Magnetic-Fe/Fe₃O₄-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages

Abstract

SummaryThe targeted delivery of therapeutics to the tumor site is highly desirable in cancer treatment, because it is capable of minimizing collateral damage. Herein, we report the synthesis of a nanoplatform, which is composed of a 15 ± 1 nm diameter core/shell Fe/Fe3O4 magnetic nanoparticles (MNPs) and the topoisomerase I blocker SN38 bound to the surface of the MNPs via a carboxylesterase cleavable linker. This nanoplatform demonstrated high heating ability (SAR = 522 ± 40 W/g) in an AC-magnetic field. For the purpose of targeted delivery, this nanoplatform was loaded into tumor-homing double-stable RAW264.7 cells (mouse monocyte/macrophage-like cells (Mo/Ma)), which have been engineered to express intracellular carboxylesterase (InCE) upon addition of doxycycline by a Tet-On Advanced system. The nanoplatform was taken up efficiently by these tumor-homing cells. They showed low toxicity even at high nanoplatform concentration. SN38 was released successfully by switching on the Tet-On Advanced system. We have demonstrated that this nanoplatform can be potentially used for thermochemotherapy. We will be able to achieve the following goals: (1) Specifically deliver the SN38 prodrug and magnetic nanoparticles to the cancer site as the payload of tumor-homing double-stable RAW264.7 cells; (2) Release of chemotherapeutic SN38 at the cancer site by means of the self-containing Tet-On Advanced system; (3) Provide localized magnetic hyperthermia to enhance the cancer treatment, both by killing cancer cells through magnetic heating and by activating the immune system.

Targeted drug delivery using genetically engineered diatom biosilica

“…The challenging task of loading hydrophobic chemotherapy drugs onto the antibody-labelled biosilica was solved by electrostatic adsorption of drug-loaded, positively charged liposomes and micelles for later deployment. Up to 85.8% DL% was achieved, which is higher than has been reported for other nanoparticle systems 36 . For both liposomal and micellar nanocarriers adsorbed to diatom biosilica, release studies showed that more than the required effective drug dose was released into the culture medium, indicating the potential to kill targeted cells.…”

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38

“…Treatment using the SN38-dextran loaded Mo/Ma cells in conjunction with doxycycline showed 10% longer survival time in a murine disseminated pancreatic cancer model, in comparison to the SN38 control group. To further optimize Mo/Ma based targeted delivery, a nanoplatform composed of Fe/Fe 3 SO 4 magnetic nanoparticles (MNPs) and SN38 bound to the outer layer of MNPs via a carboxylesterase cleavable linker was synthesised and was loaded into the Mo/Ma cells [109]. The MNPs showed low toxicity to the Mo/Ma cells even at high concentrations (up to 320 μg/ml), thus allowing high drug loading efficiency in the Mo/Ma cells.…”

“…Bioengineered and tumour-homing cells have been utilised as targeted delivery carriers of both SN38 prodrugs and the prodrugactivating enzyme [107][108][109]. For example, RAW 264.7 cells (mouse monocytes/macrophage-like cells, Mo/Ma) for inducible expression of carboxylesterase have been engineered.…”

Nested Helmholtz coil design for producing homogeneous transient rotating magnetic fields

“…[9][10][11] In addition, magnetic hyperthermia treatments last for several minutes and hours. A more effective way to destroy cancer cells is to utilize the nanoparticles as little magnetically driven drill bits.…”