Release Of Paclitaxel Research Articles

Smart releasing electrospun nanofibers—poly: L.lactide fibers as dual drug delivery system for biomedical application

An ongoing challenge in drug delivery systems for a variety of medical applications, including cardiovascular diseases, is the delivery of multiple drugs to address numerous phases of a treatment or healing process. Therefore, an extended dual drug delivery system (DDDS) based on our previously reported cardiac DDDS was generated. Here we use the polymer poly(L-lactide) (PLLA) as drug carrier with the cytostatic drug Paclitaxel (PTX) and the endothelial cell proliferation enhancing growth factor, human vascular endothelial growth factor (VEGF), to overcome typical in-stent restenosis complications. We succeeded in using one solution to generate two separate DDDS via spray coating (film) and electrospinning (nonwoven) with the same content of PTX and the same post processing for VEGF immobilisation. Both processes are suitable as coating techniques for implants. The contact angle analysis revealed differences between films and nonwovens. Whereas, the morphological analysis demonstrated nearly no changes occurred after immobilisation of both drugs. Glass transition temperatures (Tg ) and degree of crystallinity (χ) show only minor changes. The amount of immobilised VEGF on nonwovens was over 300% higher compared to the films. Also, the nonwovens revealed a much faster and over three times higher PTX release over 70 d compared to the films. The almost equal physical properties of nonwovens and films allow the comparison of both DDDS independently of their fabrication process. Both films and nonwovens have significantly increased in vitro cell viability for human umbilical vein endothelial cells (EA.hy926) with dual loaded PTX and VEGF compared to PTX-only loaded samples.

Macrophage-Membrane-Camouflaged Disintegrable and Excretable Nanoconstruct for Deep Tumor Penetration.

The consolidation of nanovectors with biological membranes has recently been a subject of interest owing to the prolonged systemic circulation time and delayed clearance by the reticuloendothelial system of such systems. Among the different biomembranes, the macrophage membrane has a similar systemic circulation time, with an additional chemotactic aptitude, targeting integrin proteins. In this study, we aimed to establish a laser-activated, disintegrable, and deeply tumor-penetrative nanoplatform. We used a highly tumor-ablative and laser-responsive disintegrable copper sulfide nanoparticle, loaded it with paclitaxel, and camouflaged it with the macrophage membrane for the fabrication of PTX@CuS@MMNPs. The in vitro paclitaxel release profile was favorable for release in the tumor microenvironment, and the release was accelerated after laser exposure. Cellular internalization was improved by membrane encapsulation. Cellular uptake, cytotoxicity, reactive oxygen species generation, and apoptosis induction of PTX@CuS@MMNPs were further improved upon laser exposure, and boosted permeation was achieved by co-administration of the tumor-penetrating peptide iRGD. In vivo tumor accumulation, tumor inhibition rate, and apoptotic marker expression induced by PTX@CuS@MMNPs were significantly improved by laser irradiation and iRGD co-administration. PTX@CuS@MMNPs induced downregulation of cellular proliferation and angiogenic markers but no significant changes in body weight, survival, or significant toxicities in vital organs after laser exposure, suggesting their biocompatibility. The disintegrability of the nanosystem, accredited to biodegradability, favored efficient elimination from the body. In conclusion, PTX@CuS@MMNPs showed promising traits in combination therapies for excellent tumor eradication.

A Novel Targeted Co-Delivery Nanosystem for Enhanced Ovarian Cancer Treatment Via Multidrug Resistance Reversion

Multidrug resistance (MDR) is a major challenge in successful chemotherapy treatment of ovarian cancer patients, and 50%–75% of ovarian cancer patients eventually relapse because of MDR. One of an effective strategy for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. This study developed a novel hyaluronic acid (HA)-targeted co-delivery nanosystem using functionalized mesoporous silica nanoparticle–coated gold nanorods (HA-PTX/let-7a-GNR@MSN) to co-deliver paclitaxel (PTX), a hydrophobic chemotherapy drug, and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. We also analyzed the molecular mechanism of miR let-7a in ovarian cancer treatment. The nanosystem enabled protective drug delivery and stable binding of PTX and miRs. Analysis of drug-resistant SKOV3TR cells and an SKOV3TR xenograft model in BALB/c-nude mice showed significant P-glycoprotein downregulation in heterogeneous tumor sites, PTX release, and apoptosis induction later. Results showed that HA-modified nanocomposites can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3 TR cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. More importantly, this nanosystem resulted in synergistic inhibition of ovarian tumor growth. Overall, the data provide a model for overcoming PTX resistance in ovarian cancer.

