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The use of glioblastoma-targeted drug delivery system facilitates efficient delivery of chemotherapeutic agents to malignant gliomas in the central nervous system while minimizing high systemic doses associated with debilitating toxicities. To employ the high binding affinity of a cyclic RGD peptide (c(RGDyK), cyclic Arginine–Glycine–Aspartic acid- d -Tyrosine-Lysine) with integrin α v β 3 over-expressed on tumor neovasculature and U87MG glioblastoma cells, we prepared paclitaxel-loaded c(RGDyK)-Poly(ethylene glycol)- block -poly(lactic acid) micelle (c(RGDyK)-PEG-PLA-PTX). In vitro physicochemical characterization of these novel micelles showed satisfactory encapsulated efficiency, loading capacity and size distribution. In vitro cytotoxicity studies proved that the presence of c(RGDyK) enhanced the anti-glioblastoma cell cytotoxic efficacy by 2.5 folds. The binding affinity of c(RGDyK)-PEG-PLA micelle with U87MG cells was also investigated. The competitive binding IC 50 value of c(RGDyK)-PEG-PLA micelle was 26.30 nM, even lower than that of c(RGDyK) (56.23 nM). In U87MG glioblastoma-bearing nude mice model, biodistribution of 125 I-radiolabeled c(RGDyK)-PEG-PLA or DiR encapsulated micelles and anti-glioblastoma pharmacological effect was investigated after intravenous administration. c(RGDyK)-PEG-PLA micelle accumulated in the subcutaneous and intracranial tumor tissue, and when loaded with PTX (c(RGDyK)-PEG-PLA-PTX), exhibited the strongest tumor growth inhibition among the studied paclitaxel formulations. The anti-glioblastoma effect of c(RGDyK)-PEG-PLA-PTX micelle was also reflected in the median survival time of mice bearing intracranial U87MG tumor xenografts where the median survival time of c(RGDyK)-PEG-PLA-PTX micelle-treated mice (48 days) was significantly longer than that of mice treated with PEG-PLA-PTX micelle (41.5 days), Taxol® (38.5 days) or saline (34 days). Therefore, our results suggested that c(RGDyK)-PEG-PLA micelle may be a potential drug delivery system in the treatment of integrin α v β 3 over-expressed glioblastoma.
Polymer–drug conjugates have demonstrated application potentials in optimizing chemotherapeutics. In this study a new bioconjugate, HA-ss-PTX, was designed and synthesized with cooperative dual characteristics of active tumor targeting and selective intracellular drug release. Paclitaxel (PTX) was covalently attached to hyaluronic acid (HA) with various sizes (MW 9.5, 35, 770 kDa); a cross-linker containing disulfide bond was also used to shield drug leakage in blood circulation and to achieve rapid drug release in tumor cells in response to glutathione . Incorporation of HA to the conjugate enhanced the capabilities of drug loading, intracellular endocytosis and tumor targeting of micelles in comparison to mPEG. HA molecular weight showed significant effect on properties and antitumor efficacy of the synthesized conjugates. Intracellular uptake of HA-ss-PTX toward MCF-7 cells was mediated by CD44-caveolae-mediated endocytosis. Compared to Taxol and mPEG-ss-PTX, HA9.5-ss-PTX demonstrated improved tumor growth inhibition in vivo with a TIR of 83.27 ± 5.20%. It was concluded that HA9.5-ss-PTX achieved rapid intracellular release of PTX and enhanced its therapeutic efficacy, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics. Statement of Significance Polymer–drug conjugates, promising nanomedicines , still face some technical challenges including a lack of specific targeting and rapid intracellular drug release at the target site. In this manuscript we designed and constructed a novel bioconjugate HA-ss-PTX, which possessed coordinated dual characteristics of active tumor targeting and selective intracellular drug release. Redox-responsive disulfide bond was introduced to the conjugate to shield drug leakage in blood circulation and to achieve rapid drug release at tumor site in response to reductant like glutathione. Paclitaxel was selected as a model drug to be covalently attached to hyaluronic acid (HA) with various sizes to elucidate the structure–activity relationship and to address whether HA could substitute PEG as a carrier for polymeric conjugates. Based on a series of in vitro and in vivo experiments, HA-ss-PTX performed well in drug loading, cellular internalization , tumor targeting by entering tumor cells via CD44-caveolae-mediated endocytosis and rapidly release drug at target in the presence of GSH. One of the key issues in clinical oncology is to enhance drug delivery efficacy while minimizing side effects. The study indicated that this new polymeric conjugate system would be useful in delivering anticancer agents to improve therapeutic efficacy and to minimize adverse effects, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics.
