Tumor Targeting platform with Nanoghosts

By Marcelle Machluf, Associate Professor, The  Faculty of Biotechnology & Food Engineering, Technion – Israel Institute of  Technology, Haifa, Israel.


nanomanufacturing-2(Nanowerk Spotlight) The field of drug discovery is  growing at a remarkable pace, leading to the development of many new drugs, most  of which are generally more potent than their predecessors, yet suffer from poor  solubility and/or high toxicities.

Targeted drug-delivery vehicles (e.g.,  liposomes, nano-particles) have often been proposed in an effort to reduce the  side effects of such drugs and improve their overall efficacy for treating  genetic, viral and malignant diseases.   Three main considerations must be addressed when designing any  such delivery system: It should be biocompatible; bioavailable; and highly  selective to its specific target.

Targeting may be improved by conjugating drug carrying vehicles  with targeting moieties that substantially improve their selectivity. For  example, antibodies, proteins etc. have been incorporated into nano-sized  drug-carriers made from polymeric particles, micelles or liposomes, yet their  relatively short circulation time and the complexity of their production render  them too costly and inefficient.

The need for drug delivery vehicles is particularly stressed in  cancer treatment, where high doses of toxic drugs are often required.  Passively-targeted drug-loaded vehicles are still the predominantly used  delivery systems for cancer therapy. Because of their nano-size and physical  properties, such systems were shown to achieve extended circulation times, and  retention in the tumor microenvironment—owing to the Enhanced Permeability and  Retention (EPR) effect of tumor vasculature and microenvironment.

These systems,  nonetheless, are limited by tumor vascularization and permeability that are  largely dependent on the stage of the malignancy and tumor type. Consequently,  active targeting vehicles, once a promising therapeutic approach, have almost  exhausted their potential, particularly in the area of cancer therapy where such  solutions are desperately needed.

In our recent paper (“Reconstructed Stem Cell Nanoghosts: A Natural Tumor  Targeting Platform”) we report on a novel targeted drug-delivery vehicle for  cancer therapy, which can selectively target the tumor niche while delivering an  array of therapeutic agents.   This targeting platform is based on unique vesicles  (‘nanoghosts’) that are produced, for the first time, from intact cell membranes  of stem cells with inherent homing abilities, and which may be loaded with  different therapeutics.

     Binding of nanoghosts to cells Binding of nanoghosts (white arrow) to PC3 cells; cell, green (GFP);  nucleolus, blue (DAPI) evaluated using confocal microscopy over short (3 h)  incubation times. (Reprinted with permission from American Chemical Society)  

We have shown that such vesicles, encompassing the cell surface  molecules and preserving the targeting mechanism of the cells from which they  were made, can outperform conventional delivery systems based on liposomes or  nanoparticles.   These vesicles leverage the benefits related to the size, and  chemical and physical properties of nano-liposomes, allowing them to efficiently  entrap various hydrophilic and hydrophobic drugs, and be administered through  different routes while exhibiting versatile and controllable release profiles.

The prior art pertaining to the design of this unique and novel drug-delivery  platform is drawn from and associated with the production and utilization of  cell-derived vesicles, and the inherent tumor-targeting abilities of mesenchymal  stem cells (MSCs).   A similar therapeutic effect, to what we have achieved, was  previously demonstrated for prostate cancer, using monoclonal antibodies against  N-cadherin, which is highly expressed in castration-resistant prostate cancer;  however, it requires more frequent and higher dosing.

Our therapeutic outcome is comparable to that demonstrated by De  Marra et al. (“New self-assembly nanoparticles and stealth  liposomes for the delivery of zoledronic acid: a comparative study”) who  used no less than three administrations per week of liposomes encapsulating  Zoledronic acid and exceeded the effect achieved by a weekly administration of  an imatinib–mitoxantrone liposomal formulation.

The efficiency of our delivery system is even more compelling in  light of the results reported by Srivastava et al. (“Effects of sequential treatments with chemotherapeutic drugs  followed by TRAIL on prostate cancer in vitro and in vivo”), which  demonstrated no inhibition of tumor growth after two weeks and as many as four  IV administrations of similar quantities of free sTRAIL. The efficacy of our  system also exceeded that of previously reported liposomal formulations  containing sTRAIL tested on glioblastoma and lung cancer.

Till now, nanoghosts made from mammalian cells have been used to  study cell membranes and were utilized for cancer immunotherapy but have never  been tested as targeted drug-delivery vehicles. Recently, we reported a novel  concept describing a targeted drug-delivery system based on nanoghosts, which  were prepared from the outer cell membranes of a non-human cells engineered to  express the human receptor (CCR5) of a viral ligand (gp120) found on the surface  of HIV-infected cells (“Cell derived liposomes expressing CCR5 as a new  targeted drug-delivery system for HIV infected cells”).

Drug-loaded  nanoghosts selectively targeted HIV-infected cells in vitro, achieving  over 60% reduction in their viability compared to empty nanoghosts, free drug,  or nanoghosts applied on control uninfected cells that were not affected at all.   This intrinsically-targeted system, which does not entail the  elaborate production of targeting molecules and their incorporation into passive  vehicles, represents a simpler and more clinically relevant approach than  existing particulate drug-delivery vehicles.

Our success in using nanoghosts to target HIV-infected cells has  prompted us to devise a more sophisticated universal and non-immunogenic  delivery platform, in which the nanoghosts will be produced from stem cells that  are known to naturally target various tumors.   Insights gained from this work may pave the way for new research  utilizing nanoghosts’ inherent targeting to treat not only tumors but also sites  of inflammations, wound healing, and trauma.

The knowledge accumulated on the entrapment of diverse drugs can  facilitate the loading of nanoghosts with nucleic acid (DNA, siRNA etc.) for  gene therapy.   Nanoghosts loaded with MRI contrast agents (Indocyanine or  magnetite nano-crystals) can open unique research avenues in imaging and  diagnosis. Their small size and specific targeting abilities may enable the  nanoghosts to freely travel in the body possibly detecting small and  sub-metastatic cancer nuclei and lesions, which are otherwise undetectable using  conventional methodologies.

Owing to MSCs natural role in regenerative medicine, nanoghosts  can be also investigated in tissue engineering applications for delivering  growth factors for regenerating tissues.   Finally, MSCs can be engineered to express additional targeting  molecules and used to treat other diseases manifested by the expression of  unique targetable ligands.

This work was conducted by PhD students Naama Ester  Toledano-Furman, Yael Lupu-Haber, Limor Kaneti, and the Lab manager Dr. Tomer  Bronshtein.

By Marcelle Machluf, Associate Professor, The  Faculty of Biotechnology & Food Engineering, Technion – Israel Institute of  Technology, Haifa, Israel.

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