Abstract PO-216: Design, fabrication, and evaluation of dual-loaded biodegradable nanoparticles for breast cancer treatment

Abstract Introduction: The purpose of this study was to design, fabricate and determine the cytotoxic effects of dual-loaded (paclitaxel and 17-AAG) stealth polymeric nanoparticles. HSP90 inhibitors, such as 17-AAG, sensitize lung and breast cancer cells to paclitaxel induced cytotoxicity both in vitro and in vivo. Concurrent exposure to 17-AAG and paclitaxel is required for the synergistic activity of the two drugs. Further, clinical evaluations of 17-AAG in combination with approved therapies such trastuzumab and other drugs have shown enhancement or synergistic effects. Stealth nanoparticles are capable of providing site-specific tumor targeting thereby reducing toxicity in healthy cell, improving the solubility of anticancer drugs and synchronizing the disposition of encapsulated drugs (varying biodistribution/pharmacokinetics of combination drugs through cocktail administration has been attributed to their ineffectiveness in the clinic). Further, therapeutic nanoparticles could overcome drug resistance due to P-glycoprotein efflux pump. The stealth property of nanoparticles (PEG on the surface) will prevent capture by the reticuloendothelial system (RES) and will facilitate tethering ligands (mAbs) to the surface of the nanoparticles for receptor mediated endocytosis (active targeting). Dose reduction coupled with a better quality of life during treatment would also improve patient compliance. Experimental Procedures: A central composite face-centered statistical experimental design (CCF) in three independent factors and seventeen runs was implemented for the fabrication nanoparticles by dispersion polymerization technique using biodegradable poly-ϵ-caprolactone and a pH (acid) sensitive crosslinker, followed by computer optimizations. Numerical and graphical optimizations were carried out to select the factor combination to minimize the particle size, to minimize the 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 optimal formulation was used for nanoparticle fabrication for biological studies in SKBR3 cell line (HER-2- overexpressing human breast cancer cell line) and MCF7 cell line (human breast cancer cell line). Results and Conclusion: The dispersion polymerization method was successfully used to fabricate an optimized dual-loaded nanoparticle formulation using an acid (pH) sensitive crosslinker and a macromonomer. The cytotoxic effects of the paclitaxel treatment and that of the drug combination (free drugs or nanoparticles) observed were similar in both SKBR3 and MCF7 cell lines suggesting synergistic or potentiation effects. Also, since paclitaxel and 17-AAG in the combination were half their concentrations, when used alone, and still yielded similar cytotoxic effects, we have been able to reduce the dose of paclitaxel without lowering its therapeutic efficacy. 17AAG on its own was not as effective as paclitaxel. Citation Format: Emmanuel O. Akala. Design, fabrication, and evaluation of dual-loaded biodegradable nanoparticles for breast cancer treatment [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-216.

Paclitaxel Priming of TRAIL Expressing Mesenchymal Stromal Cells (MSCs-TRAIL) Increases Antitumor Efficacy of Their Secretome.

Adipose tissue derived MSCs engineered with the tumor necrosis factor-related apoptosis-inducing ligand protein (MSCs-TRAIL) have a significant anticancer activity. MSCs, without any genetic modifications, exposed to high doses of chemotherapeutic agents are able to uptake the drug and release it in amount affecting tumor proliferation. The purpose of this study was to verify the ability of MSCs-TRAIL to uptake and release paclitaxel (PTX) by providing an increased antitumor efficacy. MSCs and MSCs-TRAIL were tested for their sensitivity to Paclitaxel (PTX) by MTT assay and the cells were loaded with PTX according to a standardized procedure. The secretome was analysed by HPLC for the presence of PTX, microarray assay for soluble TRAIL (s-TRAIL) and tested for in vitro anticancer activity. MSCs-TRAIL were resistant to PTX and able to incorporate and then release the drug. The secretion of s-TRAIL by PTX loaded MSCs-TRAIL was not inhibited and the PTX delivery together with s-TRAIL secretion resulted into an increased antitumor efficacy of cell secretoma as tested in vitro on human pancreatic carcinoma (CFPAC-1) and glioblastoma (U87-MG). Our result is the first demonstration of the possible merging of two new MSCs therapy approaches based on genetic manipulation and drug delivery. If confirmed in vivo, this could potentiate the efficacy of MSCs-TRAIL and strongly contribute to reduce the toxicity due to the systemic treatment of PTX.

