Pluronic-F127/Platelet Microvesicles nanocomplex delivers stem cells in high doses to the bone marrow and confers post-irradiation survival

Abstract

Platelet microvesicles (pMVs) are submicron-sized heterogeneous vesicles released upon activation and contain several membrane receptors and proteins (CD41, CD61, CD62, CXCR4, PAR-1, etc.). We have revealed their ability to adhere to the triblock copolymer pluronic-F127 (PF127) and form a platelet microvesicular nanocloud which has the potential to enhance the transvascular migration of hematopoietic stem cells across the sinusoidal endothelium to the bone marrow. Besides, the pMVs nanoclouds bestow survival benefits when present on the cells used for infusion, particularly with PF127-stabilized with chitosan-alginate (PF127-CA HSCs). The vesicles were found to be firmly associated with PF127 in the nanocloud, which was detected by confocal laser scanning microscopy. The abrogation of CXCR4/SDF-1 axis regulating the transmigration of the cells by antagonist AMD3100 revealed that the enriched CXCR4 receptors on pMVs robustize the transmigration of the infused cells. The homing of the cells led to effective engraftment and faster regeneration of the critical blood lineages, which elicited 100% survival of the mice receiving lethal doses of radiation. The Human Long-Term Culture Initiating Cells (LTC-ICs), Severe Combined Immunodeficient (SCID) -Repopulating Cells (SRCs) and Colony Forming Cells (CFCs) responsible for the regeneration, but present in extremely low numbers in the infused cell dose, have enabled the cells to reach the bone marrow in high numbers. This potential of the PF127 to sequester the pMVs and its application to achieve over 10-fold delivery of HSCs across the trans-endothelial checkpoint has so far not been reported. Thus, this mechanistic innovation is a potential post-exposure life-saving regimen capable of circumventing the irreparable damage to the bone marrow caused by lethal doses of radiation.Pluronics, also known as poloxamers, are amphiphilic triblock copolymers consisting of hydrophobic polyoxypropylene (PPO) and hydrophilic polyoxyethylene (PEO) domains. Owing to their physiological properties of low toxicity and high biocompatibility, these materials are used in many pharmaceutical applications that require solubilization or stabilization of the compounds. Their rich phase behavior (micelles, hydrogels, self-assembling and repelling behaviors, etc.) makes them amenable to multiple processes and product forms 1,2 . In the latter application, their repelling behavior is exploited to minimize or abolish the fatal thrombogenic cascade, which occurs when the platelets are activated by extending their hydrophilic PEO domains, thereby reducing protein adsorption and platelet aggregation on the surface 3,4 . These properties are invaluable in different pathophysiological conditions such as leukemia, septicemia, nephritic syndromes, thrombophilia, and cardiovascular diseases. These polymers are also utilized in DNA delivery technologies, brain injury management, ophthalmic treatment, and drug delivery systems 5-7 .The mechanistic basis and mode of interaction (both attraction and repulsion) ...

Nanoparticles targeting hematopoietic stem and progenitor cells: Multimodal carriers for the treatment of hematological diseases

“…More recently, Chander and Gangenahalli revealed that complexes between pMVs and pluronics form “nanoclouds” that cover single HSCs and increase the migration of HSCs across sinusoidal ECs to the BM ( Chander and Gangenahalli, 2020b ). Pluronics represent a group of thermoreversible copolymers which can firmly associate with pMVs ( Zhong et al, 2018 ) and have been frequently used for drug delivery approaches.…”

“…In a study from the early 90s, coating of polystyrene NPs with Pluronic F-127 directed more than 50% of intravenously infused polystyrene NPs to the BM ( Porter et al, 1992 ). Loading of HSCs with pMV nanoclouds, in particularly with PF127-stabilized chitosan-alginate, prior to transplantation into lethally irradiated mice led to a 10-fold increase in homing, and effective engraftment and regeneration of the blood lineages ( Chander and Gangenahalli, 2020b ).…”

Nanoformulation of CCL21 greatly increases its effectiveness as an immunotherapy for neuroblastoma

“…Pluronic F127 is a hydrophilic, nontoxic copolymer that is widely used as a pharmaceutical excipient. Biocompatibility, bioadhesion, adaptability, thermosensitivity, and ability to stabilize and protect cargo have all promoted the use of Pluronic F127 as a component in many therapeutic modalities, including nanogels or nanocontainers, microvesicle nancompexes, and engineered tissues [57][58][59][60][61][62]. In these alginate nanoparticles, Pluronic F127 was used as a matrix-stabilizing agent that permits sustained drug release.…”

Enhanced Transdermal Delivery of Pranoprofen Using a Thermo-Reversible Hydrogel Loaded with Lipid Nanocarriers for the Treatment of Local Inflammation

“…The term Pluronic ® (also known as Poloxamer) identifies a generic block copolymer made up of two units of poly(ethylene glycol) (PEG), separated by a central poly(propylene oxide) unit (PPO). One of the different varieties of Pluronic ® is the F127 (Figure 1b), which is commercially available due to its physiological properties of low toxicity and high biocompatibility [14]. Furthermore, it displays a double behaviour.…”