Paclitaxel Loading Research Articles

Synthesis and characterization of bile acid‐based poly β amino esters for paclitaxel delivery

AbstractNew biodegradable poly β amino esters were synthesized by the polymerization of Deoxycholic acid (DOCA) in all the structural planes by 1, 4 addition of Trimethylene dipiperidine (TMDP) to diacrylates of Deoxycholyl glycol, Methyl deoxycholate and Trimethylolpropane deoxycholate esters. 1H‐NMR, 13C‐NMR and IR studies confirmed presence of amine and Deoxycholyl units in polymers. XRD and TGA studies indicated that all the polymers were amorphous and thermostable up to 300°C. DSC studies revealed glass transition temperature (Tg) in the range 70–80°C. All the polymers degraded very slowly in the buffers of pH 1.1, 7.4 and 10 because of the hydrophobic nature of Deoxycholate units. These polymers also exhibited pH sensitivity due to the incorporation of amines along with Deoxycholate units in the backbone. P‐Nitroaniline (PNA) release followed anomalous release kinetics. Paclitaxel (PTX) loaded nanospheres prepared from these polymers were spherical and uniform in the size range 75–250 nm and 0.4–1μ depending upon the method of preparation. PTX loading was in the range 60–90%, while release (up to 20–60%) was sustained over a period of 100 h. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Abstract 4439: A reversibly self-crosslinking nano-carrier system for efficient anticancer drug delivery

Abstract It is known that the intracellular concentration of glutathione (GSH) is substantially higher than that in the cellular exterior (∼10 mM vs ∼2 μM) and many types of tumor cells have an elevated GSH level compared to normal cells. This dramatic variation of the GSH concentration provides an opportunity for designing tumor specific drug delivery systems. Most of the chemotherapeutic drugs used in clinic suffer from severe dose-limiting side effects. In order to enhance the therapeutic efficacy and minimum the side effect of these drugs, we developed a stable and efficient nano-carrier drug delivery system based on the disulfide crosslinked micelles comprise of poly (ethylene glycol) (PEG) and dendritic oligmers of cholic acids and cysteines. Various poorly water-soluble anticancer drugs can be efficiently incorporated inside these polymeric nano-carriers. The nano-carriers are stabilized by disulfide bridges in the core to avoid premature release of the loaded drugs during circulation. After reaching the tumor sites via enhanced permeability and retention (EPR) effect, the nano-carriers will disassemble to release the core-loaded drugs upon the cleavage of disulfide bridges under reductive conditions following the intracellular uptake or triggered by additional reducing agents. The crosslinked nano-carriers were spherical with a uniform size of 30 ± 5 nm, and can load paclitaxel (PTX) in the core with drug loading content up to 35% (w/w). Cross-linking of the nano-carriers within the core reduced their critical aggregate concentration and greatly enhanced their stability in non-reductive physiological conditions. The release of PTX from the crosslinked nano-carriers was significantly slower than that from non-crosslinked nano-carriers and can be gradually facilitated in a reducing environment. The fluorescence intensity of BODIPY 650/665 (near infrared dye) labeled disulfide crosslinked nano-carriers sustained up to 24 hours within the blood stream of nude mice while that of non-crosslinked nano-carriers decreased faster and fell into the background level within 8 hours post injection. Targeted drug delivery to tumor site with these crosslinked nano-carriers was demonstrated by near infrared fluorescence imaging in nude mice bearing ovarian cancer xenograft. The nano-formulation of PTX was found to be less toxic than its free drug form in nude mice. We further demonstrated the crosslinked nano-formulation of PTX was more efficacious than both free drug and non-crosslinked nano-formulation of PTX in ovarian cancer xenograft model. This new class of nano-therapeutics shows great promise in the future cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4439. doi:10.1158/1538-7445.AM2011-4439

Active Targeting Behaviors of Biotinylated Pluronic/Poly(Lactic Acid) Nanoparticles In Vitro through Three-Step Biotin–Avidin Interaction