Scaling Laws in the Diffusive Release of Neutral Cargo from Hollow Hydrogel Nanoparticles: Paclitaxel-Loaded Poly(4-vinylpyridine).

We study the nonequilibrium diffusive release of electroneutral molecular cargo encapsulated inside hollow hydrogel nanoparticles. We propose a theoretical model that includes osmotic, steric, and short-range polymer-cargo attractions to determine the effective cargo-hydrogel interaction, ueff*, and the effective diffusion coefficient of the cargo inside the polymer network, Deff*. Using dynamical density functional theory (DDFT), we investigate the scaling of the characteristic release time, τ1/2, with the key parameters involved in the process, namely, ueff*, Deff*, and the swelling ratio. This effort represents a full study of the problem, covering a broad range of cargo sizes and providing predictions for repulsive and attractive polymer shells. Our calculations show that the release time through repulsive polymer networks scales with q2eβueff*/Deff* for βueff* ≫ 1. In this case, the cargo molecules are excluded from the shell of the hydrogel. For attractive shells, the polymer retains the cargo molecules on its internal surface and its interior, and the release time grows exponentially with the attraction strength. The DDFT calculations are compared to an analytical model for the mean first passage time, which provides an excellent quantitative description of the kinetics for both repulsive and attractive shells without fitting parameters. Finally, we apply the method to reproduce experimental results on the release of paclitaxel from hollow poly(4-vinylpyridine) nanoparticles and find that the slow release of the drug can be explained in terms of the strong binding attraction between the drug and the polymer.

A selective drug delivery system based on phospholipid-type nanobubbles for lung cancer therapy.

Aim: To develop a micelle-type nanobubble decorated with fluorescein-5-isothiocyanate-conjugated transferrin, with encapsulation of paclitaxel (PTX@FT-NB) for lung cancer treatment. Materials & methods: PTX@FT-NBs were characterized to determine their physicochemical properties, structural stability and cytotoxicity. Lung cancer cell and mouse xenograft tumor models were used to evaluate the therapeutic effectiveness of PTX@FT-NB. Results: The PTX@FT-NBs not only showed selective targeting to lung cancer cells but also inhibited tumor growth significantly via paclitaxel release. Furthermore, paclitaxel-induced microtubule stabilization demonstrated the release of the drug from PTX@FT-NB in the targeted tumor cell both in vitro and in vivo. Conclusion: PTX@FT-NB has the potential as an anticancer nanocarrier against lung cancer cells because of its specific targeting and better drug delivery capacity.

Redox dual-responsive dendrimeric nanoparticles for mutually synergistic chemo-photodynamic therapy to overcome drug resistance

Combination therapy has exhibited crucial potential in the treatment of cancers, especially in drug-resistant cancers. In this work, a novel tumor-targeted, redox dual-responsive and paclitaxel (PTX) loaded nanoparticle based on multifunctional dendrimer and lentinan was developed for combinational chemo-photodynamic therapy of PTX-resistant cancers. The nanoparticles exhibited enhanced cellular uptake and tumor penetration based on phenylboronic acid-sialic acid interactions, and had the ability to control drug release in response to intracellular high concentration of glutathione and H2O2. Specifically, light irradiation not only triggered the photodynamic effect of the nanoparticles for prominent photodynamic cytotoxicity, but also resulted in increased internalization and accelerated release of PTX into cytoplasm through the lysosome disruption, as well as the obvious damage to microtubules and actin microfilaments, for drug resistance reversal of A549/T cells. Meanwhile, PTX treatment would arrest cells in G2/M phase, thereby prolonging the period when nuclear membrane is broken down, which further facilitated photosensitizer accumulation in nuclei and improved DNA damage response. Consequently, the combination of PTX and photodynamic treatment lead to excellent antitumor effects to drug-resistant A549/T cells in vitro and in vivo, which provides a new strategy for the design of co-delivery system to overcome drug resistance.

