New dry powders for inhalation containing temozolomide-based nanomicelles for improved lung cancer therapy

Abstract

Abstract. Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1 H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10 -7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomideloaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F-PEG-HMD-based dry powders for inhalation could constitute an interesting drug delivery system able to release nanomicelles that are useful in adenocarcinomas that overexpress folate receptors.

Dual-Drug Containing Core-Shell Nanoparticles for Lung Cancer Therapy

“…Folate receptor-targeting nanomicelles for lung cancer therapy by dry powder inhalation have also been developed by Rosière et al . 63 . Similarly, a significantly higher accumulation of folate-conjugated Gadolinium (Gd)-based nanoparticles than PEG-conjugated Gd nanoparticles was also found in the folate receptor-expressing KB (human nasopharyngeal carcinoma) tumors of athymic mice 24 hours following tail vein injection 64 .…”

Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities

“…The drug lung concentrations in rats were also 13-fold higher with TAS-103-loaded PLGA nanoparticles compared with the free drug administered via the intravenous route [84] . Some studies have shown that the carrier excipients dissolve and release primary nanoparticles upon deposition and thus achieve the aerosolization properties of microparticles while maintaining the release benefit of nanoparticles [84,204,205] . L-leucine is a commonly used force-control agent that is known to reduce inter-particle cohesion and improve the dispersibility of small particles [206,207] .…”

Inhaled Medicines for Targeting Non-Small Cell Lung Cancer

“…In a different study, findings confirmed that in a mouse inhalation model, the repeated inhalation exposure to SLN at concentrations lower than a 200-µg deposit dosage was safe [ 121 ]. Dry powder formulations using chitosan-derivative-coated solid lipid nanoparticles for inhalation have contributed to increased anti-cancer action in folate receptor-positive lung tumors [ 122 ]. According to a different study, epirubicin solid lipid nanoparticles (EPI-SLNs) could be used as an inhalable delivery strategy for lung cancer treatment [ 123 ].Finally, another study has reported that SLNs are a promising pulmonary delivery mechanism for enhancing the bioavailability of medicines that are weakly water soluble, such as naringeninin NSCLC [ 124 ].…”