Preparation and Characterization of Amphiphilic Calixarene Nanoparticles as Delivery Carriers for Paclitaxel

Abstract

Two types of amphoteric calix[n]arene carboxylic acid (CnCA) derivative, i.e., calix[6]arene hexa-carboxylic acid (C 6 HCA) and calix[8]arene octo-carboxylic acid (C 8 OCA), were synthesized by introducing acetoxyls into the hydroxyls of calix[n]arene (n 6, 8). C 6 HCA and C 8 OCA nanoparticles (NPs) were prepared successfully using the dialysis method. CnCA NPs had regular spherical shapes with an average diameter of 180-220 nm and possessed negative charges of greater than 30 mV. C 6 HCA and C 8 OCA NPs were stable in 4.5% bovine serum albumin solutions and buffers (pH 5-9), with a low critical aggregation concentration value of 5.7 mg·L 1 and 4.0 mg·L 1 , respectively. C 6 HCA and C 8 OCA NPs exhibited good paclitaxel (PTX) loading capacity, with drug loading contents of 7.5% and 8.3%, respectively. The overall in vitro release behavior of PTX from the CnCA NPs was sustained, and C 8 OCA NPs had a slower release rate compared with C 6 HCA NPs. These favorable properties of CnCA NPs make them promising nanocarriers for tumortargeted drug delivery.Key words calix[n]arene carboxylic acid; nanoparticle; paclitaxel; tumor therapy Paclitaxel (PTX) is a well-known anticancer drug that is used primarily to treat lung, breast and ovarian cancers. Similar to most anticancer drugs, its poor solubility in water limits the clinical applications of PTX. Taxol, a widely used clinical formulation of paclitaxel, requires the use of Cremphor-EL as a solubilizer, which has been known to cause serious problems, including hypersensitivity reactions, neurotoxicity, and nephrotoxicity.1,2) Moreover, the lack of selectivity of PTX results in significant toxicity to noncancerous cells and severely impacts patients' quality of life. Therefore, there is a dire need for the development of a novel formulation that improves the solubility of PTX and decreases its side effects.Among various alternatives, nano-sized drug delivery system (nano-DDS) is one of the best choices. Nano-DDS not only greatly enhances the solubility of PTX without side effects, but it also promotes intra-tumoral drug accumulation through the enhanced permeability and retention (EPR) effect.3,4) Many nano-DDSs of PTX have been reported, and some of them have been marketed. Abraxane, a nanosuspension of paclitaxel encapsulated in human albumin was approved by the Food and Drug Administration (FDA) in 2005 for the treatment of metastatic breast cancer.5) A liposomebased PTX formulation, Lipusu, has been applied for the treatment of ovarian cancer in China.6) In addition to these approved drugs, a number of PTX nano-DDSs, such as polymeric nanoparticles (NPs), 7-9) inorganic NPs, 10) nano-emulsions, 11) carbon nanotubes, 12) and nanogels, 13) have been reported in preclinical studies. Although these novel PTX nano-DDSs exhibit varying levels of success, methods for improving the safety, stability and specificity of nano-DDS still warrant further research.Calixarenes have been used as an important class of macrocyclic host molecules in supramolecular chemistry.14) Becaus...

Preparation of High-Payload, Prolonged-Release Biodegradable Poly(lactic-<i>co</i>-glycolic acid)-Based Tacrolimus Microspheres Using the Single-Jet Electrospray Method

“…Encapsulation efficiency (EE) and drug-LC were calculated with the following formula as described previously. [26][27][28] Observed amount of TAC EE (%) 100% Added amount of TAC Weight of TAC in microspheres LC (%) 100% Weight of microspheres…”

An ultrasensitive LC–MS/MS method with liquid phase extraction to determine paclitaxel in both cell culture medium and lysate promising quantification of drug nanocarriers release in vitro

“…Moreover, poor aqueous solubility and serious side effects associated with commercial preparation of PTx (Taxol ® ) triggered the development of alternative PTx formulations without cremophor. Different nanocarrier systems including nanoparticles, liposomes, micelles, bioconjugates and dendrimers have been employed to improve PTx solubility and eliminate undesired side effects [10][11][12][13][14][15]. It was reported that PTx, delivered in polyanhydrides, was released very slowly, and only 15% of 0.042 mg/mL of PTx was released in 77 days [16].…”

“…Since PTx release kinetic is time and medium composition depending, a highly sensitive quantification of drug at short time is required to validate the use of such nanocarriers for drug delivery in cancer therapy. Indeed, due to its high hydrophobicity, most of in vitro studies of PTx release from nanocarriers were performed in simulated physiological medium supplemented with surfactant Tween 80 [11][12][13][14][15][16][17][18]. Numerous analytical methods using liquid phase extraction and solid phase extraction combined to the LC-MS/MS technique were developed for ultrasensitive quantifi- cation of PTx in biological samples such as cells, plasma, urine, feces or tissues [19][20][21][22][23][24][25][26][27][28][29][30].…”

“…Numerous analytical methods using liquid phase extraction and solid phase extraction combined to the LC-MS/MS technique were developed for ultrasensitive quantifi- cation of PTx in biological samples such as cells, plasma, urine, feces or tissues [19][20][21][22][23][24][25][26][27][28][29][30]. Nevertheless, most of the published works use high-performance liquid chromatography or spectrophotometric UV-vis absorbance [11][12][13][14][15]17] and radio labeled [16] detection to determine the in vitro profile of PTx release from nanocarriers. This makes us thinking about to what extend LC-MS/MS reported methods were suitable to quantify PTx in biological medium such as complete cell culture medium supplemented with 10% of fetal bovine serum.…”

Preparation and Characterizations of RSPP050-Loaded Polymeric Micelles Using Poly(ethylene glycol)-<i>b</i>-Poly(ε-caprolactone) and Poly(ethylene glycol)-<i>b</i>-Poly(D,L-lactide)

“…Several kinds of nanocarriers including liposome, micelle, dendrimer, and nanocrystal have been used for drug delivery systems. 5,[10][11][12] Polymeric micelles were selected as a nanocarrier in this study. Polymeric micelles are self-assembling nanostructure comprising of core and shell which are made up by amphiphilic copolymers.…”