In order to prepare targeted drug carriers, previously a biotin group has been attached by our group to the end of Pluronic F87/poly(lactic acid) and Pluronic P85/poly(lactic acid) block co-polymers to obtain B-F87–PLA and B-P85–PLA, respectively. In this paper, the active targeting properties of B-F87–PLA and B-P85–PLA nanoparticles in vitro were investigated through a three-step biotin–avidin interaction by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) tests and fluorescence microscopy (FM). Two kinds of human ovarian cancer cells (OVCAR-3 and SKOV-3) and paclitaxel were chosen for the cytotoxicity tests. CA-125 antigen is over-expressed on OVCAR-3 cells but not on SKOV-3 cells. The loading and release behavior of paclitaxel loaded in B-Pluronic–PLA nanoparticles were also studied. Paclitaxel loaded in both B-F87–PLA and B-P85–PLA nanoparticles shows an initial rapid release followed by a slow release period. Compared with SKOV-3 cells, the cytotoxicity results implied that paclitaxel-loaded B-Pluronic–PLA nanoparticles were delivered more effectively to OVCAR-3 cells due to the specific interaction between the biotin groups on the surface of B-Pluronic–PLA nanoparticles and the avidin/biotinylated MAb X306/CA-125 antigen complexes on the surface of OVCAR-3 cells. The active targeting properties of B-F87–PLA nanoparticles were further confirmed by FM.

Folate-Decorated Hybrid Polymeric Nanoparticles for Chemically and Physically Combined Paclitaxel Loading and Targeted Delivery

In this study, folate-functionalized hybrid polymeric nanoparticles (NPs) were prepared as carriers of low water solubility paclitaxel for tumor targeting, which were composed of monomethoxy-poly(ethylene glycol)-b-poly(lactide)-paclitaxel (MPEG-PLA-paclitaxel) and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-folate (TPGS-FOL). NPs with various weight ratios of MPEG-PLA-paclitaxel and TPGS-FOL were prepared using a solvent extraction/evaporation method, which can also physically encapsulate paclitaxel. The size, size distribution, surface charge, and morphology of the drug-loaded NPs were characterized using a Zetasizer Nano ZS, scanning electron microscope (SEM), and atomic force microscopy (AFM). The encapsulation and drug loading efficiencies of these polymeric NPs are analyzed using high-performance liquid chromatography (HPLC) at 227 nm. The combination of covalent coupling and physical encapsulation is found to improve the loading of paclitaxel in NPs greatly. The in vitro antitumor activity of the drug-loaded NPs is assessed using a standard method of transcriptional and translational (MTT) assays against HeLa and glioma C6 cells. When the cells were exposed to NPs with the same paclitaxel weights, cell viability decreases in relation to the increase in TPGS-FOL in drug-loaded NPs. To investigate drug-loaded NP cellular uptake, the fluorescent dye coumarin-6 is utilized as a model drug and enveloped in NPs with 0 or 50% TPGS-FOL. Confocal laser scanning microscopy (CLSM) analysis shows that cellular uptake is lower for coumarin-6-loaded NPs with 0% TPGS-FOL than those with 50% TPGS-FOL. However, no difference for NIH 3T3 cells with normally expressed folate receptors is found. Results from in vitro antitumor activity and cellular uptake assay demonstrate that folic acid promotes drug-loaded NP cellular uptake through folate receptor-mediated endocytosis (RME). All of these results demonstrate that folate-decorated hybrid polymeric NPs are potential carriers for tumor-targeted drug delivery.

Design and Evaluation of Peptide Amphiphiles with Different Hydrophobic Blocks for Simultaneous Delivery of Drugs and Genes

In this study, peptides with six different compositions were designed and synthesized to study the effect of the structure of the hydrophobic block in triblock oligopeptide amphiphiles ((A(m) X)(n) H(5) K(15) ) on self-assembly properties, drug loading capacity and gene expression efficiency. The peptides were synthesized using a standard Fmoc-solid phase peptide synthesis protocol, which are A(12) H(5) K(15) , A(11) FH(5) K(15) , (A(5) F)(2) H(5) K(15) , (A(3) F)(3) H(5) K(15) , (AF)(6) H(5) K(15) and (AL)(6) H(5) K(15) . A(12) H(5) K(15) , A(11) FH(5) K(15) , (A(5) F)(2) H(5) K(15) and (A(3) F)(3) H(5) K(15) , formed micelles at concentrations above 200 mg · L(-1) with large size or aggregation. However, (AF)(6) H(5) K(15) and (AL)(6) H(5) K(15) had CMC values of 42 and 49 mg · L(-1) respectively, and the resulting micelles were much smaller in size as compared to the other peptide designs (108 and 233 nm for (AF)(6) H(5) K(15) and (AL)(6) H(5) K(15) , respectively). In addition, both peptides were able to load paclitaxel (PTX) into nanoparticles although PTX-loaded (AF)(6) H(5) K(15) nanoparticles had a smaller size (278 versus 295 nm, respectively). Encapsulation efficiency of PTX with (AF)(6) H(5) K(15) nanoparticles was 74%. Gene transfection studies showed that luciferase expression level induced by (AF)(6) H(5) K(15) micelles in HepG2 cell line was much higher than that mediated by (AL)(6) H(5) K(15) micelles at their respective optimal N/P ratios (3.2 × 10(8) versus 3.9 × 10(7) RLU · mg proteins(-1) ). Therefore, simultaneous delivery of PTX and luciferase-encoding plasmid was conducted using (AF)(6) H(5) K(15) micelles against HepG2 cells, and the results demonstrated that the co-delivery of PTX at 0.01 mg · L(-1) further increased luciferase expression level from 3.2 × 10(8) to 8.0 × 10(8) RLU · mg proteins(-1) at the optimal N/P ratio (i.e., 18). In summary, it is important to optimize the hydrophobic block of the oligopeptide amphiphiles in order to achieve desired properties for co-delivery of drugs and genes.

