Daratumumab Immunopolymersomal Nanomedicine For CD38 And PLK1 Cascade Targeted Therapy Of Hematological Malignancies

Polo-like kinase 1(PLK1)plays an important role in the mitosis of cancer cells and its level is closely related to cancer prognosis,making it a potential target for cancer therapy.Several small molecular PLK1 inhibitors are currently in clinical trials,for instance,volasertib has obtained breakthrough therapy and orphan drug status from FDA for the treatment of acute myeloid leukemia(AML).However,similar as traditional chemotherapeutic drugs,they also suffer short half-life in vivo,drug resistance and serious side effects,resulted in compromised efficacy.CD38 is extensively overexpressed on hematological malignancies and has attracted much attention.Wherein,daratumumab with high affinity to CD3 8 has been marketed for the treatment of multiple myeloma(MM)and its clinical evaluation for leukemia and lymphoma is also ongoing.It should be noted,however,the therapeutic benefit of daratumumab in different patients varies a lot,due to the uneven CD38 expression level.To this end,all-trans retinoic acid(ATRA)was employed to augment the CD38 expression on cancer cells and thus combined with daratumumabmodified polymersomes carrying PLK1 targeted drugs to achieve CD38 and PLK1 cascade targeted therapy of hematological malignancies.In Chapter 1,the clinical regimens,PLK1 targeted therapeutic strategies,as well as monoclonal antibody,antibody-drug conjugates,and antibody directed nanomedicines for hematological malignancies were briefly summarized.The approaches of regulating CD38 expression on the surface of cancer cells were also introduced.In Chapter 2,daratumumab-modified multifunctional polymersomes carrying volasertib(Dar-Ps-Vol)were engineered and combined with ATRA to boost CD38-targeted delivery of Vol,thus downregulating PLK1 level,inducing cell apoptosis and achieving CD38 and PLK1 cascade targeted therapy of orthotopic AML.Dar-Ps-Vol was prepared via coassembly of PEG-b-P(TMC-co-DTC)-b-KD15 and N3-PEG-b-P(TMC-co-DTC)with synchronous Vol loading via electrostatic interactions and subsequent Dar conjugation by click reaction.Dar-Ps-Vol with tunable Dar surface density exhibited a small size of～30 nm,efficient and stable Vol loading,as well as reduction-triggered fast Vol release.ATRA significantly increased the CD38 levels on AML cell lines and primary cells originally with low CD38 expression,thus boosted the cellular uptake and anti-AML activity of Dar-Ps-Vol,displaying an IC50 of 10.1 ng/mL in ATRA-stimulated MV-4-11 cells,3.9-4.9 fold lower than that in MV-4-11 cells as well as free Vol and non-targeted Ps-Vol.Intriguingly,the combination of ATRA with Dar-Ps-Vol dramatically reduced the leukemia burden in orthotopic MV-4-11 and Molm-13-Luc bearing mice,resulting in 5.2 and 2.5 fold longer median survival,respectively,superior to all controls.In comparison to small molecular Vol inhibitor,small interfering RNA has higher specificity and lower side effects.In Chapter 3,daratumumab-decorated polymersomes carrying siPLK1(Dar-Ps-siPLK1)were further constructed for targeted therapy of CD38overexpressed orthotopic MM.Dar-Ps-siPLK1 was prepared from PEG-b-P(TMC-coDTC)-b-PEI(PEI:polyethyleneimine)and N3-PEG-b-P(TMC-co-DTC)copolymers,showing a size of 50-60 nm and quantitative siPLKl loading at a N:P ratio of 2:1.Dar-PssiPLK1 effectively silenced 75.6%of PLK1 mRNA in LP-1 cells,thus downregulating PLK1 protein and inducing cell apoptosis.Preliminary in vivo studies revealed that Dar-PssiPLK1 could effeciently inhibit the growth of orthotopic LP-1-Luc MM model with a 50fold lower Luc signal than PBS group.In Chapter 4,a summary of the thesis and prospect of future works were provided.