Fabrication of polylactic acid/paclitaxel nano fibers by electrospinning for cancer therapeutics

Polylactic acid (PLA) is a thermoplastic and biodegradable polyester, largely derived from renewable resources such as corn starch, cassava starch and sugarcane. However, PLA is only soluble in a narrow range of solvents such as tetrahydrofuran, dioxane, chlorinated solvents and heated benzene. The limited choices of solvent for PLA dissolution have imposed significant challenges in the development of specifically engineered PLA nanofibers with electrospinning techniques. Generally, the electrospun polymeric materials have been rendered with unique properties such as high porosity and complex geometry while maintaining its biodegradability and biocompatibility for emerging biomedical applications. In this study, a new anticancer drug delivery system composed of PLA nanofibers with encapsulated paclitaxel was developed by the electrospinning of the respective nanofibers on top of a spin-coated thin film with the same chemical compositions. Our unique approach is meant for promoting strong bonding between PLA-based nanofibers and their respective films in order to improve the prolonged release properties and composite film stability within a fluctuative physiochemical environment during cell culture. PLA/paclitaxel nanofiber supported on respective polymeric films were probed by scanning electronic microscope, Fourier transform infrared spectrometer and water contact measurement for determining their surface morphologies, fibers’ diameters, molecular vibrational modes, and wettability, respectively. Moreover, PLA/paclitaxel nanofibers supported on respective spin-coated films at different loadings of paclitaxel were evaluated for their abilities in killing human colorectal carcinoma cells (HCT-116). More importantly, MTT assays showed that regardless of the concentrations of paclitaxel, the growth of HCT-116 was effectively inhibited by the prolonged release of paclitaxel from PLA/paclitaxel nanofibers. An effective prolonged delivery system of paclitaxel based on PLA nanofiber-based film has demonstrated exciting potentials for emerging applications as implantable drug delivery patch in post-surgical cancer eradication.

Novel biomimetic nanostructured lipid carriers for cancer therapy: preparation, characterization, and in vitro/in vivo evaluation

Nanostructured lipid carriers (NLC) have become a research hotspot, wherein cancer-targeting effects are enhanced and side effects of chemotherapy are overcome. Usually, accelerated blood clearance (ABC) occurs after repeated injections, without changing the immunologic profile, despite PEGylation which prolongs the circulation function. To overcome these problems, we designed a red blood cell-membrane-coated NLC (RBCm-NLC), which was round-like, with a particle size of 60.33 ± 3.04 nm and a core-shell structure. Its stability was good, the drug paclitaxel (PTX) release from RBCm-PTX-NLC was less than 30% at pH7.4 and pH6.5, and the integrity of RBC membrane surface protein was maintained before and after preparation. Additionally, in vitro assays showed that, with the RBCm coating, the cellular uptake of the NLC by cancer cells was significantly enhanced. RBCm-NLC can avoid recognition by macrophage cells and prolong circulation time in vivo. In S180 tumor-bearing mice, the DiR-labeled RBCm-NLC group showed a stronger fluorescence signal and longer retention in tumor tissues, indicating a prompt tumor-targeting effect and extended blood circulation. Importantly, RBCm-PTX-NLC enhanced the antitumor effect and extended the survival period significantly in vivo. In summary, biomimetic NLC offered a novel strategy for drug delivery in cancer therapy.

Perdurable PD-1 blockage awakes anti-tumor immunity suppressed by precise chemotherapy