Well-Defined, Size-Tunable, Multifunctional Micelles for Efficient Paclitaxel Delivery for Cancer Treatment

We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes, and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptake of the smaller paclitaxel-loaded micelles (17-60 nm) by the tumor and the larger micelles (150 nm) by the liver and lung. The toxicity and antitumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol and Abraxane.

Delivery of paclitaxel by physically loading onto poly(ethylene glycol) (PEG)-graftcarbonnanotubes for potent cancer therapeutics

Physically loading of paclitaxel (PTX) onto carbon nanotubes (CNTs) is achieved throughimmersion of poly(ethylene glycol) (PEG)-graft-single walled CNTs (PEG-g-SWNTs)or PEG-graft-multi-walled CNTs (PEG-g-MWNTs) in a saturated solution ofPTX in methanol. After loading once the loading capacity (LD%) is 26% (w/w) and36% (w/w) for PEG-g-SWNTs or PEG-g-MWNTs, respectively. With these PTX contents, PTXloaded PEG-g-SWNTs and PTX loaded PEG-g-MWNTs still have good dispersity inaqueous solution and individual CNTs can be observed in TEM images. PTX can bereleased from PEG-g-CNTs several times faster than from free PTX but still in a sustainedprofile with less than 40% of PTX being released in 40 days at pH 7 or 5. In vitrocytotoxicity of samples is evaluated in HeLa cells and MCF-7 cells. PEG-g-SWNTs andPEG-g-MWNTs show low cytotoxicity in both cells with insignificant effects on the cellproliferation rates. However, both PTX loaded PEG-g-SWNTs and PTX loadedPEG-g-MWNTs show high efficacy to kill HeLa cells and MCF-7 cells, as reflected byIC50 lower than free PTX. Therefore, PTX loaded PEG-g-CNTs are promising for cancertherapeutics. Keywords: carbon nanotubes, poly(ethylene glycol), drug delivery, cancertherapy, nanomedicine.

Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature

Antiangiogenic cancer therapy can be achieved through the targeted delivery of antiangiogenic agents to the endothelial cells of tumor neovasculature. In the present study, we developed a drug delivery system (DDS), nanoparticles conjugated with K237-(HTMYYHHYQHHL) peptides for tumor neovasculature targeting drug delivery. Paclitaxel, a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. We synthesized the aldehyde poly(ethylene glycol)–poly(lactide) (aldehyde-PEG–PLA) block copolymer by ring opening polymerization. The nanoparticles loading paclitaxel (PTX-NP) were fabricated using the O/W emulsion and evaporation technique. K237 ligand, a peptide that can bind to the KDR receptors predominantly expressed on the surface of tumor neovasculature endothelial cells with high affinity and specificity and inhibit the VEGF-KDR angiogenic signal pathway, was conjugated to the aldehyde group of PEG chain using the N-terminal PEGylation technique. The K237 conjugated paclitaxel-loaded nanoparticles (K237-PTX-NP) had a hydrodynamic diameter of 150 nm. The K237 density on nanoparticle surface was 474 and the mean distance between two neighboring PEG chains linked to K237 peptide was 12 nm. The K237 conjugated nanoparticles could be significantly internalized by human umbilical vein endothelial cells (HUVEC) through the K237-KDR interaction, and this facilitated uptake led to the expected enhanced antiangiogenic activity shown by HUVEC proliferation, migration and tube formation compared to cells treated with the commercial formulation Taxol ® and PTX-NP. The long-circulating property and the K237 ligand of K237-PTX-NP warranted rapid, long-term, and accurate in vivo tumor neovasculature targeting, and thereafter the significant apoptosis of tumor neovasculature endothelial cells and necrosis of tumor tissues of MDA-MB-231 breast tumors implanted in female BLAB/c nude mice. This nanoparticulate DDS offers a new strategy for paclitaxel chemotherapy application and it could also be used to carry other chemotherapeutic drugs, genes, and proteins with antiangiogenic activity for antiangiogenic cancer therapy.

