Manganese-loaded lipid-micellar theranostics for simultaneous drug and gene delivery to lungs

Abstract

Gadolinium (Gd) contrast agents are predominantly used for T1 MR imaging. However, the high toxicity of Gd3+ and potential side effects including nephrogenic systemic fibrosis have led to the search for alternative T1 contrast agents. Since manganese (Mn) has paramagnetic properties with five unpaired electrons that permit high spin number, long electronic relaxation times, and labile water exchange, we evaluated Mn as a T1 magnetic resonance imaging (MRI) contrast agent for lung imaging. Here we report on the design and synthesis of multifunctional lipid-micellar nanoparticles (LMNs) containing Mn oxide (M-LMNs) for MRI that can also be used for DNA and drug delivery. Oleic acid-coated MnO nanoparticles were encapsulated in micelles composed of polyethylene glycol (PEG-2000), phosphatidylethanolamine (PE), DC-cholesterol, and dioleoyl-phosphatidylethanolamine (DOPE). The particles are taken up in vitro by human embryonic kidney (HEK293), Lewis lung carcinoma (LLC1), and A549 cells and are devoid of cytotoxicity. When administered to mice intranasally, they preferentially accumulate in the lungs. In vitro phantom and ex vivo lung MRI results confirmed that M-LMNs are able to enhance T1 MRI contrast. M-LMNs loaded with plasmid DNA and/or doxorubicin are efficiently taken up by HEK293 cells in vitro and by target cells in vivo. Taken together, these results demonstrate that M-LMNs are capable of simultaneously providing MRI contrast and DNA and/or drug delivery to target cells in the lung and therefore may prove useful as a lung theranostic, especially for lung cancers.

Magneto-reactance based detection of MnO nanoparticle-embedded Lewis lung carcinoma cells

“…MnO nanoparticles and MLMNs were prepared as described previously in Howell et al 14 Briefly, MnO nanoparticles were encapsulated in a lipid mixture containing, PEG-2000 PE, DC-cholesterol, and DOPE in chloroform. The chloroform was then evaporated in a vacuum oven, and the dry film was heated at 80 C. Water was added to the dry film and the solution was sonicated.…”

“…Phospholipid micelles encapsulating DOX and MnO (DMLMNs) were prepared, as previously described. 14 The 3 mg of MnO was replaced by 1.5 mg of DOX and 1.5 mg of MnO. Cells were seeded 24 h prior to transfection into a 8-well chamber slide at a density of 20,000 cells per well in 300 ll of complete medium (Dulbecco's modified eagle's medium (DMEM) containing 10% FBS (Foetal Bovine Serum), 2 mM L-glutamine, and 1% penicillin/streptomycin).…”

Overview of the role of nanotechnological innovations in the detection and treatment of solid tumors

“…123 Howell et al formulated a self-assembling lipid-micellar nanoparticle containing a DOX or DNA therapeutic payload and encapsulating a manganese core, illustrated in Figure 7D. 124 This multifunctional nanosystem has application in contrast magnetic resonance imaging for tumor diagnosis, as well as in tumor therapy with conventional chemotherapeutic drugs or gene delivery. 124 …”

“…124 This multifunctional nanosystem has application in contrast magnetic resonance imaging for tumor diagnosis, as well as in tumor therapy with conventional chemotherapeutic drugs or gene delivery. 124 …”

Tailorable nanocarrier emulsion for drug delivery

“…Drugs with poor water-solubility and instability under external or enzymatic environments can be encapsulated within the hydrophobic compartments of the nanocarriers, such as liposomes, emulsions and micelles , Ashley et al, 2011, Howell et al, 2013. Obstacles arising from aberrant side effects and inability to cross biological barriers could be tackled by surface engineering with immune evading polymers and biologically reactive ligands (Boyd, 2008).…”