Carrier For Delivery Of Paclitaxel Research Articles

Synthesis and characterization of paclitaxel-imprinted microparticles for controlled release of an anticancer drug

In this study, novel molecularly imprinted polymer (MIP) microparticles containing methacryl polyhedral oligomeric silsesquioxane (M-POSS) were synthesized through the RAFT precipitation polymerization (RAFTPP) method using paclitaxel (PTX) as the templates. During the course of this investigation, methacrylic acid (MAA) was used as the functional monomer, while ethylene glycol dimethacrylate (EGDMA) was utilized as a cross-linker. The effects of different molar ratios of M-POSS on the microparticles were characterized. The obtained MIP microparticles were confirmed by FT-IR and TGA-DSC. The results of SEM showed regular spherical-shaped MIP microparticles with diameters around 170–490 nm. The PTX loading quantity was closely correlated with the content of M-POSS, and the MIP microparticles showed a satisfactory affinity to PTX with high drug loading (17.1%) and encapsulation efficiency (85.5%). Moreover, these MIP microparticles were sensitive to pH, and consequently the release rates of PTX at pH 5 were much faster than those at pH 7 due to the acid cleavage of the hydrogen bonds. In addition, the results from release experiments of the MIP microparticles showed a very slow and controlled release of PTX, which heralded promising potential as a carrier for PTX delivery in cancer therapy.

Polyacrylamide–b-copolypeptide hybrid copolymer as pH-responsive carrier for delivery of paclitaxel: Effects of copolymer composition on nanomicelles properties, loading efficiency and hemocompatibility

In the current study, a series of pH-responsive di/tri-block copolymers of poly N-(2-hydroxypropyl) methacrylamide–b-poly histidine/poly leucine (pHPMA-pHis/pLeu) were developed through sequential RAFT and ring-opening polymerization. Chemical structure of the synthesized copolymers was studied by FT-IR and 1H NMR spectroscopy and their molecular weight was characterized by size exclusion chromatography (SEC). The study of dynamic light scattering (DLS) revealed that copolymers could self-assemble into nanomicelles with particle size (PS) of 96–233nm which increased in acidic media. Higher fpLeu and fpLeu/fpHis led to significantly smaller PS and CMC values, respectively. Higher CMC values, together with zeta potential reversal at acidic pH and having buffering activity at pH range of about 6–8 were indications of protonation of imidazole groups of histidine residues and pH-sensitiveness of hybrid copolymers. Atomic force microscopy also proved the DLS data. Hemocompatibility assay demonstrated that while only tri-block copolymers caused hemolysis at neutral pH, all copolymers caused significant hemolysis at low concentrations at pH 5.2 and pLeu had opposite effects on hemolysis percent at different pH values. Paclitaxel was efficiently loaded in nanomicelles with highest loading efficiency (LE) of 75% which was influenced by the composition of the copolypeptide block. PTX-loaded micelles of tri-block copolymer 5-5-3 showed accelerated PTX release in endosomal pH. In conclusion, the optimum designed copolymer can be considered as a good pH-sensitive candidate for drug delivery to solid tumors.

A biomimetic and pH-sensitive polymeric micelle as carrier for paclitaxel delivery.

As nano-scale drug delivery systems, smart micelles that are sensitive to specific biological environment and allowed for target site-triggered drug release by reversible stabilization of micelle structure are attractive. In this work, a biocompatible and pH-sensitive copolymer is synthesized through bridging poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) block and poly (D, L-lactide) (PLA) block by a benzoyl imine linkage (Blink). Biomimetic micelles with excellent biocompatibility based on such PLA-Blink-PMPC copolymer are prepared as carriers for paclitaxel (PTX) delivery. Due to the rapid breakage of the benzoyl imine linkage under acidic condition, the micelle structure is disrupted with accelerated PTX release. Such pH-sensitive triggered drug release behavior in synchronization with acidic conditions at tumor site is helpful for improving the utilization of drug and facilitating antitumor efficacy. These micelles can be used as promising drug delivery systems due to their biocompatible and smart properties.

D-α-tocopherol polyethylene glycol succinate-based derivative nanoparticles as a novel carrier for paclitaxel delivery.