Preparation and in vitro characterization of paclitaxel-loaded injectable microspheres

The main objective of this study was to develop paclitaxel loaded poly (caprolactone) injectable microspheres prepared by solvent evaporation method. Mircoparticles were characterized in terms of particle size and size distribution, surface morphology, drug physical state, and crystalline nature by using master size analyzer, scanning electron microscope,differential scanning calorimetry, and X-ray diffraction. Paclitaxel loading over different concentrations was analyzed by high-performance liquid chromatography. In vitro drug release studies were performed in phosphate buffer saline. Best formulation was selected for in vitro cytotoxic studies by using MCF-7 breast cancer cell lines.

PH-Sensitive degradable polymersomes for triggered release of anticancer drugs: A comparative study with micelles

pH-Sensitive degradable polymersomes and micelles were prepared based on diblock copolymer of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidenepentaerythritol carbonate) (PTMBPEC). Polymersomes of PEG(1.9k)–PTMBPEC(6k) revealed average sizes of 100–200 nm. The acetals of polymersomes, similar to those of PEG(5k)–PTMBPEC(5.8k) micelles, though stable at pH 7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0, with half lives of 0.5 and 3 d, respectively. The acetal hydrolysis resulted in significant size increase of polymersomes, to over 1000 nm in 24 h at pH 4.0. Drug encapsulation studies revealed that polymersomes were able to simultaneously load paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX·HCl, hydrophilic), whereas micelles loaded PTX only. Notably, polymersomes showed lower drug loading efficiencies for PTX than micelles (30.0–37.7% versus 61.4–65.2%). The in vitro release studies demonstrated that release of PTX and DOX·HCl from polymersomes was highly pH-dependent, i.e. significantly faster drug release at mildly acidic pH of 4.0 and 5.0 compared to physiological pH. Furthermore, much higher release rates were observed for PTX release from the polymersomes compared to that from the micelles under otherwise the same conditions. These pH-sensitive nano-sized degradable polymersomes hold great promise for combination therapy for cancers.

Thermal Process for Enhancing Mechanical Strength of PLGA Nanoparticle Layers on Coronary Stents

Poly (lactic-co-glycolic acid) (PLGA) nanoparticles loading paclitaxel have been deposited on coronary stents by self-assembling properties of colloidal particles. The layers of the nanoparticles were enhanced to a sufficient mechanical strength by a thermal process under the proper temperature and humidity conditions. In vitro release studies proved the controlled paclitaxel release of the nanoparticle layers. This technique gives rise to a new range of applications for nanoparticles and drug-eluting stents.

Paclitaxel-Eluting Biodegradable Synthetic Vascular Prostheses

Clinical small-caliber vascular prostheses are unsatisfactory. Reasons for failure are early thrombosis and late intimal hyperplasia. We thus prepared biodegradable small-caliber vascular prostheses using electrospun polycaprolactone (PCL) with slow-releasing paclitaxel (PTX), an antiproliferative drug. PCL solutions containing PTX were used to prepare nonwoven nanofibre-based 2-mm ID prostheses. Mechanical morphological properties and drug loading, distribution, and release were studied in vitro. Infrarenal abdominal aortic replacement was carried out with nondrug-loaded and drug-loaded prostheses in 18 rats and followed for 6 months. Patency, stenosis, tissue reaction, and drug effect on endothelialization, vascular remodeling, and neointima formation were studied in vivo. In vitro prostheses showed controlled morphology mimicking extracellular matrix with mechanical properties similar to those of native vessels. PTX-loaded grafts with suitable mechanical properties and controlled drug-release were obtained by factorial design. In vivo, both groups showed 100% patency, no stenosis, and no aneurysmal dilatation. Endothelial coverage and cell ingrowth were significantly reduced at 3 weeks and delayed at 12 and 24 weeks in PTX grafts, but as envisioned, neointima formation was significantly reduced in these grafts at 12 weeks and delayed at 6 months. Biodegradable, electrospun, nanofibre, polycaprolactone prostheses are promising because in vitro they maintain their mechanical properties (regardless of PTX loading), and in vivo show good patency, reendothelialize, and remodel with autologous cells. PTX loading delays endothelialization and cellular ingrowth. Conversely, it reduces neointima formation until the end point of our study and thus may be an interesting option for small caliber vascular grafts.