The application of nanocarriers as drug delivery system for chemotherapeutic drugs has become a research hotspot in cancer treatment. Chemotherapy with high tumor-targeting accuracy and drug release specificity is the key to improve the efficacy of tumor chemotherapy and reduce the side effects caused by repeated doses drugs.Here, we synthesized a redox-sensitive nano-micelle formed by hyaluronic acid (HA) conjugated with d-α-tocopherol succinate (TOS) using a disulfide bond as the linker (HA-SS-TOS, HSST), which could actively accumulate to the tumor sites and metastasis cancer cells with high expression of CD44. The micelles could dissociate under the high GSH level in cancer cells, triggering a release of paclitaxel (PTX). Surprisingly, the precise chemotherapy instead induced a suppressive tendency of immune system, manifested by a significant increase in TGF-β, which weakened the therapeutic effect of micelles. Moreover, the high levels of TGF-β might be related to the increased drug-resistance of cancer cells. Research has shown that PD-1 pathway blockade can result in reduction in TGF-β expression, thus, a PLGA microsphere encapsulating PD-1 antagonist peptides A12 (A12@PLGA) was further prepared to activate the host immune response. Our data indicated that PTX-loaded HSST could accurately “find” the tumors as well as metastasis cancer cells, and efficiently kill most of them. The joining of a durable PD-1 blockage significantly boosted the efficacy of PTX@HSST on multiple tumor models, including lung metastatic tumors and even multidrug-resistant tumors. Thus, our work presented an optimal chemo-immunotherapy combined system, which shows profound significance for future cancer therapy in clinic.

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 the process of 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 (inhibition rate up to 98%). The introduction of Ca2+ endowed the gel with the excellent hemostatic effect. The combination of reversible chemical bonds and electrostatic interaction made Gel/PF127 have good mechanical stability, excellent 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.

Design and characterization of a novel pH-sensitive biocompatible and multifunctional nanocarrier for in vitro paclitaxel release

Breast cancer is one of the main reasons of women's mortality. A novel ternary combination of ZnAl-layered double hydroxides (LDH), cobalt ferrite (CoFe2O4) and N-graphene quantum dots (N-GQDs) proposes a pH-sensitive multifunctional nanocomposite that can improve therapeutic features of each compound; this is a notable strategy to make biocompatible materials with unique properties for paclitaxel (PTX) delivery in breast cancer cells. For proving the surface modification process of materials, electrochemical techniques including cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were carried out. By coating PEG on the surface of the N-GQDs/CoFe2O4/LDH, it developed a drug delivery system with low toxicity, an excellent encapsulation efficiency 88.4%, drug loading capacity of ca. 31%, and slow and sustained release behavior (9% after 72 h) under normal physiological conditions. Besides, a high drug release (~69%) at low-pH as a model of the extracellular tumor environment indicated a pH-sensitive release behavior. Moreover, cell viability assay proved the negligible cytotoxicity on normal cells (L929) and the improved growth inhibition effect of PTX/N-GQDs/CoFe2O4/LDH nanocarrier on MCF7 cancer cells. Blood compatibility test values with respect to red blood cell aggregation (RBC), coagulation prothrombin time (PT), activated partial thromboplastin time (APTT), and complement activation (C3 and C4 levels) remained within normal ranges without toxicity effect on RBCs and complement factors. Overall, this novel designed PTX/N-GQDs/CoFe2O4/LDH nanocarrier with tremendously biocompatible, slow-release and pH-dependent features could be considered as a theranostic candidate for various anticancer drugs delivery and cancer therapy.

Fabrication, Optimization and Characterization of Paclitaxel and Spirulina Loaded Nanoparticles for Enhanced Oral Bioavailability

Background: Paclitaxel and spirulina when administered as nanoparticles, are potentially useful. Methods: Nanoformualtions of Paclitaxel and Spirulina for gastric cancer were formulated and optimized with Central composite rotatable design (CCRD) using Response surface methodology (RSM). Results: The significant findings were the optimal formulation of polymer concentration 48 mg, surfactant concentration 45% and stirring time of 60 min gave rise to the EE of (98.12 ± 1.3)%, DL of (15.61 ± 1.9)%, mean diameter of (198 ± 4.7) nm. The release of paclitaxel and spirulina from the nanoparticle matrix at pH 6.2 was almost 45% and 80% in 5 h and 120 h, respectively. The oral bioavailability for the paclitaxel spirulina nanoparticles developed is 24.0% at 10 mg/kg paclitaxel dose, which is 10 times of that for oral pure paclitaxel. The results suggest that RSM-CCRD could efficiently be applied for the modeling of nanoparticles. The paclitaxel and spirulina release rate in the tumor cells may be higher than in normal cells. Paclitaxel spirulina nanoparticle formulation may have higher bioavailability and longer sustainable therapeutic time as compared with pure paclitaxel. Conclusion: Paclitaxel-Spirulina co-loaded nanoparticles could be effectively useful in gastric cancer as chemotherapeutic formulation.

