​Research

Targeted nanoparticles of drugs and genes for therapy and imaging

We are formulating nanoparticles (NPs) of drugs and genes for the therapy of various disorders. The formulated NPs (liposome and polymeric-based) are characterized by both high yield and encapsulation efficiency. NPs of siRNA are examined in animal models for the therapy of mammary carcinoma, Herpes simplex virus infection, and pancreatic cancer. The NPs are decorated with ligands enabling effective targeting to the diseased site. Recently we have demonstrated effective formulation of Quantum Dots for imaging of inflammation associated with cardiovascular injury and mammary carcinoma.

1. S. Ron-Doitch, B. Sawodny, A. Kuhbacher, M.M. David, A. Samanta, J. Phopase, A. Burger-Kentischer, M. Griffith, G. Golomb and S. Rupp, Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV, J. Control. Release, 229, 163-71 (2016)
2. G. Aizik, N. Waiskopf, M. Agbaria, Y. Levi-Kalisman, U. Banin and G. Golomb, Delivery of liposomal quantum dots via monocytes for imaging of inflamed tissue, ACS Nano, 11, 3038-3051 (2017)
3. M. Ben David-Naim, E. Grad, G. Aizik, M.M. Nordling-David, O. Moshel, Z. Granot and G. Golomb, Polymeric nanoparticles of siRNA prepared by a double-emulsion solvent-diffusion technique: Physicochemical properties, toxicity, biodistribution and efficacy in a mammary carcinoma mice model, Biomaterials, 145, 154-167 (2017)

​Immunomodulation in cardiovascular injury

Restenosis is re-obstruction of the artery following percutaneous coronary angioplasty. Currently, restenosis is treated by local delivery from drug eluting stents. However, there are certain limitations in their use including late in-stent thrombosis. We hypothesized that partial and transient depletion of circulating monocytes could decrease macrophage recruitment in the arterial wall, and consequently result in attenuation of neointimal formation. Monocyte inhibition has been achieved with a systemic injection of nanoparticles (liposomes or polymeric) containing bisphosphonates (BPs). The nanoparticles encapsulating BPs controls the targeting of these bone-seeking agents, in clinical use for bone related disorders, to monocytes/macrophages capable of effective phagocytosis. The drug is protected in the circulation for a sufficient period of time to be taken up by monocytes, while still rapidly and sufficiently releasing the drug inside the cells for their inhibition, resulting in reduced ingress of monocytes to the injured artery. Inhibition of systemic monocytes/macrophages suppresses this inflammatory link. This work established that Inflammation has a major role in linking early vascular injury to restenosis, and is a major shift of restenosis paradigm, a presumed localized pathogenic process. A single injection of BP-containing nanoparticles at the time of angioplasty is capable of preventing restenosis, regardless of the procedure and the device(s) used. The use of a systemic treatment modality allows flexibility in choosing the type and number of stents to be deployed. Following successful Phase I & IIa clinical studies, the results of phase IIb are expected soon. In ongoing research, we explore of the role of pro- and anti-inflammatory monocyte sub-populations, classical monocytes (CM) and non-classical monocytes (NCM) in cardiovascular disorders.

Representative publications:

1. H.D. Danenberg, I. Fishbein, J. Gao, J. Mönkkönen, R. Reich, I. Gati, E. Moerman, G. Golomb, Macrophage depletion by clodronate-containing liposomes reduce neointimal formation following balloon injury in rats and rabbits, Circulation, 106:599-605 (2002)
2. H. Epstein, E. Afergan, T. Moise, Y. Richter, Y. Rudich, G. Golomb, Number-concentration of nanoparticles in liposomal and polymeric multiparticulate preparations: Empirical and calculation methods, Biomaterials, 27:651-657 (2006)
3. E. Cohen-Sela, O. Rosenzweig, J. Gao, H. Epstein, I. Gaty, R. Reich, H.D. Danenberg, G. Golomb, Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis, J. Control. Release.113:23-30 (2006)
4. 122.     E. Grad, K. Zolotarevsky, H.D. Danenberg, M.M. Nordling-David, D. Gutman and G. Golomb, The role of monocyte subpopulations in vascular injury following partial and transient depletion, Drug Deliv. Transl. Res., 8(4), 945-953 (2018)

​Blood-brain barrier transport via monocytes

Many drugs are not able to enter the brain due to the presence of the blood-brain barrier (BBB) and therefore cannot be used in the treatment of diseases of the brain. Since it is now known that the brain is under immunological surveillance, we hypothesized that phagocytic cells of the innate immune system, mainly monocytes, can be exploited as transporters of drugs to the brain. As phagocytosis is required for liposomal uptake, this method does not affect non-phagocytic cells. We formulated functionalized liposomes and polymeric nanoparticles, which are avidly phagocytized by monocytes, containing drugs to be transported to the brain, but do not affect the courier (monocytes). We have demonstrated the brain transport of serotonin, and the protein, lysozyme (14 kDa), a BBB impermeable drugs.

1. E. Afergan, H. Epstein, R. Dahan, N. Koroukhov, K. Rohekar, H.D. Danenberg and G. Golomb, Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes, J. Control. Release, 132, 84-90 (2008) - Editorial cover story
2. M.M. Nordling-David, R. Yaffe, D. Guez, H. Meirow, D. Last, E. Grad, S. Salomon, S. Sharabi, Y. Levi-Kalisman, G. Golomb, Y. Mardor, Liposomal temozolomide drug delivery using convection enhanced delivery, J Control. Release, 261, 138-146 (2017).

3. M.M. Nordling-David, E. Rachmin, E. Grad, and G. Golomb, Lysozyme transport to the brain by Liposomes, Prec. Nanomed., 1(2), 146-161 (2018).