A series of novel amphiphilic paclitaxel (PTX) small molecule prodrugs , PTX-succinic anhydride-cystamine (PTX-Cys), PTX-dithiodipropionic anhydride (PTX-SS-COOH) and PTX-succinic anhydride-cystamine-valine (PTX-SS-Val) were designed, synthesized and evaluated against cancer cell lines. Compared with paclitaxel, these prodrugs contained water-soluble groups such as amino, carboxyl and amino acid , which improved the aqueous solubility of the prodrugs. More importantly, the valine was introduced in PTX-SS-Val molecule and made the molecule conform to the structural characteristics of intestinal oligopeptide transporter PEPT1 substrate. Thus the oral bioavailability of prodrug could be improved because of the mediation of PEPT1 transporter. These small molecule paclitaxel prodrugs could self-assemble into nanoparticles in aqueous solution, which effectively improved the solubility of paclitaxel, and had certain stability in pH 6.5, pH 7.4 buffer solutions and simulated gastrointestinal fluids. Some of these prodrugs, especially for PTX-Cys and PTX-SS-Val, exhibited nearly equal or slightly better anticancer activity when compared to paclitaxel. Further studies on PTX-Cys and PTX-SS-Val showed that both had good intestinal absorption in the rat single-pass intestinal perfusion (SPIP) experiments. Oral pharmacokinetic experiments showed that PTX-SS-Val could effectively improve the oral bioavailability of PTX.
Aim: Tumor metastasis is one of the leading causes of insufficient chemotherapy during cancer treatment. In this study, a poly(β-amino ester) derivate was developed to fabricate paclitaxel (PTX) entrapped pH-responsive copolymer micelles for inhibition of breast cancer metastasis. Materials & methods: PTX-loaded micelles were fabricated by thin film hydration method. The inhibition efficacy of the as-prepared micelles was evaluated on MDA-MB-231 cells and tumor bearing mice. Results: PTX-loaded micelles were successfully prepared. Such micelles could promote drug uptake and MDA-MB-231 cell deaths, and suppress tumor metastasis. Conclusion: The pH-responsive PTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor microenvironments with improved inhibitory effects on tumor metastasis.
Background: Chemotherapeutic drugs are associated with toxic effects. Metastasis is the leading cause of death in breast cancer patients. Aim: To evaluate the antitumor effect of paclitaxel (PTX) combined with psoralen-loaded polymeric lipid nanoparticles (PSO-PLNs) in triple-negative breast cancer. Methods: After treatment of samples, cell viability, apoptosis, migration, invasion, expression of proteins in the IRAK1/NF-κB/FAK signal pathway, biodistribution and pathological characteristics were detected. Results: Compared with the control group, the PTX + PSO-PLNs group showed increased apoptosis and reduced migration, invasion and expression of phosphorylated IRAK1 and NF-κB, with significant inhibition of tumor growth and lung metastases and no obvious toxicity. Conclusion: Combined administration of PTX and PSO-PLNs exerted a synergistic effect and significantly inhibited the growth and metastasis of triple-negative breast cancer.Graphical abstract
A novel multi-functional micelle delivery system was developed for enhancing the oral absorption of paclitaxel (PTX). The delivery carriers were constructed by modifying chitosan-stearic acid (CS-SA) micelles with L-carnitine (LC) and co-encapsulating quercetin (Que), and the PTX-loaded micelles were prepared by film-sonication dispersing technique. The as-prepared micelles showed homogeneous spherical shapes with a small particle size of 148.3 ± 1.7 nm, high drug loading of 7.05% and low critical micelle concentration (CMC) of 16.89 µg/ml. Compared to the in-house PTX formulation similar to the commercial injection Taxol™, the target PTX-loaded micelles had obvious sustained-release effects and exhibited an oral relative bioavailability of 168.08%. The cellular uptake studies of Caco-2 cells confirmed the micellar modification of LC and the co-loading of Que played important roles in promoting the absorption of drug loaded in micelles. The CYP3A4 enzyme test demonstrated the micelles had an inhibitory effect on the metabolic enzyme due to the presence of Que. These findings confirmed the potential of the multi-functional chitosan polymeric micelles based on synergistic effect as an effective oral delivery system. Graphical abstract
Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to the impaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile, acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1 (PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps, we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer with mitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF- β dual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase (AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugating mitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembled with albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticles effectively decreased the expression of collagen in vitro , which then led to the enhanced accumulation of PTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF- β in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cell infiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy to inhibit PTX@Alb-resistant tumors, further supporting its better clinical application.
