursuing the development of our technology. We look forward to and accelerated pace of translating our pre-clinical findings toward commercial and clinical applications.