Paclitaxel Loading Research Articles

Computer Optimization of Stealth Biodegradable Polymeric Dual-loaded Nanoparticles for Cancer Therapy Using Central Composite Face-centered Design.

Combination chemotherapy capable of overcoming cancer drug resistance can be facilitated by nanotechnology. Synthesis, characterization, statistical experimental design, analysis and optimization of stealth pH-sensitive polymeric nanoparticles suitable as a platform for simultaneous delivery of paclitaxel and 17-AAG in breast cancer therapy were investigated. An acetal crosslinker and a poly(ɛ)caprolactone macromonomer were synthesized and characterized. The statistical experimental design used was the response surface method (RSM). We used the central composite face-centered design (CCF) in three independent factors and seventeen runs. Nanoparticles were fabricated by dispersion polymerization techniques. Response variables evaluated were: particle size, drug loading, encapsulation efficiency, and in vitro availability. Scanning electron micrographs showed the formation of spherical nanoparticles. Computer software was used for the analysis of variance with a 95% confidence level and Q2 (goodness of prediction) to select an appropriate model for each of the response variables. Each term in each of the models was tested for the significance of the regression coefficients. The computer software optimizer was used for optimization to select factor combination to minimize particle size, time (h) for maximum release of paclitaxel and 17-AAG, to maximize paclitaxel and 17-AAG loading efficiency and to maximize paclitaxel and 17-AAG encapsulation efficiency. The optimization was successful, as shown by the validation data which lie within the confidence intervals of predicted values of the response variables. The selected factor combination is suitable for the in vivo evaluation of the nanoparticles loaded with paclitaxel and 17-AAG.

Cell-Penetrating Peptide and α-Tocopherol-Conjugated Poly(amidoamine) Dendrimers for Improved Delivery and Anticancer Activity of Loaded Paclitaxel.

Even though existing chemotherapeutic agents, including paclitaxel (PTX), possess superior anticancer activity, their application is limited because of extreme hydrophobicity. Here, a dendrimer-based nanoparticles system has been prepared for improved delivery of loaded paclitaxel to the tumor. The cell-penetrating peptides, octa-arginine (R) and vitamin-E succinate (VES), had been conjugated to the PEGylated generation 4 polyamidoamine dendrimer (D) to form RVES-PD. The synthesized polymers had been characterized by 1NMR, IR, and gel permeation chromatography. The PTX-loaded RVES-PD (RVES-PD-PTX) was physicochemically characterized for particle size, zeta potential analysis, drug loading, release, and encapsulation studies. Cellular uptake, cytotoxicity, and apoptosis determination studies were carried out in human lung cancer cells (A549) in monolayers and spheroids. In vivo antitumor efficacy of RVES-PD-PTX was determined using B16F10 tumor-bearing mice. The results indicated that the RVES-PD nanoparticles were taken up by cancer cells effectively and demonstrated improved cellular translocation compared to nontargeted VES-PD. The cytotoxicity study revealed that RVES-PD-PTX exhibited the highest cytotoxicity of PTX compared to nontargeted VES-PD-PTX and free PTX in the PTX concentration range of 0-50 μg/mL. RVES-PD-PTX-induced apoptosis as analyzed by the Annexin V assay and suppressed the growth of spheroids to the highest extent compared to VES-PD-PTX and free PTX. Furthermore, the biodistribution study indicated that the RVES-PD had higher accumulation in tumor compared to VES-PD. The in vivo experiment using B16F10 tumor-bearing mice demonstrated that the RVES-PD treatment resulted in the highest rate of tumor volume reduction and apoptosis primarily by upregulating caspase 3/7 to the highest extent compared to VES-PD and free PTX. In conclusion, the developed RVES-PD could load PTX and showed efficient cell penetration and improved PTX-mediated cytotoxicity in all tested in vitro and in vivo assay systems. The results strongly suggest further exploration of this developed PTX-nanoformulation in cancer treatment.

Novel Surface Modification of ZnO QDs for Paclitaxel-Targeted Drug Delivery for Lung Cancer Treatment.

