Enhanced Stability of Polymeric Micelles Based on Postfunctionalized Poly(ethylene glycol)-<i>b</i>-poly(γ-propargyl l-glutamate): The Substituent Effect

One of the major obstacles that delay the clinical translation of polymeric micelle drug delivery systems is whether these self-assembled micelles can retain their integrity in blood following intravenous (IV) injection. The objective of this study was to evaluate the impact of core functionalization on the thermodynamic and kinetic stability of polymeric micelles. The combination of ring-opening polymerization of <i>N</i>-carboxyanhydride (NCA) with highly efficient “click” coupling has enabled easy and quick access to a family of poly­(ethylene glycol)-block-poly­(γ-R-glutamate)­s with exactly the same block lengths, for which the substituent “R” is tuned. The structures of these copolymers were carefully characterized by ¹H NMR, FT-IR, and GPC. When pyrene is used as the fluorescence probe, the critical micelle concentrations (CMCs) of these polymers were found to be in the range of 10^–7–10^–6 M, which indicates good thermodynamic stability for the self-assembled micelles. The incorporation of polar side groups in the micelle core leads to high CMC values; however, micelles prepared from these copolymers are kinetically more stable in the presence of serum and upon SDS disturbance. It was also observed that these polymers could effectively encapsulate paclitaxel (PTX) as a model anticancer drug, and the micelles possessing better kinetic stability showed better suppression of the initial “burst” release and exhibited more sustained release of PTX. These PTX-loaded micelles exerted comparable cytotoxicity against HeLa cells as the clinically approved Cremophor PTX formulation, while the block copolymers showed much lower toxicity compared to the cremophor–ethanol mixture. The present work demonstrated that the <b>PEG-<i>b</i>-PPLG</b> can be a uniform block copolymer platform toward development of polymeric micelle delivery systems for different drugs through the facile modification of the PPLG block

Material Viscoelastic Properties Modulate the Mesenchymal Stem Cell Secretome for Applications in Hematopoietic Recovery

Human mesenchymal stem cells (MSCs) exhibit morphological and phenotypic changes that correlate with mechanical cues presented by the substratum material to which those cells adhere. Such mechanosensitivity has been explored <i>in vitro</i> to promote differentiation of MSCs along tissue cell lineages for direct tissue repair. However, MSCs are increasingly understood to facilitate indirect tissue repair <i>in vivo</i> through paracrine signaling via secreted biomolecules. Here we leveraged cell–material interactions <i>in vitro</i> to induce human bone marrow-derived MSCs to preferentially secrete factors that are beneficial to hematopoietic cell proliferation. Specifically, we varied the viscoelastic properties of cell-culture-compatible polydimethylsiloxane (PDMS) substrata to demonstrate modulated MSC expression of biomolecules, including osteopontin, a secreted phosphoprotein implicated in tissue repair and regeneration. We observed an approximately 3-fold increase in expression of osteopontin for MSCs on PDMS substrata of lowest stiffness (elastic moduli <1 kPa) and highest ratio of loss modulus to storage modulus (tan­(δ) > 1). A specific subpopulation of these cells, shown previously to express increased osteopontin <i>in vitro</i> and to promote bone marrow recovery <i>in vivo</i>, also exhibited up to a 5-fold increase in osteopontin expression when grown on compliant PDMS relative to heterogeneous MSCs on polystyrene. Importantly, this mechanically modulated increase in protein expression preceded detectable changes in the terminal differentiation capacity of MSCs. In coculture with human CD34+ hematopoietic stem and progenitor cells (HSPCs) that repopulate the blood cell lineages, these mechanically modulated MSCs promoted <i>in vitro</i> proliferation of HSPCs without altering the multipotency for either myeloid or lymphoid lineages. Cytokine and protein expression by human MSCs can thus be manipulated directly by mechanical cues conferred by the material substrata prior to and instead of tissue lineage differentiation. This approach enables enhanced <i>in vitro</i> production of both mesenchymal and hematopoietic stem and progenitor cells that aid regenerative clinical applications