The intragastrointestinal fate of paclitaxel-loaded micelles: Implications on oral drug delivery

The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel (PTX). Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact, except in fed-state simulated intestinal fluid and fasted-state pig intestinal fluid, thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles showing higher stability than other micelles. All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles. The transport of the micelles across Caco-2/Raji (1.6%–3.5%), Caco-2 (0.8%–1%), and Caco-2/HT29-MTX (0.58%–1%) cell monolayers further verified the absorption of micelles and their subsequent transport; however, more TPGS micelles transported across cell monolayers than other groups. Moreover, the histological examination also confirmed that micelles entered the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups. Thus, these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug, uptake by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups. In conclusion, these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.

Succinylated casein functionalized mesoporous silica nanoplatforms to overcome multiple gastrointestinal barriers

Oral delivery of nanocarriers is exceedingly limited owing to the two speed-limited processes of epithelial absorption and mucus permeation, which demands totally opposite surface characters of nanoparticles. In order to address this contradiction, we proposed a reasonable idea about functionalizing the surface of mesoporous silica with positively charged amino groups and hydrophilic succinylated casein (SCN) polymer. Mesoporous silica nanoparticles doped with quantum dots (QMSN) with an average particle size at 160 nm were employed as the nanocarriers. Paclitaxel (PTX) with poor solubility and permeability was loaded in the nanoplatforms in a non-crystalline state to realize a relatively high drug loading efficacy of 11.9% and controlled release property. The coated SCN can hinder the premature release in gastric environment, and be specifically detachable in intestine to accelerate PTX release under the existence of trypsin, promote the mucus permeation and result in exposure of amino groups after degradation to realize efficient transepithelial transport. Compared with amino modified QMSN, QMSN-SCN showed increased intestinal uptake in vivo. Toxicity studies showed the both QMSN and QMSN-SCN had the excellent biosecurity for in vivo application. In summary, successive and easy functionalization of amino groups and SCN polymers on the surface of QMSN provide a promising strategy to conquer the multiple gastrointestinal barriers.

Co-delivery of paclitaxel and curcumin by biodegradable polymeric nanoparticles for breast cancer chemotherapy

Multi-drug chemotherapy has been one of the most popular strategies for the treatment of malignant tumors, and has achieved desirable therapeutic outcomes. The objective of the present study is to develop biodegradable PCEC nanoparticles (NPs) for the co-delivery of paclitaxel (PTX) and curcumin (CUR), and investigate the antitumor effect of the drug delivery system (DDS: PTX-CUR-NPs) against breast cancer both in vitro and in vivo. The prepared PTX-CUR-NPs had a small size of 27.97±1.87nm with a low polydispersity index (PDI, 0.197±0.040). The results exhibited slow release of PTX and CUR from the DDS without any burst effect. Further, the PTX-CUR-NPs displayed a dose-dependent cytotoxicity in MCF-7 cells with a higher apoptosis rate (64.29%±1.97%) as compared to that of free drugs (PTX+CUR, 34.21%±0.81%). The cellular uptake study revealed that the drug loaded PCEC polymeric nanoparticles were more readily uptaken by tumor cells in vitro. To evaluate the in vivo anti-tumor effect, the PTX-CUR-NPs were intravenously administered to BALB/c nude mouse xenografted with MCF-7 cells and the results exhibited significant inhibition of tumor growth with prolonged survival time and reduced side effect when compared with free drugs (PTX+CUR). Moreover, the administration of PTX-CUR-NPs treatment led to lower Ki67 expression (p<0.05), and enhanced TUNEL positivity (higher apoptosis, p<0.01) in tumor cells as compared to other treatment groups, suggesting the therapeutic efficacy of the DDS. Altogether, the present study suggests that the DDS PTX-CUR-NPs could be employed for the effective treatment of breast cancers in near future.

