Combination Chemotherapeutic Dry Powder Aerosols via Controlled Nanoparticle Agglomeration

Abstract

Purpose To develop an aerosol system for efficient local lung delivery of chemotherapeutics where nanotechnology holds tremendous potential for developing more valuable cancer therapies. Concurrently, aerosolized chemotherapy is generating interest as a means to treat certain types of lung cancer more effectively with less systemic exposure to the compound. Methods Nanoparticles of the potent anticancer drug, paclitaxel, were controllably assembled to form low density microparticles directly after preparation of the nanoparticle suspension. The amino acid, L-leucine, was used as a colloid destabilizer to drive the assembly of paclitaxel nanoparticles. A combination chemotherapy aerosol was formed by assembling the paclitaxel nanoparticles in the presence of cisplatin in solution. Results Freeze-dried powders of the combination chemotherapy possessed desirable aerodynamic properties for inhalation. In addition, the dissolution rates of dried nanoparticle agglomerate formulations (~60% to 66% after 8 h) were significantly faster than that of micronized paclitaxel powder as received (~18% after 8 h). Interestingly, the presence of the water soluble cisplatin accelerated the dissolution of paclitaxel. Conclusions Nanoparticle agglomerates of paclitaxel alone or in combination with cisplatin may serve as effective chemotherapeutic dry powder aerosols to enable regional treatment of certain lung cancers.

Aerosolization System for Experimental Inhalation Studies of Carbon-Based Nanomaterials

“…The use of nanomaterials as a drug carrier system and the delivery of these vehicles by inhalation are a possible approach to targeting drugs to the lungs. This therapeutic noninvasive approach would potentially offer high local drug concentrations that may lower therapeutic doses, reduce systemic effects, and reduce metabolic degradation of drugs in the liver 95 compared with oral or systemic treatment (El-Gendy and Berkland 2009;Sung et al 2009). However, in order to understand the deposition, fate, and transport of nanomaterials that enter the respiratory tract and their potential for biocompatibility or toxicity, it is critical to have a means to deliver these aerosolized materials in experimental studies in a manner comparable with that experienced in different human exposure settings (e.g., inhalation).…”

Loco-regional administration of nanomedicines for the treatment of lung cancer

“…Paclitaxel nanoparticles were prepared by ultrasound-controlled precipitation in the presence of lecithin, polyvinylpyrrolidone, or cetyl alcohol as stabilizers and subsequently assembled in form of low-density microparticles using the amino acid leucine as colloid destabilizer and freeze-dried. The powders obtained not only provided faster dissolution rates compared to micronized paclitaxel but also showed small MMAD (52 mm) with high fine particle fractions (480%) when tested directly without a DPI device using a Tisch Ambient Cascade Impactor (El-Gendy & Berkland, 2009). …”

“…These treatments in many cases display limited efficacy due to poor selectivity, dose-limiting levels of systemic toxicity (including anemia, nausea, vomiting, neurotoxicity, and nephrotoxicity), and the development of multidrug resistance such as that seen with P-glycoprotein and multi-drug-resistant pumps (Tseng et al, 2009;Jinturkar et al, 2012;Videira et al, 2012). Furthermore, many of the most effective treatments for lung cancer such as paclitaxel, docetaxel, doxorubicin, camptothecins, and quercetin are highly lipophilic molecules with very poor aqueous solubility (El-Gendy & Berkland, 2009;Willis et al, 2012;Verma et al, 2013). Low aqueous solubility coupled with unacceptable systemic toxicity limit the therapeutic effect of the commercially available formulations of the aforementioned drugs, with low levels of drug actually reaching the site of action (Tseng et al, 2009;Zarogoulidis et al, 2012a).…”

Inhaled Chemotherapy in Lung Cancer: Safety Concerns of Nanocomplexes Delivered

“…The efficacy and safety of such approaches have been evaluated in vitro and in vivo for several chemo therapeutic drugs, either in their commer cial or nanocomplexed forms [7,[11][12][13][14][15][16][17][18]. The major advantages of inhaled chemotherapeutic agents include reduced systematic side effects and effi cient control of micrometastasis.…”