Improving nanomedicine uptake by tumor cells is key to achieving intracellular drug delivery. In this study, we found that methyl-β-cyclodextrin (MβCD) can significantly promote the intracellular accumulation of nanoparticulated α-linolenic acid-paclitaxel conjugates (ALA-PTX NPs) via enhanced clathrin-mediated endocytosis and limited degradation in lysosomes. Our in vitro results indicated that MβCD not only reduced the plasma membrane cholesterol content and increased plasma membrane fluidity, leading to ALA-PTX NPs being more easily incorporated into the plasma membrane, further enhancing membrane fluidity and making the plasma membrane more susceptible to tensile deformation, forming intracellular vesicles to enhance ALA-PTX NP cellular uptake, but also destroyed lysosomes and then limited ALA-PTX NPs’ degradation in lysosomes. In HepG2 tumor-bearing mice, MβCD was also able to enhance the antitumor activity of ALA-PTX NPs in vivo. Moreover, we found that MβCD specifically promoted PUFA-paclitaxel conjugate NP cellular uptake. The cellular uptake of PTX liposome which shares an endocytosis pathway with ALA-PTX NPs could be enhanced by MβCD combined with ALA or ALA-PTX NPs. Therefore, we suggested that MβCD combined with polyunsaturated fatty acid-conjugation would be an effective strategy for improving intracellular delivery of nanoparticulated chemotherapeutic drugs used for combination administration to enhance antitumor efficiency.
In this study, bovine serum albumin-γ-cyclodextrin (BSA-CD) conjugate was prepared to explore its solubilization effect on Paclitaxel (PTX) and the underlying mechanism. The aqueous solubility studies revealed that when 0.1 mM BSA-CD conjugate was complexed with 4 mM PTX, the maximum aqueous solubility of PTX reached 34 mM, which was approximately 5-fold higher than that of the clinical formulation Abraxane™, with drug loading capacity increased by about 2.8-fold. In vitro release studies demonstrated that the inclusion complex exhibited a cumulative PTX release of approximately 14% over 72 h at pH 7.4 and approximately 23% at pH 5.5, indicating a pH-responsive release profile. MTT assays confirmed that the BSA-CD carrier was non-cytotoxic, and the inclusion complex at the concentration of 10 μM exhibited superior cytotoxicity against melanoma B16F10 cells compared to free PTX and Abraxane™. This study confirms that the BSA-CD conjugate, through the synergistic “dual encapsulation” effect of the BSA hydrophobic pocket and the γ-CD hydrophobic cavity combined with a moderately aggregated state modulated by specific ionic strength, significantly enhances the aqueous solubility and delivery efficiency of PTX, providing a novel and efficient carrier as well as new insights for the formulation optimization of hydrophobic anticancer drugs.
In this work, paclitaxel was loaded into porous starch in the form of nanoparticles (PNPS), and the properties of PNPS were investigated by using raw paclitaxel and the system of paclitaxel directly loaded into porous starch (PPS) as control groups. According to the tested results, the drug loading ( DL ) and encapsulation efficiency ( EE ) of PNPS were 14.13% ± 0.27% and 73.92% ± 0.54%, higher than that of PPS (9.79% ± 0.31% and 71.17% ± 0.67%) respectively. Compared with raw paclitaxel and PPS, PNPS exhibited the more prominent dissolution rate and bioavailability, in which the bioavailability of PPS and PNPS were 2.94 and 5.42 times of that of raw paclitaxel respectively. In addition, the IC 50 values of raw paclitaxel, PPS and PNPS on Lewis Lung Carcinoma (LLC) cells were 17,703.41 ± 15.76 μM, 95.10 ± 5.32 μM and 85.68 ± 7.38 μM respectively. Furthermore, the residues of acetone in PPS and PNPS were less than the ICH limit for acetone in class III solvents. To summarize, the preparation of PNPS was a potential method to improve the dissolution and bioavailability of paclitaxel.
Due to the high morbidity and mortality, cancer has become a global health crisis, posing a great threat to human health. Traditional cancer treatments include surgery, chemotherapy and radiotherapy, but these methods can lead to serious adverse reactions. Therefore, it is of great significance to develop new and effective methods for cancer diagnosis and treatment. In this article, orange fluorescent carbon dots (CDs) were synthesized by the hydrothermal method using biogenic amines. Upon further surface modification with a salivary acid, a novel nanocomplex (CDs-SA-PTX) was prepared by loading the chemotherapeutic drug paclitaxel that could be released under a pH-responsive behavior. In addition, upon irradiation with a near-infrared laser, the temperature of the CDs-SA-PTX nanocomplexes increased to 45.7 °C, indicating a good photothermal effect with a conversion efficiency of 43.8%. In the cellular uptake experiment, CDs-SA-PTX exhibited good capability for nucleolar targeting similar to CDs. The cell viability experiment showed that CDs-SA-PTX together with laser irradiation demonstrated the best breast cancer cell killing ability than other groups. Further in vivo data indicated that CDs-SA-PTX could be efficiently enriched in tumor tissues and could almost completely inhibit tumor growth with laser irradiation. The nanocomplexes provide an ideally versatile platform with the advantages of simple ingredients, easy preparation, active targeting, imaging-guided photothermal therapy and chemotherapy.
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