Adipic dihydrazide and heparin were attached to ZnO quantum dots surface, and the ZnO-adipic dihydrazide-heparin nanocomplex was used as a drug delivery system to deliver paclitaxel for chemotherapy. The surface modification and the loading of paclitaxel were confirmed by Fourier transform infrared spectrum, featured by characteristic peaks from functional groups of adipic dihydrazide, heparin, and paclitaxel. The impacts of pH on the drug release were investigated, and the cytotoxicity studies were conducted with A549 cells. The pharmacokinetic study was conducted with male Wistar rats. Both in vitro and in vivo study indicated that ZnO-adipic dihydrazide-heparin-paclitaxel nanocomplex could deliver paclitaxel in a more controllable way, and it has the potential to be a high-efficiency drug delivery system for cancer treatment.

Glycol chitosan in situ coating on PLGA nanoparticle curtails extraneous paclitaxel precipitates and imparts protein corona independent hemocompatibility

Poly (lactide-co-glycolide) (PLGA) nanoparticles surface functionalized with water soluble glycol chitosan (GC) and carboxymethyl chitosan (CMC) has been studied for their drug (Paclitaxel and Doxorubicin) loading, yield, cellular uptake, serum protein adsorption and hemocompatibility. It was observed that Paclitaxel (Ptxl) phase out as Extraneous Ptxl Precipitates (EPP) (>25 %) in case of uncoated and CMC coated low molecular weight (LMW) PLGA nanoparticles (PNPs). The EPP formation was significantly reduced to ∼5 % with GC coating as it enhanced LMW PLGA precipitation and yield predominantly spherical polymeric nanoparticles towards better encapsulation of Ptxl and thus uniform intracellular drug distribution. Interestingly, protein corona analysis showed cmcPNPs and gcPNPs to be distinct from each other in associating mainly with serum proteins of molecular weight < 30 kDa and >30 kDa respectively. While CMC functionalization showed >10 % hemolysis, at similar concentration GC coating was found to provide superior hemocompatibility even in the absence of protein corona.

Self-assembly of oxidation-responsive polyethylene glycol-paclitaxel prodrug for cancer chemotherapy

Amphiphilic drug conjugates can self-assemble into nanovehicles for cancer drug delivery, but the key is to design stable yet intracellular labile drug linkers for drug retention during blood circulation but fast intracellular drug release. The conjugation of paclitaxel (PTX) is generally via the ester of its 2′-hydroxyl group, but the ester is either too stable to release PTX in the cytosol or so labile that hydrolyzes during circulation. Herein, we report a p-(boronic ester)benzyl-based tumor-specifically cleavable linker for preparing PTX-conjugate with polyethylene glycol (PEG, Mw = 5000 Da) (PEG-B-PTX). The amphiphilic PEG-B-PTX self-assembled into micelle with an average size of ~50 nm and a PTX loading content of 13.3 wt%. The PEG-B-PTX micelles were very stable at the normal physiological environment and thus circulated long in the blood compartment, but fast dissociated and released PTX in response to the elevated reactive‑oxygen species (ROS) level in tumors. The conjugate micelles showed significantly improved antitumor efficiency in vitro and in vivo against human glioma and breast cancer cells, and reduced toxicity compared to the clinically used Taxol. Thus, the PTX-conjugate micelles were characteristic of well-characterized chemical structure and nanostructure, precise and reproducible drug loading efficiency (i.e., 100%) and fixed loading content, high PTX loading content due to PTX itself as part of the carrier, no burst drug release, and easy and reproducible fabrication of the micelles, which are all essential for clinical translation.

Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy

Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD50. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.

Synergistic enhancement of cytotoxicity against cancer cells by incorporation of rectorite into the paclitaxel immobilized cellulose acetate nanofibers

Current studies have shown that many natural substances have important effects on the treatment and prevention of diseases. Paclitaxel is one of them, which has been proved to be a potential anti-neoplastic agent. Rectorite is also a kind of natural layered silicate, which can be used in biomedical area. Cellulose acetate is an ideal drug carrier with excellent biocompatibility and can be easily fabricated into nanofibers via electrospinning. In this work, electrospinning technology was used to load paclitaxel and rectorite into cellulose acetate nanofibers. The introduction of rectorite facilitated the fixation of paclitaxel without changing the thermal performance of the nanofibrous mats. After the addition of rectorite in the mats, although the release rate of paclitaxel from the nanofibrous mats was decreased, the cytotoxicity of human gastric adenocarcinoma SGC7901 cells grown on the mats was enhanced, which suggested that rectorite may have potential values in the treatment of gastric cancer in the future. This work may provide some inspiration for using natural substances in tumor treatment.