Paclitaxel (PTX) is one of the most effective antineoplastic drugs. Its current clinical administration Taxol® is formulated in Cremophor EL, which causes serious side effects. Nanoparticles (NP) with lower systemic toxicity and enhanced therapeutic efficiency may be an alternative formulation of the Cremophor EL-based vehicle for PTX delivery. In this study, novel amphipathic 4-arm-PEG-TPGS derivatives, the conjugation of D-α-tocopherol polyethylene glycol succinate (TPGS) and 4-arm-polyethylene glycol (4-arm-PEG) with different molecular weights, have been successfully synthesized and used as carriers for the delivery of PTX. These 4-arm-PEG-TPGS derivatives were able to self-assemble to form uniform NP with PTX encapsulation. Among them, 4-arm-PEG5K-TPGS NP exhibited the smallest particle size, highest drug-loading efficiency, negligible hemolysis rate, and high physiologic stability. Therefore, it was chosen for further in vitro and in vivo investigations. Facilitated by the effective uptake of the NP, the PTX-loaded 4-arm-PEG5K-TPGS NP showed greater cytotoxicity compared with free PTX against human ovarian cancer (A2780), non-small cell lung cancer (A549), and breast adenocarcinoma cancer (MCF-7) cells, as well as a higher apoptotic rate and a more significant cell cycle arrest effect at the G2/M phase in A2780 cells. More importantly, PTX-loaded 4-arm-PEG5K-TPGS NP resulted in a significantly improved tumor growth inhibitory effect in comparison to Taxol® in S180 sarcoma-bearing mice models. This study suggested that 4-arm-PEG5K-TPGS NP may have the potential as an anticancer drug delivery system.

PEG-Farnesylthiosalicylate Conjugate as a Nanomicellar Carrier for Delivery of Paclitaxel

S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a potent and especially nontoxic Ras antagonist. It inhibits both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. In this work, an FTS conjugate with poly(ethylene glycol) (PEG) through a labile ester linkage, PEG5K-FTS2(L), was developed. PEG5K-FTS2 conjugate readily forms micelles in aqueous solutions with a critical micelle concentration of 0.68 μM, and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these particles. Both drug-free and PTX-loaded micelles were spherical in shape with a uniform size of 20-30 nm. The release of PTX from PTX-loaded PEG5K-FTS2 micelles was significantly slower than that from Taxol formulation. In vitro cytotoxicity studies with several tumor cell lines showed that PEG5K-FTS2(L) was comparable to FTS in antitumor activity. Western immunoblotting showed that total Ras levels were downregulated in several cancer cell lines treated with FTS or PEG5K-FTS2(L). The micellar formulation of PTX exhibited more in vitro cytotoxic activity against several tumor cell lines compared with free PTX, suggesting a possible synergistic effect between the carrier and the codelivered drug. The antitumor activity of the PTX loaded PEG5K-FTS2(L) micelles in a syngeneic murine breast cancer model was found to be significantly higher than that of Taxol, which may be attributed to their preferential tumor accumulation and a possible synergistic effect between PEG5K-FTS2 carrier and loaded PTX.

Archaeosome: as new drug carrier for delivery of Paclitaxel to breast cancer.

In the present study, paclitaxel was archaeosomed to reduce side effects and improve its therapeutic index. Carriers have made a big evolution in treatment of many diseases in recent years. Lipid carriers are of special importance among carriers. Archaeosome is one of the lipid carriers. Paclitaxel is one of the drugs used to treat breast cancer which has some unwanted side effects despite its therapeutic effects. Archaeosomes were extracted from methanogenic archi bacteria and synthesized with a certain ratio of paclitaxel in PBS. The mean diameter of archaeosomal paclitaxel was measured by Zeta sizer instrument, Drug releasing of archaeosomal paclitaxel was examined within 26h which results showed that the most drug releasing occurs during first 3h. The cytotoxicity effect of archaeosomal paclitaxel on breast cancer's cell line was evaluated by MTT assay which results showed that the cytotoxicity effect of archaeosomal paclitaxel on breast cancer's cell line is more than that of the standard paclitaxel formulation. The results indicated that new drug delivery of paclitaxel using archaeosome, increases the therapeutic index of the drug.

PEG-derivatized embelin as a nanomicellar carrier for delivery of paclitaxel to breast and prostate cancers

Paclitaxel (PTX) is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its therapeutic benefit is often limited by severe side effects. We have developed a micelle-based PTX formulation based on a simple conjugate derived from polyethylene glycol 5000 (PEG5K) and embelin (EB). Embelin is a natural product and exhibits antitumor activity through blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). PEG5K-EB2 conjugate self-assembles to form stable micelles in aqueous solution and efficiently encapsulates hydrophobic drugs such as PTX. PEG5K-EB2 micelles have a relatively low CMC of 0.002 mg/mL (0.35 μm) with sizes in the range of 20 ∼ 30 nm with or without loaded PTX. In vitro cell uptake study showed that the PEG5K-EB2 micelles were efficiently taken up by tumor cells. In vitro release study showed that PTX formulated in PEG5K-EB2 micelles was slowly released over 5 days with much slower release kinetics than that of Taxol formulation. PTX formulated in PEG5K-EB2 micelles exhibited more potent cytotoxicity than Taxol in several cultured tumor cell lines. Total body near infrared fluorescence (NIRF) imaging showed that PEG5K-EB2 micelles were selectively accumulated at tumor site with minimal uptake in major organs including liver and spleen. PTX-loaded PEG5K-EB2 micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of 100–120 mg PTX/kg in mice, which was significantly higher than that for Taxol (15–20 mg PTX/kg). Finally, PTX formulated in PEG5K-EB2 micelles showed superior antitumor activity compared to Taxol in murine models of breast and prostate cancers.