Encapsulation of Water-Insoluble Drugs in Poly(butyl cyanoacrylate) Nanoparticles

Hydrophobic drugs, loperamide and paclitaxel, were loaded in poly(butyl cyanoacrylate) nanoparticles by polymerization of n-butyl-2-cyanoacrylate in aqueous-organic media in the presence of a drug. The particles were stabilized by dextran 70,000 and poloxamer 188 or by 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000] sodium salt. It was shown that in the presence of dichloromethane, methanol or ethanol the encapsulation efficiency of loperamide in the nanoparticles reached 80%. Loading of paclitaxel was efficient only in the presence of the lipid. The organic solvents did not significantly influence the nanoparticle morphology or their physicochemical parameters. Thus produced poly(butyl cyanoacrylate) nanoparticles enabled delivery of loperamide across the blood-brain barrier, which was evidenced by the drug analgesic effect evaluated by the tail-flick test.

Elaboration of radiopaque iodinated nanoparticles for in situ control of local drug delivery

Drug delivery systems can benefit from intrinsic radiopacity as this property will allow following up the diffusion path of the nanoparticles containing the therapeutic drug after their local administration. Herein, we report the synthesis of iodinated derivatives of cellulose acetate (CA) and their formulation into aqueous radiopaque nanoparticle suspensions. Modification and purification of CA with mono- or tri-iodobenzoyl chloride were characterized by NMR spectroscopy and elemental analysis of iodine. In particular, measurements of diffusion coefficients by the DOSY 2D NMR method allowed controlling the complete elimination of non-grafted iodinated materials. Pure radiopaque CA was successfully achieved with an iodine content varying between 14 and 32%. Aqueous suspensions of nanoparticles were successfully formed, characterized by being spherical, <100 nm in size and stable as a suspension over 3 months. The degree of substitution, in particular the triiodo moieties, imparted a good level of radiopacity whether in dry powder form (2627 HU) or as a nanoparticle suspension (298 HU). These values are comparable to radiopacity of systems reported in literature to be in vivo visible. Loading of paclitaxel was successfully attempted, suggesting that the developed radiopaque nanoparticles can ultimately function as a drug delivery system.

The gastrointestinal stability of lipid nanocapsules

The in vitro gastrointestinal stability of lipid nanocapsules (LNCs) was studied in different media. The size of LNCs was determined in simulated gastric and intestinal media. In updated fasted state simulated intestinal fluid (FaSSIF-V2) and updated fed state simulated intestinal fluid (FeSSIF-V2) media, the encapsulation ratio of paclitaxel-loaded LNCs was also measured. The size of LNCs was not modified after 3 h in simulated gastric fluid and simulated intestinal fluid described by the United States Pharmacopeia, in FaSSIF, FaSSIF-V2, and in FeSSIF. Moreover, in the presence of pancreatin in FeSSIF-V2, a decreased above 30% of the loading of paclitaxel was observed. This was attributed to the presence of lipase in pancreatin that could interact with Lipoid ® (a mixture of phosphatidylcholine and phosphatidylethanolamine), present on the shell of LNC. As a conclusion, LNCs were stable on gastric medium and fasted state intestinal medium.

Simple Approach to Stabilized Micelles Employing Miktoarm Terpolymers and Stereocomplexes with Application in Paclitaxel Delivery