Erythrocyte-mimicking paclitaxel nanoparticles for improving biodistributions of hydrophobic drugs to enhance antitumor efficacy

Recent decades have witnessed several nanocrystal-based hydrophobic drug formulations because of their excellent performance in improving drug loading and controlling drug release as mediate drug forms in tablets or capsules. However, the intravenous administration of drug nanocrystals was usually hampered by their hydrophobic surface properties, causing short half-life time in circulation and low drug distribution in tumor. Here, we proposed to enclose nanocrystals (NC) of hydrophobic drug, such as paclitaxel (PTX) into erythrocyte membrane (EM). By a series of formulation optimizations, spherical PTX nanoparticles (PN) with the particle size of around 280 nm were successfully cloaked in erythrocyte membrane, resulting in a PTX-NP-EM (PNM) system. The PNM could achieve high drug loading of PTX (>60%) and stabilize the particle size significantly compared to PN alone. Besides, the fluorescence-labeling PNM presented better tumor cell uptake, stronger cytotoxicity, and higher drug accumulation in tumor compared to PN. Finally, the PNM was found to be the most effective against tumor growth among all PTX formulations in tumor-bearing mice models, with much lower system toxicity than control formulation. In general, the PNM system with high drug-loading as well as superior bio-distributions in vivo could be served as a promising formulation.

A Distinctive Nanocomposite Hydrogel Integrated Platform for the Healing of Wound after the Resection of Melanoma

During the surgical removal of melanoma, that the incompletely eradicated cancer cells enter the circulatory system with blood flow will lead to the risk of distant metastasis and then the recurrence of postoperative residual tumor, which will greatly reduce the cure rate. Additionally, microbial resistance makes the problem of infection more serious during defect repair. Considering these problems, we developed a nanocomposite hydrogel (Gel/PF127) with excellent mechanical properties, hemostasis and broad-spectrum antibacterial activity. It was used for the dual release system based on micelles and hydrogel used for maintaining long-term release of paclitaxel (PTX) at the wound site after melanoma surgery, thereby killing residual tumor cells and repairing tissue defects better. The results showed that PF127 nano micelles could effectively load PTX and release it in tumor environment. Moreover, the quaternary ammonium gel network showed excellent growth inhibition for E. coli and S. aureus (more than 98%). The introduction of Ca2+ endowed the gel with excellent hemostatic effect. The combination of reversible chemical bonds and electrostatic interaction made Gel/PF127 have excellent mechanical, tissue adhesion and self-healing properties. The experimental results showed that such nanocomposite hydrogel could stop bleeding quickly and avoid wound infection, induce apoptosis of tumor cells and inhibit their recurrence very effectively, thus suggesting that the construction of in situ chemotherapy platform which integrates trauma repair and tumor inhibition will greatly promote the recurrence inhibition and trauma repair of melanoma. At the same time, it provides a simple and efficient strategy for other cancer postoperative wound healing.

Biomineralized Gd2 O3 @HSA Nanoparticles as a Versatile Platform for Dual-Modal Imaging and Chemo-Phototherapy-Synergized Tumor Ablation.

