Paclitaxel and quercetin nanoparticles co-loaded in microspheres to prolong retention time for pulmonary drug delivery

Abstract

High drug resistance, poor water solubility, short half-life, and low local drug concentration are obstacles for successful delivery of chemotherapeutic drugs for lung cancer. A new method involving the use of nanoparticles (NPs) for pulmonary delivery is proposed. However, use of NPs is limited by the particle size range for pulmonary drug delivery considering that NPs cannot be deposited directly into the lungs. NPs polymerized into microspheres (polymeric microspheres, PMs) will result in suitable particle sizes and retain the advantages of nanodrugs after redispersion when applied in pulmonary delivery. We report the development of novel NPs in the form of PMs loaded with paclitaxel (PTX) and quercetin (QUE) double drugs based on the synthesis of oleic acid-conjugated chitosan (OA-CTS) for pulmonary delivery. This approach is aimed toward prolonging PTX retention time in the presence of QUE and bypassing P-glycoprotein drug efflux pumps. NPs loaded with PTX or QUE were prepared with 11% substitution degree using OA-CTS as the carrier by ionic cross-linking method, which NPs loaded with PTX or QUE were used in the preparation of PMs by spray-drying. The diameters of the PMs ranged from 1 to 5 μm which had uniform size range. Scanning electron microscopy showed that PMs were polymers formed by a large number of NPs and readily redispersed (after redispersion, size of NPs ranged between 250 and 350 nm) in water within 1 h. PMs displayed slow-release characteristics at pH 4.5 and 7.4. The in vivo pharmacokinetic and biodistribution studies suggested that PMs exhibit prolonged circulation time and a markedly high accumulation in the lung. The obtained results indicate that PMs can serve as a promising pulmonary delivery system for combined pharmacotherapy using hydrophobic anticancer drugs.

A review on chitosan and its development as pulmonary particulate anti-infective and anti-cancer drug carriers

“…Further, nanoprecipitation and chemical vapor deposition are adopted to produce chitosan nanoparticles containing lipid or carbon based composition. Microparticles or microencapsulated nanoparticles are produced to elicit aerodynamic behavior required for pulmonary inhalation ( Liu et al, 2017 ; Rosière et al, 2018 ; Silva et al, 2017 ). Targeting ligand such as folate and hyaluronic acid, and permeation enhancer such as gallic acid are introduced to the backbone of chitosan for the purpose of raising the affinity of carrier with cancer target and cellular permeabilisation ( Almutairi et al, 2019 ; Rosière et al, 2018 ).…”

Nanotechnology for Cancer Therapy Based on Chemotherapy

“…In vivo pharmacokinetic and biodistribution studies, PMs exhibited enhanced drugs accumulation and prolonged circulation time in the lung. These results indicated that co-delivery of two chemotherapeutic agents could eliminate cancer cells more effectively by reversing MDR [ 59 ]. Dasatinib (DAS), another tyrosine kinase inhibitor targeting various kinases, could reverse the MDR to chemotherapeutic drugs by inhibition of the activation of EPK signaling pathway to downregulate the expression of P-gp [ 60 , 61 , 62 , 63 ].…”

“… Synthesis and preparation scheme of PMs (PMs, polymeric microspheres; CTS, chitosan; OA, oleic acid; OA-CTS, OA-conjugated CTS; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NHS, N -hydroxysuccinimide; PTX, paclitaxel; TPP, sodium tripolyphosphate; QUE, quercetin; PTX-OA-CNPs, nanoparticles loaded with PTX; QUE-OACNPs, nanoparticles loaded with QUE); reproduced with the permission from [ 59 ], Copyright (2017) DOVE Medical Press. …”

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

“…Patients generally show a favorable initial response to PTX, however, the efficacy of PTX is frequently restricted by the lack of tumor specificity. What's worse, increasing dose can cause a variety of severe side effects [9]. Therefore, it is urgently needed to develop new drug formulations that can effectively improve the PTX tumor-specific efficacy and reduce the adverse reactions in cancer treatment.…”