CD38-Directed Vincristine Nanotherapy for Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although intensive chemotherapy greatly improved the survival rate, it is often accompanied by severe and lifelong side effects as a result of weak ALL selectivity. The intensive and poorly selective chemotherapy is also detrimental to patients' immune system. There is an urgent need to develop more selective and less toxic chemotherapy for ALL. Here, we report daratumumab-polymersome-vincristine (DP-VCR) as a CD38directed nanotherapy for ALL. DP-VCR showed selective uptake in CD38-positive 697 and Nalm-6-Luc ALL cells and potent anti-ALL activity with an IC 50 as low as 0.06 nM VCR, which was 13.7-fold more potent than free VCR. In contrast, no toxicity to human peripheral blood mononuclear cells was detected for DP-VCR even at 108.3 nM VCR. The apoptotic assays confirmed a high selectivity of DP-VCR to CD38-positive ALL cells. DP-VCR exhibited superior treatment of both 697 and Nalm-6-Luc orthotopic ALL models to all controls, as revealed by significant survival benefit and marked reduction of leukemia burden in bone marrow, blood, spleen, and liver. Importantly, DP-VCR induced few side effects. DP-VCR emerges as a safe and potent nanotherapy for CD38-positive ALL.

Nanotechnology-based diagnostics and therapeutics in acute lymphoblastic leukemia: a systematic review of preclinical studies

“…One hundred and fifty two studies for treatment and detection were considered for the full-text evaluation, and 54 studies were also excluded because of not satisfying the inclusion criteria, using other cell lines instead of humane ALL ( n = 5), 34–38 not being totally relevant to our objective, or lacking detailed and obvious data ( n = 23 for treatment; 39–61 n = 14 for detection) 20,62–74 and not having full-text publications available ( n = 12). 64,75–85 Finally, 63 articles matched the inclusion criteria for the treatment section ( n = 63) and 35 articles for the detection section ( n = 35). Tables 1–6 summarize the characteristics and findings of the studies included.…”

Input–Output Analysis of China’s Forest Industry Chain

“…The distribution coefficient refers to the proportion of the amount of products sold by forestry or distributed to another industry in relation to the total amount of product sold by forestry to all industries. It is used to observe the distribution of the industrial chain in which forestry sells its own products to various industries as production supplies and indicates the forward correlation of forestry and its degree of impact [15,16].…”

Antibody-Mediated Nanodrug of Proteasome Inhibitor Carfilzomib Boosts the Treatment of Multiple Myeloma

“…Featuring elevated bioavailability, improved in vivo pharmacokinetics, and largely decreased adverse events, nanoformulations of chemotherapeutics have received tremendous attention as superior alternatives in the past decades. − For example, liposomes, poly­(lactic- co -glycolic acid) (PLGA), and polycarbonate-based nanoparticles have been developed to accomplish the encapsulation and controlled delivery of proteasome inhibitors including CFZ and BTZ. − However, they usually presented minor loading content (<5 wt %) and loading efficiency (<50%), possibly owing to the relatively feeble interactions between drugs and carriers. In addition, targeting ligands such as alendronate, A6 peptide, glycoprotein, and anti-CD38 antibody have been decorated on the surface of nanodrugs to improve their binding with bone and MM-associated endothelial cells, the internalization in MM cells, and therapeutic outcomes. ,− The introduction of targeting ligands was shown to enhance the anti-MM effect only to a certain extent, possibly due to insufficient stability and suboptimal targetability of nanoformulations.…”

“…CFZ was the second-generation proteasome inhibitor and had an established place in relapsed MM through selective and irreversible binding with the chymotrypsin-like site (β5) of proteasome 20S. , With a tetrapeptide-based epoxy skeleton, CFZ could be readily loaded in micellar core filled with PAPA polypeptide moieties through the “like dissolve like” principle, as demonstrated for peptide drugs like monomethyl auristatin E . Dar can specifically target CD38, which is overexpressed on myeloma cells and has emerged as the first-in-class monoclonal antibody for MM treatment via immune mediation and also been exploited to guide the precise delivery of nanotherapeutics through a CD38-mediated mechanism. ,− Here, Dar was decorated on the micelle surface to direct the enrichment of Dar-PMs-CFZ in MM. In orthotopic LP-1 MM-bearing mice, Dar 3.2 -PMs-CFZ significantly suppressed the tumor bioluminescence intensity, decreased the osteolytic lesions, and greatly extended the survival rate in comparison with nontargeting PMs-CFZ and free drug.…”