A great challenge still remains to explore the facile approaches to construct multifunctional nanoparticles for acquiring precise cancer theranostics. Herein, a biocompatible theranostic nanoplatform capable of simultaneous cancer imaging and therapy is attempted by loading of paclitaxel (PTX) and indocyanine green (ICG) molecules into the matrix of Gd2 O3 @human serum albumin (HSA) nanoparticles (PIGH NPs) via hydrophobic interaction. The subsequent in vitro investigations reveal that the PIGH NPs afford uniform particle size, sustained drug release profile, strong longitudinal relaxivity, potent photothermal effect, effective singlet oxygen generation, and ideal resistance to photobleaching. Moreover, the PIGH NPs achieve high cellular uptake, efficient cytoplasmic drug translocation based on singlet oxygen-triggered endolysosomal disruption and prominent cytotoxicity effect against 4T1 cells under 808 nm near-infrared (NIR) irradiation in contrast to PTX/ICG-loaded HSA nanoparticles (PIH NPs) and free PTX/ICG. After intravenous injection, the PIGH NPs exhibit preferable tumor accumulation and achieve effective tumor ablation in 4T1 tumor bearing mouse model with excellent dual near-infrared fluorescence/magnetic resonance (NIRF/MR) imaging guided synergistic chemo-phototherapy. Hence, the PIGH NPs can be utilized as potential theranostic nanosystem for simultaneous cancer imaging and therapy.

A Nanoemulsion with A Porphyrin Shell for Cancer Theranostics.

A nanoemulsion with a porphyrin shell (NewPS) was created by the self-assembly of porphyrin salt around an oil core. The NewPS system has excellent colloidal stability, is amenable to different porphyrin salts and oils, and is capable of co-loading with chemotherapeutics. The porphyrin salt shell enables porphyrin-dependent optical tunability. The NewPS consisting of pyropheophorbide a mono-salt has a porphyrin shell of ordered J-aggregates, which produced a narrow, red-shifted Q-band with increased absorbance. Upon nanostructure dissociation, the fluorescence and photodynamic reactivity of the porphyrin monomers are restored. The spectrally distinct photoacoustic imaging (at 715 nm by intact NewPS) and fluorescence increase (at 671 nm by disrupted NewPS) allow the monitoring of NewPS accumulation and disruption in mice bearing KB tumors to guide effective photodynamic therapy. Substituting the oil core with Lipiodol affords additional CT contrast, whereas loading paclitaxel into NewPS facilitates drug delivery.

Mucoadhesive paclitaxel-loaded chitosan-poly (isobutyl cyanoacrylate) core-shell nanocapsules containing copaiba oil designed for oral drug delivery

The development of drug delivery systems for potent anticancer drugs like paclitaxel remains a challenger. The aim of this work was to study the mucoadhesive properties of paclitaxel-loaded chitosan-poly (isobutyl cyanoacrylate) core-shell nanocapsules designed for oral drug delivery. Using an experimental design approach, the nanocapsules were produced and, then, physicochemically characterized. Mucoadhesion assays were performed in-vitro by the aggregation test with mucin and ex-vivo, in Ussing Chamber, using freshly excised rat intestinal mucosa. [3H]-paclitaxel dosages were carried out by liquid scintillation. Paclitaxel-loaded nanocapsules showed a mean hydrodynamic diameter of 470 nm with low polydispersity index and spherical form. Encapsulation efficiency and drug loading of paclitaxel were 74 ± 1% and 1.70 ± 0.02%, respectively. After drying, nanocapsules could be redispersed with no changes on their nanostructure. Dispersions of nanocapsules were stable in simulated gastric medium for 120 min, and after six months of storage at 4 °C. They showed interesting mucoadhesive properties with mucins and good association (9%) with the intestinal mucosa of the rat. Taking together, results from the present work are encouraging to pursue the development of chitosan-coated nanocapsules for oral delivery of paclitaxel as a new treatment for cancer with possible synergetic anticancer effect with the therapeutically active components found in copaiba oil.