Facile synthesis of redox-responsive paclitaxel drug release platform using metal-organic frameworks (ZIF-8) for gastric cancer treatment

This paper investigated the dual-role of cystamine as a surface modification linker and stimuli-responsive material, and simplify redox-responsive drug delivery system synthesis. ZIF-8 is used as the drug delivery vehicle (due to its exceptional biocompatibility), cystamine is used as the linker and redox-sensitive material, and paclitaxel (PTX) is selected as the anti-tumor drug. Redox-responsive paclitaxel drug delivery platform based on metal-organic frameworks (MOFs) was synthesized by using ZIF-8 as the drug delivery vehicle, and cystamine as the linker and redox-sensitive material. The morphology of ZIF-8 was determined by the Transmitting Electron Microscope (TEM), and the crystal structure was determined by x-ray diffraction (XRD). The surface modification of ZIF-8 was studied by the Fourier-transform infrared (FT-IR) spectroscopy. The Brunauer–Emmett–Teller (BET) study indicated that surface modification has little impact on the specific surface area and pore size distribution of ZIF-8. The drug release of ZIF-8/cystamine/paclitaxel was studied under different pH and glutathione concentrations. The cytotoxicity was investigated with human gastric cancer cells. Higher glutathione (GSH) concentration and lower pH were favorable to the release of paclitaxel from ZIF-8/cystamine/paclitaxel, and the drug release platform provided a higher tumor-killing effect than free paclitaxel solution.

The effect of drug position on the properties of paclitaxel-conjugated gold nanoparticles for liver tumor treatment

Structure-efficacy effect of small molecular drug attracts wide attentions, but it has always been ignored in nanomedicine research. To reveal the efficacy modulation of nanomedicine, we developed a new type of paclitaxel (PTX)-conjugated gold nanoparticles (PTX-conjugated GNPs) to investigate the influence of drug position in controlling their in vitro properties and in vivo performance. Two therapeutic ligands (TA-PEG-NH-N=PTX and TA-PTX=N-NH-PEG) were synthesized to conjugate PTX on the surface of GNPs at different positions, locating on the surface of gold conjugate and inserting between GNPs and polyethylene glycol (PEG, molecular weight 1000 Da), respectively. It was found that PEG-PTX@GNPs with PTX located between GNP and PEG exhibited higher aqueous solubility, biocompatibility, and stability. In addition, an acid sensitive hydrazone bond has been inserted between PTX and PEG in both ligands for drug release of PTX and PTX-PEG segment, respectively, at the tumor site. Further release of PTX from PTX-PEG segment is based on the esterase hydrolysis of an ester bond between PTX and PEG. This two-step drug release mechanism offers PEG-PTX@GNPs effective and sustained release behavior for desirable anticancer activity, enhanced therapeutic efficacy, and lower systematic toxicity in Heps-bearing animal models.

Targeted delivery of quercetin by nanoparticles based on chitosan sensitizing paclitaxel-resistant lung cancer cells to paclitaxel

Chemotherapy plays crucial roles in the clinical treatment of non-small cell lung cancer (NSCLC). Nevertheless, acquired chemoresistance is a common and critical problem that limits the clinical application of chemotherapy. Quercetin (QUE), a natural bioflavonoid, has significant antitumor potential, which has been verified in many drug-resistant cancer cell lines and animal models. Here, we explored whether QUE could reverse the resistance of NSCLC to paclitaxel (PTX)-based therapy. The results of cell viability revealed that QUE could synergistically enhance the cytotoxicity of PTX in A549 and A549/Taxol cells. Furthermore, Akt and ERK phosphorylation had no significant changes in A549/Taxol cells treated with PTX. However, it was significantly inhibited by the combination treatment of QUE and PTX. To improve the antitumor activity of PTX due to its hydrophobicity and eliminate its toxicity, we prepared targeted biodegradable cetuximab chitosan nanoparticles (Cet-CTS NPs) to deliver PTX and QUE using ionic cross-linking technique. The targeted NPs displayed a particle size of 290 nm and sustained release of PTX and QUE. In addition, the targeted Cet-CTS NPs loaded with PTX and QUE inhibited tumor growth in PTX-resistant A549/Taxol cells. Cet-QUE NPs decreased tumor growth in PTX-resistant xenografts. In conclusion, the administration of QUE by using Cet-CTS NPs could provide a prospective strategy for the treatment of PTX-resistant lung cancer.