Liposomal drug delivery in an in vitro 3D bone marrow model for multiple myeloma

Abstract

PurposeLiposomal drug delivery can improve the therapeutic index of treatments for multiple myeloma. However, an appropriate 3D model for the in vitro evaluation of liposomal drug delivery is lacking. In this study, we applied a previously developed 3D bone marrow (BM) myeloma model to examine liposomal drug therapy.Material and methodsLiposomes of different sizes (~75–200 nm) were tested in a 3D BM myeloma model, based on multipotent mesenchymal stromal cells, endothelial progenitor cells, and myeloma cells cocultured in hydrogel. The behavior and efficacy of liposomal drug therapy was investigated, evaluating the feasibility of testing liposomal drug delivery in 3D in vitro. Intracellular uptake of untargeted and integrin α4β1 (very late antigen-4) targeted liposomes was compared in myeloma and supporting cells, as well as the effectivity of free and liposome-encapsulated chemotherapy (bortezomib, doxorubicin). Either cocultured myeloma cell lines or primary CD138+ myeloma cells received the treatments.ResultsLiposomes (~75–110 nm) passively diffused throughout the heterogeneously porous (~80–850 nm) 3D hydrogel model after insertion. Cellular uptake of liposomes was observed and was increased by targeting very late antigen-4. Liposomal bortezomib and doxorubicin showed increased cytotoxic effects toward myeloma cells compared with the free drugs, using either a cell line or primary myeloma cells. Cytotoxicity toward supporting BM cells was reduced using liposomes.ConclusionThe 3D model allows the study of liposome-encapsulated molecules on multiple myeloma and supporting BM cells, looking at cellular targeting, and general efficacy of the given therapy. The advantages of liposomal drug delivery were demonstrated in a primary myeloma model, enabling the study of patient-to-patient responses to potential drugs and treatment regimes.

Ex Vivo Models Simulating the Bone Marrow Environment and Predicting Response to Therapy in Multiple Myeloma

“…The 3D model was highly superior when compared to a similar 2D approach and considered appropriate for clinical testing as it was successfully applied to 13 patients’ samples. The same 3D model was also implemented to test liposomal delivery of drugs, such as doxorubicin and bortezomib [ 61 ]. This study showed increased cytotoxic effects of loaded liposomes against MM cells compared with free drugs, using either an MM cell line or primary BM-derived cells.…”

In Vitro 3D Cultures to Reproduce the Bone Marrow Niche

“…It was found that the 3D model enabled superior analysis of the homing behavior of the TEGs, in addition to improved evaluation of the on‐ and off‐target effects of this potential therapy . Braham and colleagues further employed this Matrigel model to examine liposomal drug delivery in the context of myeloma, which showed increased cytotoxic effects of bortezomib and doxorubicin as compared with free drugs . To study oxygen and drug gradients, drug resistance, and myeloma–microenvironment interaction, de la Puente and colleagues created 3D tissue‐engineered BM cultures derived from BM supernatant of MM patients.…”

“…(88) Braham and colleagues further employed this Matrigel model to examine liposomal drug delivery in the context of myeloma, which showed increased cytotoxic effects of bortezomib and doxorubicin as compared with free drugs. (89) To study oxygen and drug gradients, drug resistance, and myeloma-microenvironment interaction, de la Puente and colleagues created 3D tissue-engineered BM cultures derived from BM supernatant of MM patients. Their study found that this 3D model more accurately simulated the tumor interaction with the microenvironment, and that drug resistance was induced at a higher rate than in 2D or commercial 3D systems.…”

A 3D‐Bioprinted Multiple Myeloma Model

“…Given this fact, 3D models of MM cells inside native‐mimicking microenvironments display unique advantages in terms of establishing proper cell functions and associated signaling pathways, making the evaluations of drug effects more efficient and accurate in a (patho)physiologically relevant context. [ 17–19 ]…”

“…Given this fact, 3D models of MM cells inside native-mimicking microenvironments display unique advantages in terms of establishing proper cell functions and associated signaling pathways, making the evaluations of drug effects more efficient and accurate in a (patho)physiologically relevant context. [17][18][19] Recently, 3D bioprinting has been explored extensively for forming well-organized volumetric structures of human tissues and organs, [20] which has also found increasing utility in tumor modeling in vitro. [21,22] For example, we [23][24][25][26][27][28] and others [29][30][31] have previously reported the multichannel coaxial extrusion systems for bioprinting multilayered tubular tissues for various application scenarios.…”