Computer-assisted engineering of programmed drug releasing multilayer nanomedicine via indomethacin-mediated ternary complex for therapy against a multidrug resistant tumor

Nanomedicine with programmed drug release can give full play to the synergistic effect of multi-component system in complicated tumor environment. However, the construction of these programmed drug delivery systems often depends on the sophisticated materials design and synthesis. In this study, we successfully designed an indomethacin (IND)-mediated ternary complex system based on a PEG cleavable polyethyleneimine (PEI), indomethacin (IND) and benzene ring containing chemotherapeutic drugs (such as paclitaxel (PTX), doxorubicin and docetaxel). Based on the difference of hydrophobicity in these components, these components were one-pot self-assembled into drug-loaded IND mediated PEGylation cleavable nanoassemblies (IPCNs) in multilayer structure. In drug-loaded IPCNs, PEG fragments, PEI/IND, and chemotherapeutic drug were respectively distributed from the out layer to core of nanomedicine. When drug-loaded IPCNs reached tumor site through EPR effect, the PEG fragment would firstly responsively release to the acidic tumor microenvironment to expose the intermediate layer of drug-loaded IPCNs that composed by mixture of PEI and IND for increasing the surface potential to promote the uptake by tumor cells. After entering cells, IND would be released faster than chemotherapeutic drug encapsulated in core to efficiently inhibit the expression of multidrug resistance protein 1 to reverse MDR of tumor cells before chemotherapeutic drug releasing. Contributed by the staged responsively releasing of PEG fragments, IND and encapsulated chemotherapeutic drug, the drug-loaded IPCNs exhibited a superior antitumor efficacy against A549/MDR tumor cells both in vitro and in vivo. Statement of SignificanceThe way to develop programmed released drug delivery system is commonly relied on complicated material design and synthesis. Herein, under the computer-assist design, we successfully designed a ternary complex derived from indomethacin (IND), paclitaxel (PTX) and a pH-responsive PEGylated polyethyleneimine (PEG-s-PEI), and employed this ternary complex to successfully prepare a high drug loading and multilayer structured nanomedicine of PTX (PTX IPCNs). Contribute by the different location of PTX, IND and PEG-s-PEI in PTX IPCNs, PEG fragments, IND and PTX molecules could programmed release after reaching tumor for perfectly realizing the synergistic anti-tumor effect of tumor targeting, reversal of MDR and chemotherapy. Based on a fusion of these multiple mechanisms, PTX IPCNs showed a superior antitumor efficacy in mice loading A549/MDR tumor.

Abstract 3623: Mesenchymal stem cells engineered with TAT peptide functionalized nanoparticles improve therapeutic efficacy of paclitaxel in an orthotopic lung tumor model

Abstract Tumors are characterized by uneven vascular perfusion with near normal blood flow in the outer most regions, while the inner regions can be avascular. In addition, elevated interstitial fluid pressure and rigid extracellular matrix compromise intra-tumoral solute transport and hence limited drug efficacy. Mesenchymal stem cells (MSCs) have the unique advantage of being able to migrate specifically to both primary tumors and metastases following systemic administration. However, poor payload capacity of MSCs limits their use as drug delivery carriers. To address this issue, we investigated polymeric nanoparticles that were functionalized with transactivator of transcription (TAT) peptide. Paclitaxel loaded PLGA nanoparticles (15-16 % w/w paclitaxel; diameter of 225 ± 7 nm; and zeta potential of −15 ± 4 mV) were prepared by emulsion-solvent evaporation method, followed by TAT-conjugation to the surface of nanoparticles via maleimide-thiol chemistry. Nanoengineered MSCs were generated by incubating MSCs in suspension with 100 µg/mL paclitaxel loaded nanoparticles for 4 hours at 37°C. Our studies demonstrated that TAT functionalization improved the paclitaxel loading in MSCs. In addition, engineering MSCs with TAT functionalized nanoparticles did not affect the differentiation and migration properties of MSCs. Further, MSCs engineered with TAT peptide functionalized nanoparticles resulted in significant inhibition of tumor growth and overall improved survival in a mouse orthotopic model of lung cancer compared to that with free drug treatment. In summary, our results demonstrated that MSCs nanoengineered using TAT functionalized nanoparticles can serve as an efficient carrier for tumor specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy. Citation Format: Swayam Prabha, Gopikrishna Moku, Buddhadev Layek, Jayanth Panyam. Mesenchymal stem cells engineered with TAT peptide functionalized nanoparticles improve therapeutic efficacy of paclitaxel in an orthotopic lung tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3623.