A simple and versatile approach to miktoarm co- and terpolymers from carbonate functional oligomers is described. The key building block employed is a carboxylic acid functional cyclic carbonate, derived from 2,2-bis(methylol)propionic acid, that was readily coupled to a hydroxyl functional monomethylether poly(ethylene glycol) oligomer. Ring-opening of the cyclic carbonate using functional amines generates a carbamate linkage bearing a functional group capable of initiating either controlled radical or ring-opening polymerization, together with a primary hydroxyl group for ring-opening polymerization. Two tandem polymerization steps were possible which add the second two arms, thus generating the targeted ABC miktoarm terpolymer. The resulting amphiphilic miktoarm terpolymers containing poly(D- and L-lactide) formed polylactide stereocomplexes in the bulk. In aqueous solution, the stereocomplex mixture of Y-shaped miktoarm copolymers, poly(ethylene glycol)-poly(D-lactide)-poly(D-lactide) and poly(ethylene glycol)-poly(L-lactide)-poly(L-lactide), or the stereoblock miktoarm poly(ethylene glycol)-poly(D-lactide)-poly(L-lactide) form stabilized micelles with a significantly lower critical micelle concentration than those derived from conventional stereo regular linear or Y-shaped amphiphiles. This simple and versatile approach provides a useful synthetic route to complex macromolecular architectures that can assemble into stable micelles. These micelles provide high capacity for loading of the anticancer drug paclitaxel and possess narrow size distribution as well as unique structure, leading to sustained and near zero-ordered release of drug without significant initial burst.

Controlled Release of Paclitaxel from Amphiphilic Copolymer Hybrid Assembly Nanoparticles

A convenient pathway to control drug release from hybrid assembly nanoparticles of several kinds of copolymers was investigated in this paper. Three kinds of biodegradable amphiphilic copolymers, poly(ethylene glycol)-block-poly(L-lactic acid), poly(ethylene glycol)-block-poly(D,L-lactic acid) and poly(ethylene glycol)-block-polycaprolactone-poly(ethylene glycol) were used to assemble into hybrid assembly nanoparticles as carriers of paclitaxel. The results show that small spherical hybrid assembly nanoparticles (diameter < 100 nm) with good paclitaxel loading ability and entrapping efficiency were obtained simply through hybrid assembling of different copolymers. The in vitro release studies indicate that paclitaxel release rate can be controlled easily by varying the ratio of the hybrid copolymers. The release control mechanism is assigned to the crystallization adjustment of the cores of hybrid assembly nanoparticles which provide a convenient approach to control drug release for drug-loaded nanoparticles.

Biodegradable Films Developed by Electrospray Deposition for Sustained Drug Delivery

The objective of present study is to develop biodegradable films with controllable thickness for sustained release applications using a combination of electrospray deposition techniques. The model anticancer drug-paclitaxel is encapsulated inside PLGA films. The morphology observed by atomic force microscopy and scanning electron microscopy reveals that the film has a flat surface together with a dense structure. X-ray photo-electron spectroscopy results show that some amount of paclitaxel is found on the surface layer of films. X-ray diffractometry (XRD) analysis suggests that paclitaxel is in an amorphous form in the polymer matrix even for up to 30% drug loading. Differential scanning calorimetry (DSC) study further proved that paclitaxel is in a solid solution state in polymer films. In vitro release profile indicates that sustained release of paclitaxel from the films is for more than 85 days, without the tri-phasic release profile typically for PLGA films. The phase contrast images clearly suggests a slight decrease in the number of C6 glioma cells as the paclitaxel loading within the polymeric films is increased. The results of MTT assay employed to quantify the cell viability correlates well with the observation from phase contrast microscopy.

Paclitaxel loading in PLGA nanospheres affected the in vitro drug cell accumulation and antiproliferative activity

BackgroundPTX is one of the most widely used drug in oncology due to its high efficacy against solid tumors and several hematological cancers. PTX is administered in a formulation containing 1:1 Cremophor® EL (polyethoxylated castor oil) and ethanol, often responsible for toxic effects. Its encapsulation in colloidal delivery systems would gain an improved targeting to cancer cells, reducing the dose and frequency of administration.MethodsIn this paper PTX was loaded in PLGA NS. The activity of PTX-NS was assessed in vitro against thyroid, breast and bladder cancer cell lines in cultures. Cell growth was evaluated by MTS assay, intracellular NS uptake was performed using coumarin-6 labelled NS and the amount of intracellular PTX was measured by HPLC.ResultsNS loaded with 3% PTX (w/w) had a mean size < 250 nm and a polydispersity index of 0.4 after freeze-drying with 0.5% HP-Cyd as cryoprotector. PTX encapsulation efficiency was 30% and NS showed a prolonged drug release in vitro. An increase of the cytotoxic effect of PTX-NS was observed with respect to free PTX in all cell lines tested.ConclusionThese findings suggest that the greater biological effect of PTX-NS could be due to higher uptake of the drug inside the cells as shown by intracellular NS uptake and cell accumulation studies.

Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel

Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)- N, N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50% (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 µg/mL to 86 µg/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH sensitivity, which was clearly observed at relatively high AA contents and pH > 6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH = 6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH = 1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery.