Paclitaxel encapsulation

The solubility of paclitaxel in water at 25°C at pH 7.4 is 0.172mg/L (0.2 pM), extremely low, making any separation procedure of nonencapsulated paclitaxel from DQAsomes unnecessary i.e., in an aqueous environment, only paclitaxel encapsulated in DQAsomes would stay in colloidal solution. However, for control, a paclitaxel suspension was probe sonicated under identical conditions used for the encapsulation of paclitaxel into DQAsomes, but in the complete absence of dequalinium chloride. As expected, upon centrifugation, no paclitaxel was detectable in the supernatant using ultraviolet (UV) spectroscopy at 230 nm. 

Figure 8 Paclitaxel encapsulated into DQAsomes. (A) Transmission electron microscopic image (uranyl acetate staining). (B) Size distribution. (C) Cryo-electron microscopic image. Source-. From Ref. 43.

Drug-loaded nanoparticles were also evaluated for their safety and efficacy. Paclitaxel-encapsulated 6-O-CAPRO-p-CD nanospheres and nanocapsules were evaluated for their physical stability in a one-month period in aqueous dispersion form with repeated particle size and zeta potential measurements and AFM imaging to evaluate recrystallization in aqueous medium. Paclitaxel-loaded amphiphilic CD nanoparticles were found to be physically stable for a period of one month whereas recrystallization occurs within minutes when diluted for intravenous (IV) infusion [85], Finally, paclitaxel-loaded amphiphilic nanoparticles were demonstrated to show similar anticancer efficacy against MCF-7 cells when compared to paclitaxel solution in a cremophor vehicle [85],... 

Eichhorn ME et al (2006) Paclitaxel encapsulated in cationic Hpid complexes (MBT-0206) impairs functional tumor vascular properties as detected by dynamic contrast enhanced magnetic resonance imaging. Cancer Biol Ther 5 89-96... 

Kunstfeld R, Wickenhauser G, Michaehs U, Teifel M, Umek W, Naujoks K, Wolff K, Petzelbauer P. Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a humanized SCID mouse model. J Invest Dermatol. 2003 120 476-82. 

Cationic nanoparticles can also be obtained with cationic surfactants by incorporation during preparation or by incubation in a cationic surfactant. Didodecyldimethylammonium bromide (DMAB), dodecyltri-methylammonium bromide (DTAB), cetyltrimethylammonium bromide (CTAB), dimethyl(dioctyldodecyl)ammonium bromide (DODAB), benzyl-alkonium chloride and cetrimide are widely used as cationic surfactants for this purpose. PLGA nanoparticles which were coated with DMAB were developed for oral delivery of the anticancer drug paclitaxel. This formulation compared with intravenous administration of paclitaxel with cremo-phor showed an equivalent effect with a 50% lower dose of paclitaxel encapsulated in nanoparticles. ... 

Vascular tissue PLGA, ePTFE paclitaxel Encapsulation 92... 

M.D. Chavanpatil, Y. Patil, and J. Panyam. Susceptibility of nanoparticle-encapsulated paclitaxel to P-glycoprotein-mediated drug efflux. Int J Pharm. 320 150-156 (2006). 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

Dequalinium chloride (10 mM final) and paclitaxel (10 mM final) were dissolved in methanol in a round-bottom flask followed by removing the organic solvent with a rotary evaporator. After adding 5 mM HEPES, pH 7.4, the suspension was sonicated with a probe sonicator until a clear opaque solution of DQAsomes with encapsulated paclitaxel was obtained (usually for about one hour). To remove undissolved material, the preparation was centrifuged for 10 minutes at 3000 rpm. 

In a reproducible way, paclitaxel can be incorporated into DQAsomes at a molar ratio paclitaxel to dequalinium of about 0.6. In comparison to the free drug, encapsulation of paclitaxel into DQAsomes increases the drug s solubility by a factor of about 3000. 

Tumor Growth Inhibition Study with DQAsomal Encapsulated Paclitaxel (43)... 

Also, paclitaxel is the most widely used anticancer agent for non-small cell lung cancer [420], Liposomal encapsulated paclitaxel faces the problem of formulation due to the drug s high hydrophobicity. However, a phase I trial with liposomal paclitaxel reported dose-limiting toxicity at the dose of 150 mg/m2/week. Besides, the whole blood clearance of paclitaxel was similar for liposomal and free paclitaxel. 

A novel nanoparticulate lipid-based carrier system was developed by Mumper et al. at the University of Kentucky. ° This carrier system is composed of a lipophilic-emulsifying wax such as cetyl alcohol/ polysorbate 60 and other surfactants such as Brij 72, Brij 78, and Tween 80. The nanoparticles were formed through a warm microemulsion technique where encapsulates have included paclitaxel and plasmid DNA. The emulsification process is spontaneous, and cooling of the emulsion causes solidification of the nanoparticle-containing drug. This novel carrier has shown high efficiency in drug delivery across the blood-brain barrier. 

Preparations of liposomes via SCF processing are designated as critical fluid liposomes (CFLs). CFLs have successfully encapsulated hydrophobic drugs such as taxoids, camptothecins, doxorubicin, vincristine, and cisplatin. In addition, stable paclitaxel liposomes with a size of 150-250 nm were obtained. Aphios Co. s patent (US Patent 5,776,486) on Super-Fluids CFL describes a method that is useful for the nanoencapsulation of paclitaxel and campothecin in aqueous liposomal formulations called Taxosomes and Camposomes , respectively. 

Recently, easy to use paclitaxel formulation LEP-ETU , demonstrated bio-equivalence with Taxol (Bristol-Myers Squibb, New York, NY) and promising activity in Phase I trials. This is mainly due to a superior paclitaxel loading capacity in the liposome bilayer, at a maximum mole percent of about 3.5%. Similarly, paclitaxel has also been encapsulated in other modern formulations of cationic lipid complexes (MBT-0206) that have been shown to be bounded and internalized selectively by angiogenic tumoral endothelial cells after intravenous administration (29). 

Liposomes are predominantly used as carriers for hydrophilic molecules that are encapsulated within the aqueous inner volume which is confined by the lipid bilayer. These molecules generally do not interact with the lipid moiety of the vesicle. Long circulating liposomes modified with poly (ethylene glycol) (PEG) and other formulations carrying encapsulated cytotoxic drugs such as doxoru-bicine, paclitaxel, vincristine, lurtotecan and others are clinically approved chemotherapeutic liposome formulations (1-5). 

An improvement of medical devices based on bacterial polymers by the encapsulation of different drugs, opens up the wide prospects in applications for these new devices with pharmacological activity in medicine. PHB polymer was used as a drug delivery matrix for sustaining the release of various drugs such as dipyridamole [DP], indomethacin and antibiotics (rifampicin, metronidazole, ciprofloxacin, levofloxacin), anti-inflammatory drugs (flurbiprofen, dexamethasone, prednisolone), and antitumor drugs (paclitaxel) [132]. 

O/W emulsion technique is suitable for the encapsulation of hydrophobic (poorly water soluble) compounds since they partition favorably into the oil phase, and the technique has been employed for the encapsulation of various drugs, such as steroids, thioridazine, dexamethasone, chlorproma-zine, methadone, and anticancer agents—aclarubicin, lomustine, " " and paclitaxel." " ... 

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