A supramolecular co-delivery strategy for combined breast cancer treatment and metastasis prevention

We herein propose a co-delivery approach where small interference RNA (siRNA) and anticancer chemotherapeutic drug are simultaneously loaded into a single delivery carrier for the combined treatment of breast cancer and metastasis prevention. The co-delivery vector is composed of chondroitin sulfate (CS)-coated β-cyclodextrin-polyethylenemine polymer, which is capable of loading paclitaxel (PTX) and siRNA simultaneously to form therapeutic nanocomplexes. The nanocomplex, termed as CP-PTX-siCD146-CS, is demonstrated to have strong active targeting ability towards CD44-overexpresing breast cancer cells. Moreover, the co-delivery of PTX and siRNA not only effectively inhibits cancer cells proliferation and induces apoptosis, but also well prevents metastasis. Importantly, CP-PTX-siCD146-CS nanocomplexes exhibit stronger cytotoxic effects and anti-metastatic effects on MBA-MD-231 breast cancer cells, in comparison with PTX or siCD146 mono-treatment. The current study defines a potential therapeutic strategy for the combined breast cancer treatment and metastasis prevention from a co-delivery perspective.

Preparation of Peppermint Oil-Based Nanodevices Loaded with Paclitaxel: Cytotoxic and Apoptosis Studies in HeLa Cells.

In this work, several normal, oil-in-water (o/w) microemulsions (MEs) were prepared using peppermint essential oil, jojoba oil, trans-anethole, and vitamin E as oil phases to test their capacity to load paclitaxel (PTX). Initially, pseudo-ternary partial phase diagrams were constructed in order to find the normal microemulsion region using d-α-tocopherol polyethylene glycol 1000 succinate (TPGS-1000) as surfactant and isobutanol (iso-BuOH) as co-surfactant. Selected ME formulations were loaded with PTX reaching concentrations of 0.6mgmL-1 for the peppermint oil and trans-anethole MEs, while for the vitamin E and jojoba oil MEs, the maximum concentration was 0.3mgmL-1. The PTX-loaded MEs were stable according to the results of heating-cooling cycles and mechanical force (centrifugation) test. Particularly, drug release profile for the PTX-loaded peppermint oil ME (MEPP) showed that ∼ 90% of drug was released in the first 48h. Also, MEPP formulation showed 70% and 90% viability reduction on human cervical cancer (HeLa) cells after 24 and 48h of exposure, respectively. In addition, HeLa cell apoptosis was confirmed by measuring caspase activity and DNA fragmentation. Results showed that the MEPP sample presented a major pro-apoptotic capability by comparing with the unloaded PTX ME sample.

Nano-Carriers Based on pH-Sensitive Star-Shaped Copolymers for Drug-Controlled Release.

Polymeric nano-carriers are considered as promising tools in biomedical applications due to multiple attractive characteristics including their low toxicity, high loading capacity, controlled drug release capabilities, and highly tunable chemical properties. Here, a series of pH-sensitive star-shaped copolymers, Ad-P[(EMA-co-MAA)-b-PPEGMA]4, was prepared via electron transfer atom radical polymerization (ARGETE ATRP) and selective hydrolysis. These star-shaped copolymers can be self-assembled into micelles (Dh = 150–160 nm) and their critical micelle concentrations (CMC) were estimated to be 3.9–5.0 mg/L. The pH-sensitiveness of the micelles was evidenced by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The maximal paclitaxel (PTX) loading efficiency (DLC) and entrapment efficiency (EE) were 18.9% and 36%, respectively. In vitro release studies revealed that about 19% of the PTX released at an acidic condition of pH 1.2 over 70 h, whereas more than 70% was released within the same time interval at pH 6.8. In vitro cytotoxicity suggested that the low cytotoxicity of the blank micelles, while the PTX-loaded micelles providing the cytotoxicity close to that of free PTX. These results indicated that this novel pH-sensitive nano-carriers have great potential applications for oral drug-controlled release.

