Bovine serum albumin protected gold nanozymes as a novel anti-cancer nanodrug for acute T-type lymphoblastic leukemia treatment via effect on the expression of anti-apoptotic genes

In this paper, the bovine serum albumin protected gold nanozymes (BSA-Au nanozymes) were utilized as a novel nanodrug for treatment of acute T-type lymphoblastic leukemia (Jurkat) by production of excessive ROS and effect on the expression of anti-apoptotic genes. The effect of BSA-Au nanozymes on the Bcl-2 expression and survivin in the Jurkat cell line was checked. The results showed that the expression of anti-apoptotic genes was significantly reduced after treatment of the Jurkat cell line with the BSA-Au nanozymes (p-value of 0.001) as the potential nanodrug while their expression in the normal PBMC was not affected by the nanodrug. Moreover, the cytotoxic effect of the developed nanodrug on the Jurkat cell line was evaluated which illustrated that survival rate in the studied cell line reaches its minimum value (100% lethality, 0.0% survival) after treatment for 48 h. The IC50 for the nanodrug was calculated at 0.05 mM of the developed nanodrug. Overall, the BSA-Au nanozymes can be used as the nanodrug for treatment of T-type lymphoblastic leukemia via reducing the expression of anti-apoptotic genes, increasing the effect of common anticancer drugs such as Adriamycin and ara-C, and consequently increasing the survival of patients with leukemia.

Using the Adaptive Leadership Framework for Chronic Illness to Design a Palliative and Collaborative Intervention

Our study addresses symptoms and functional management early in acute myeloid leukemia treatment using a PAlliative and Collaborative Care inTervention (PACT) delivered by clinical staff. PACT is an interdisciplinary nurse-led intervention of nursing [RN], occupational therapy [OT], physical therapy [PT] for adults ≥ 60 years of age at time of initial treatment. Finding from our preliminary qualitative work led to use of the Adaptive Leadership Framework for Chronic Illness to guide optimal engagement of the patient in self-management of symptoms and functional activities to address QOL outcomes. We share lessons learned of how the ALFCI was applied to the PACT intervention to empower patients with self-management skills to reduce symptoms and optimize function. In summary, the team and patient identify and address emotional, motivational, attitudinal barriers so that the patient can do the work required for self- management to reduce symptoms and avoid functional decline.

Harnessing Extracellular Vesicles from Red Blood Cells for Targeted Delivery of Therapeutic Peptides and RNAs for Leukemia Treatment

Extracellular vesicles (EVs) are emerging as a new class of natural drug carriers with intrinsic ability to deliver bioactive cargo at high efficiency and low toxicity. However, clinical applications of EVs are limited by the production scale and the delivery specificity. We have recently established a new platform for purification and surface modification of EVs from red blood cells (RBCs) that are scalable and versatile for targeted delivery of small-molecule drugs and RNA therapeutics (Usman et al, Nat. Com. 2019 and Pham et al, J. Extracell. Vesicles 2021). Here, we describe a new development of the method for conjugation of RBC-EVs to obtain a higher targeting efficiency. We conjugate RBC-EVs, not only with peptides and nanobodies, but also with monoclonal antibodies, by coupling peptide conjugated EVs with streptavidin-bound biotinylated antibodies. Our data demonstrate that the conjugation is stable and does not affect the physicochemical characteristics of EVs. Conjugation of EVs with a cyclic peptide targeting CXCR4 or a monoclonal antibody targeting CD33 promotes specific binding and uptake of the conjugated EVs by leukemia cells expressing the corresponding receptors. We further use CXCR4-targeting RBC-EVs to specifically deliver the pro-apoptotic peptide KLA to CXCR4-expressing leukemia cells. Delivery of KLA using CXCR4-targeting EVs significantly suppresses leukemia burden and increases survival in a leukemia xenografted mouse model. Antibody-conjugated RBC-EVs are used to deliver RNA antisense oligonucleotides to knockdown FLT3 and miR-125b in cell lines and in patient-derived xenograft models of leukemia. Finally, we demonstrate that peptide/antibody conjugated RBC-EVs are biocompatible and nonimmunogenic. Our study provides a new platform for targeted delivery of therapeutic peptides and RNAs that is highly efficient, stable, versatile and biocompatible for potential clinical applications in leukemia treatment. Migara Kavishka Jayasinghe, Marco Pirisinu, Huan Chen, and Yuqi Yang contributed equally to this work as first authors. Disclosures Jayasinghe: Carmine Therapeutics: Patents & Royalties. Shi: Carmine Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Le: Carmine Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Evaluation of Poly(ADP-ribose) Polymerase Inhibitor, Pamiparib (BGB-290) in Treating Acute Myeloid Leukemia and the Characterization of Its Nanocarrier

Despite the continuous improvement of leukemia treatment in the clinic, the overall 5-year disease-free survival of acute myeloid leukemia (AML) is only approximately 30%–60% due to relapse and the refractoriness of AML after traditional chemotherapy. Inhibition of poly(ADP-ribose) polymerase (PARP), a member of the DNA damage repair complex, has a strong antitumor effect in solid tumors. However, the role of PARP in AML remains unclear. We found that high levels of PARP1 and PARP2 were positively related to chemotherapy resistance and poor prognosis in patients with AML. Doxorubicin (DOX)-resistant AML cells highly expressed PAPR1 and PARP2. Knockdown of PARP1 and PARP2, or pharmaceutical inhibition of PARP by the PARP inhibitor (PARPi) BGB-290, significantly enhanced the cytotoxicity of DOX in AML cells due to increased DNA damage. PLGA-loading BGB-290 was properly self-assembled into stable BGB-290@PLGA nanoparticles (NPs), which is uniform particle size and good stability. BGB-290@PLGA is easily uptake by AML cell lines and stays for a long time. Combined with DOX, BGB-290@PLGA can significantly improve the chemosensitivity of AML cell lines. Furthermore, BGB-290 and DOX combination treatment dramatically repressed the onset of leukemia and prolonged the survival of THP-1 xenografted mice. Overall, this study demonstrated that PARPi with traditional chemotherapy could be an efficient therapeutic strategy for AML.