Nanotechnology-assisted combination drug delivery: a progressive approach for the treatment of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML), a heterogeneous hematopoietic cancer prevalent in adults, has been a leading cause of leukemia-associated deaths for decades. Despite advancements in understanding its pathology and pharmacological targets, therapeutic strategies have seen minimal change. The standard treatment, combining cytarabine and anthracycline, has persisted, accompanied by challenges such as pharmacokinetic issues and non-specific drug delivery, leading to severe side effects. Nanotechnology offers a promising solution through combination drug delivery. FDA-approved CPX351 (VYXEOS™) a liposomal formulation delivering doxorubicin and cytarabine, exemplifies enhanced therapeutic efficacy. Ongoing research explores various nanocarriers for delivering multiple bioactives, addressing drug targeting, pharmacokinetics and chemoresistance. This review highlights nanotechnology-based combination therapies for the effective management of AML, presenting a potential breakthrough in leukemia.

Keywords: acute myeloid leukemia; combination delivery; nanoparticles; nanotechnology; targeted delivery.

Figure 1.

Milestones in the progression of AML treatment over time.

Figure 2.

Various parameters which need consideration in formulation development process.

Figure 3.

Different types of nanocarriers employed for the management of AML.

Figure 4.

(A) Experimental outline depicting the combined inhibition of BCL-2 and MCL-1 in an in vivo xenograft mouse model of leukemia. (B) Bioluminescence imaging and corresponding quantification illustrating the efficacy of treatment. (C) Flow cytometry data showing the circulating numbers of GFP+ and BFP+ cells after the first (left) and second (right) weeks of treatment. (D) Survival curve (n = 5 or 6/group) demonstrating the impact of AMG176 treatment over time. Error bars indicate mean ± SD values derived from individual mice. Reproduced with permission from [96] © Creative Commons Attribution 4.0 International License.

Figure 5.

(A) Schematic representation of antiCD33-LONp-PMI nanoparticles designed for targeted molecular therapy in AML that are constructed through thiol-induced molecular assembly of PMI-Cys and AntiCD33-Cys with biocompatible LONp. Nanoparticles protect peptides from enzymatic degradation, target AML cells specifically and undergo internalization by these cells. In the reducing cytosolic environment, antiCD33-LONp-PMI nanoparticles release potent peptide drugs to induce apoptosis in AML cells. (B) (a) Dose-dependent inhibition of growth in MOLM-13 cells treated with various formulations, assessed using the CCK-8 cell viability assay. Treatment with antiCD33-LONp-PMI at 500 nM equivalence shows significant growth inhibition comparable to 5 μM Nutlin3. (b) western blot analysis of protein expression levels of p53, p21 and MDM2 in MOLM-13 cells after 48 h of treatment with 500 nM antiCD33-LONp-PMI, antiCD33-LONp, LONp-PMI, or 5 μM Nutlin3, normalized to actin. Quantification was performed using Image J software. Data represent mean ± standard error (n = 3), and statistical significance between control and antiCD33-LONp-PMI treatment was assessed using a t-test (p < 0.005). (c) Flow cytometric analysis depicting the effects of antiCD33-LONp-PMI, antiCD33-LONp, LONp-PMI and Nutlin3 on MOLM-13 cells. Cells were classified as viable (Annexin V and PI negative), in early apoptosis (Annexin V positive and PI negative), or in late apoptosis or dead (both Annexin V and PI positive). Reproduced with permission from [54] © Elsevier (2018).