PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate.

Tumor-associated inflammation mediates the development of a systemic immunosuppressive milieu that is a major obstacle to effective treatment of cancer. Inflammation has been shown to promote the systemic expansion of immature myeloid cells which have been shown to exert immunosuppressive activity in laboratory models of cancer as well as cancer patients. Consequentially, significant effort is underway toward the development of therapies that decrease tumor-associated inflammation and immunosuppressive cells. The current study demonstrated that a previously described deep tissue imaging modality, which utilized indocyanine green-loaded calcium phosphosilicate nanoparticles (ICG-CPSNPs), could be utilized as an immunoregulatory agent. The theranostic application of ICG-CPSNPs as photosensitizers for photodynamic therapy was shown to block tumor growth in murine models of breast cancer, pancreatic cancer, and metastatic osteosarcoma by decreasing inflammation-expanded immature myeloid cells. Therefore, this therapeutic modality was termed PhotoImmunoNanoTherapy. As phosphorylated sphingolipid metabolites have been shown to have immunomodulatory roles, it was hypothesized that the reduction of immature myeloid cells by PhotoImmunoNanoTherapy was dependent upon bioactive sphingolipids. Mechanistically, PhotoImmunoNanoTherapy induced a sphingosine kinase 2-dependent increase in sphingosine-1-phosphate and dihydrosphingosine-1-phosphate. Furthermore, dihydrosphingosine-1-phosphate was shown to selectively abrogate myeloid lineage cells while concomitantly allowing the expansion of lymphocytes that exerted an antitumor effect. Collectively, these findings revealed that PhotoImmunoNanoTherapy, utilizing the novel nontoxic theranostic agent ICG-CPSNP, can decrease tumor-associated inflammation and immature myeloid cells in a sphingosine kinase 2-dependent manner. These findings further defined a novel myeloid regulatory role for dihydrosphingosine-1-phosphate. PhotoImmunoNanoTherapy holds the potential to be a revolutionary treatment for cancers with inflammatory and immunosuppressive phenotypes.

Patterning nanoparticles in a three-dimensional matrix using an electric-field-assisted gel transferring technique.

In this paper, we describe an electric-field-assisted gel transferring technique for patterning on two- and three-dimensional media. The transfer process starts with the preparation of a block of agarose gel doped with charged nanoparticles or molecules on top of a screen mask with desired patterns. This gel/mask construct is then brought into contact with the appropriate receiving medium, such as a polymer membrane or a piece of flat hydrogel. An electric field is applied to transfer the doped charged nanoparticles or molecules into the receiving medium with a pattern defined by the screen mask. This printing method is rapid and convenient, the results are reproducible, and the process can be done without using expensive micro/nanofabrication facilities. The capability to pattern structures such as arrays of nanoparticles into three-dimensional hydrogels may find applications for positioning cell signaling molecules to control cell growth and migration.

Combinatorial library of lipidoids for in vitro DNA delivery.

A combinatorial library of lipidoids was constructed and studied for in vitro gene delivery. The library of lipidoids was synthesized by reacting commercially available amines with lipophilic acrylates, acrylamides, or epoxides. Lipidoids derived from amine 86 (N,N-bis(2-hydroxyethyl)ethylene diamine) and amine 87 (N-(3-aminopropyl)diethaneamine) showed high efficiency in DNA delivery, some with a higher transfection efficiency than Lipofectamine 2000, a commonly used commercial gold standard for in vitro gene delivery. The structure-activity relationship between the lipidoids was further studied with respect to small variations in chemical structures and the resulting efficiency in DNA delivery in vitro. Since these lipidoids are easy to synthesize and do not require a colipid for efficient DNA delivery, they could offer an inexpensive but effective alternative to other commonly used commercial gene delivery carriers.