Redox-sensitive micelles based on retinoic acid modified chitosan conjugate for intracellular drug delivery and smart drug release in cancer therapy

Novel chitosan-cystamine-retinoic acid conjugate (CS-SS-RA) was synthesized and could self-assemble into redox-sensitive micelles in aqueous environment with low critical micelle concentration value. CS-SS-RA micelles were characterized with spherical shape, desirable particle size, negative zeta potential, high paclitaxel (PTX) loading and encapsulation efficiency and redox-sensitivity. Hemolysis and cytotoxicity studies proved the safety of CS-SS-RA micelles for intravenous administration. Cytotoxicity study against HepG2 cells and the growth inhibition study on three-dimensional multicellular tumor spheroids (MCTSs) revealed that PTX-loaded CS-SS-RA micelles exhibited higher antitumor activity than free PTX. The in vitro cellular uptake profiles of FITC-labeled CS-SS-RA micelles evaluated via confocal laser scanning microscopy and flow cytometry indicated that CS-SS-RA micelles could enhance cellular uptake efficiency of PTX, and their internalization by HepG2 cells were mediated by clathrin-mediated endocytosis and macropinocytosis. These results demonstrated that CS-SS-RA micelles could be developed as a promising platform for intracellular delivery of hydrophobic antitumor agents.

The effect of surfactants modification on nanocrystalline cellulose for paclitaxel loading and release study

The Nanocrystalline cellulose (NCC) was prepared from filter paper by acid hydrolysis process. The modification of NCC with cationic, anionic, and nonionic surfactant did not have a tremendous effect on the chemical structure of material based on the characterization of XRD and FTIR. The modified NCCs were employed as a drug carrier for paclitaxel (PTX). Increasing concentration of ionic surfactants can enhance the loading of the hydrophobic drug, while the opposite trend was observed for nonionic surfactant modified nanocrystals. The attachment of surfactant toward the particle was a more likely physical aggregation of micelle on the surface of nanocrystals. Larger particle size was observed after the modification of nanocrystal cellulose. The fitting of Higuchi and sigmoidal models were applied in the release profile to investigate the kinetic release mechanism of paclitaxel at pH 5.8 and 7.4. Cell viability was determined to check the biocompatibility of the materials toward mouse osteoblast cells 7F2 using MTT assay. Toxic behavior was not observed for NCC, while CTAB was completely not compatible with cells.

Correlation between Drug Loading Content and Biological Activity: The Complexity Demonstrated in Paclitaxel-Loaded Glycopolymer Micelle System.

Drug delivery carriers are now widely established because they can increase the therapeutic efficiency of drugs. In general, the aim in this field is to create effective carriers that have large amounts of drugs loaded to minimize drug carrier material that needs to be disposed of. However, there has been little attention so far in the literature on the effect of the amount of loaded drugs on the biological activity. In this paper, we are trying to answer the question of how the drug-loading content will affect the in vitro activity. We use two methods to load paclitaxel (PTX) into micelles based on the glycopolymer, poly(1- O-methacryloyl-β-d-fructopyranose)- block-poly(methyl methacylate) (Poly(1- O-MAFru)35- b-PMMA145). In the one-step method, the drug is loaded into the particles during the self-assembly process. However, the size of nanoparticle increased with the PTX content from 26 to 50 nm, triggering enhanced cellular uptake by MCF-7 and MDA-MB-231, which was caused by changes in diameter size and not by changes in drug concentration. To keep the nanoparticle size constant, preformed micelles were loaded with PTX (two-step process). The increasing amount of loaded drug led to decreased cellular uptake and reduced cytotoxicity by the cancer cell lines. Small-angle neutron scattering and small-angle X-ray scattering, supported by transmission electron microscopy and dynamic light scattering, exposed the PTX location in the shell. This caused shrinkage of the shell and lower levels of shell hydration, resulting in lower cellular uptake and lower cytotoxicity. Upon the release of PTX, the shell regained its original level of hydration. We could show that because drug loading causes morphology changes, in either the shell or the size, it is impossible to separate the parameters that will influence the biological activity. Although the same phenomenon may not apply to every drug delivery system, it needs to be considered that except for the well-known parameters that affect cell uptake-size, shape, surface chemistry, type of nanoparticle, and presence of bioactive groups-the amount of loaded drugs might change the physicochemical parameters of the nanoparticle and thus the in vitro and potentially the in vivo outcomes.