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

Maaike VJ Braham,1 Anil K Deshantri,2,3 Monique C Minnema,4 F Cumhur Öner,1 Raymond M Schiffelers,2 Marcel HAM Fens,2,5 Jacqueline Alblas1 1Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Pharmacology, Sun Pharma Advanced Research Company Limited, Vadodara, Gujarat, India; 4Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands; 5Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands Purpose: Liposomal 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 methods: Liposomes 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. Results: Liposomes (~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. Conclusion: The 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. Keywords: liposomes, targeted delivery, tumor microenvironment, drug sensitivity and resistance testing, multiple myelom

BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications

The purpose of these studies was to develop and characterize B-cell maturation antigen (BCMA)-specific peptide-encapsulated nanoparticle formulations to efficiently evoke BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) with poly-functional immune activities against multiple myeloma (MM). Heteroclitic BCMA72-80 [YLMFLLRKI] peptide-encapsulated liposome or poly(lactic-co-glycolic acid) (PLGA) nanoparticles displayed uniform size distribution and increased peptide delivery to human dendritic cells, which enhanced induction of BCMA-specific CTL. Distinct from liposome-based nanoparticles, PLGA-based nanoparticles demonstrated a gradual increase in peptide uptake by antigen-presenting cells, and induced BCMA-specific CTL with higher anti-tumor activities (CD107a degranulation, CTL proliferation, and IFN-γ/IL-2/TNF-α production) against primary CD138+ tumor cells and MM cell lines. The improved functional activities were associated with increased Tetramer+/CD45RO+ memory CTL, CD28 upregulation on Tetramer+ CTL, and longer maintenance of central memory (CCR7+ CD45RO+) CTL, with the highest anti-MM activity and less differentiation into effector memory (CCR7- CD45RO+) CTL. These results provide the framework for therapeutic application of PLGA-based BCMA immunogenic peptide delivery system, rather than free peptide, to enhance the induction of BCMA-specific CTL with poly-functional Th1-specific anti-MM activities. These results demonstrate the potential clinical utility of PLGA nanotechnology-based cancer vaccine to enhance BCMA-targeted immunotherapy against myeloma

Nanoparticles and molecular delivery system for nutraceuticals bioavailability

This contribution discusses methods for transferring exogenous materials and drugs, particularly, into biological tissues. The focus is on matrices such as micelles, vesicles, and oil-based dispersions as well as carbon nanotubes. An ensemble of physical forces takes a fundamental role in drug dispersion and includes van der Waals (vdW), steric (ST), double layer, (DL), osmotic (OS), etc. Combination of these forces is responsible for drug uptake in matrices and for their release in tissues. Uptake of exogenous either macro- or small molecules into cargo particles and their transfer to recipient cells is the result of complex processes, concomitant to drug partition among supramolecular aggregates and the bulk. Similar conclusions apply to drug release, mostly as to the kinetic features are concerned; therefore, adsorption of nutraceuticals and release within target organs are particularly relevant. These complex features can be accounted for on thermodynamic grounds and expressed as the combination of different forces. In what follows some details on the energies to be considered are outlined. These include terms controlling the fate of transfectants. We will consider first the forces responsible for the formation of such supramolecular entities on physicochemical grounds and the drug uptake; finally, we will review the actual possibility of transfecting cargo-mediated aggregates of nanoparticle/drug complexes to cells or tissues of interest and their bioactivity upon release within the cell matrix

Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine

Retinoids regulate a wide spectrum of cellular functions from the embryo throughout adulthood, including cell differentiation, metabolic regulation, and inflammation. These traits make retinoids very attractive molecules for medical purposes. In light of some of the physicochemical limitations of retinoids, the development of drug delivery systems offers several advantages for clinical translation of retinoid-based therapies, including improved solubilization, prolonged circulation, reduced toxicity, sustained release, and improved efficacy. In this Review, we discuss advances in preclinical and clinical tests regarding retinoid formulations, specifically the ones based in natural retinoids, evaluated in the context of regenerative medicine, brain, cancer, skin, and immune diseases. Advantages and limitations of retinoid formulations, as well as prospects to push the field forward, will be presented.Cerebrovascular Disease Grant and L’Oréal-UNESCO Portugal for Women in Scienc