Free Paclitaxel Research Articles

PH-sensitive carbon nanotubes graft polymethylacrylic acid self-assembly nanoplatforms for cellular drug release.

pH-Sensitive carbon nanotubes graft polymethylacrylic acid hybrids (CNTs-g-PMAA) were prepared through a three-step process, and self-assembled into core-shell micelle nanoparticles. The chemical structure of the hybrids were characterized by FTIR, 1H NMR and TGA. The critical micelle concentration (CMC) was measured by surface tension, and the value hinged on the Mn values or chain lengths of PMAA segments. The UV-vis transmittance, dynamical light scattering (DLS), and zeta potential measurements indicated that the hybrid self-assembly exhibited pH-sensentive responsiveness. The self-assembly was used to load an anticancer drug, paclitaxel (PTX), with an encapsulation efficiency of 77%. The PTX-loaded hybrid drug preparations were applied for cancer-cellular drug release, finding that the release rate was dependent on pH environments, and faster in acidic media of pH < 6.8 than in pH 7.4. MTT and hemolysis assays manifested that the blank hybrid drug carriers were nontoxic and safe, whereas the PTX-loaded drug preparations possessed comparable and even higher anticancer activity in comparison with free PTX. Consequently, the developed hybrid drug nanocarriers can be used for cancer therapy as a promising candidate.

Paclitaxel and Lapatinib dual loaded chitosan-coated PLGA nanoparticles enhance cytotoxicity by circumventing MDR1-mediated trastuzumab resistance in HER2 positive breast cancers: In-vitro and in-vivo studies

Treatment options for multidrug-resistant breast cancer are limited and ineffective. Few combinations of chemotherapeutic agents are clinically successful in treating multiple drug-resistant cancers. However, due to their varied pharmacokinetic characteristics, it is challenging to deliver dual drugs to the tumor simultaneously with the best proportion by simple co-administration. This study aimed to generate chitosan-coated PLGA nanoparticles delivering a synergistic combination of Paclitaxel (PTX) and Lapatinib (LPB) to improve efficacy in patients with multidrug-resistant breast cancer. In comparison to sensitive BT-474 cells, the 3:1 M ratio of PTX/LPB demonstrated significant synergism with a reversal index of approximately 13.4 in trastuzumab-resistant BT-474/TR cells. Particle diameters of the prepared chitosan (CS) PLGA Nps ranged from 157.4 ± 9.2 to 263.5 ± 13.5 nm. CS-coated Nps exhibited good EE and DL values of 80.8 ± 3.4% and 1.5 ± 0.12%, respectively. Moreover, CS-coating allowed successful co-delivery of PTX and LPB, resulting in the maximum in-vitro release within 72 h. Cytotoxicity against BT-474/TR cells was significantly increased when CS-coated dual loaded Nps were compared to other Nps, including free PTX, LPB, and their mixture. Quantification of the intracellular drug accumulation revealed that the encapsulation effectively increased drug uptake in BT-474/TR cells. These CS-coated dual loaded Nps exerted an excellent synergistic effect in BT-474/TR cells, leading to significantly improved cell inhibition via circumventing the MDR1 mediated trastuzumab resistance. Additionally, co-delivery of PTX and LPB demonstrated the most effective tumor growth reduction in the BT-474/TR human breast tumor xenograft compared to the saline control, single loaded PTX, and LPB Nps and a mixture of PTX and LPB combinations. The data suggest that CS-coated PLGA Nps loaded with PTX and LPB concurrently may be one of the most promising formulations for treating MDR1 mediated chemoresistance in HER2-positive breast tumors.

Honokiol nanosuspensions loaded thermosensitive hydrogels as the local delivery system in combination with systemic paclitaxel for synergistic therapy of breast cancer

Local administration of therapeutic agents provides a favorable approach to enhance drug accumulation at pathological sites. In this study, a novel honokiol nanosuspensions loaded thermosensitive injectable hydrogels (HK-NS-Gel) was designed as the local delivery system for the combination therapy with systemic paclitaxel (PTX). The formed HK-NS-Gel showed superior gelation time and temperature. In vitro release and in vivo drug retention assay showed that HK-NS-Gel can slowly and steadily release the HK during 12 days. Meanwhile, enhanced PTX accumulation in the tumor was observed after intratumoral injection of HK-NS-Gel. In vitro cytotoxicity and cell apoptosis tests against 4T1 cells proved the synergistic effects of free PTX combined with HK-NS-Gel. In vivo antitumor study was conducted on 4T1 bearing mice, indicating that co-administration HK-NS-Gel and PTX could effectively enhance tumor growth suppression, and the tumor inhibitory rate was as high as 72.51%. In conclusion, intravenous delivery of PTX combined with intratumoral delivery of HK-NS-Gel was a promising combination for breast cancer therapy with enhanced therapeutic response and safety.

Biosynthesis of folic acid appended PHBV modified copper oxide nanorods for pH sensitive drug release in targeted breast cancer therapy

Multifunctional nanoplatforms as nanocarriers have attracted the interest of many scientists because they can achieve greater therapeutic effect in anticancer drug delivery to tumors with potential to improve cancer treatment, while currently available therapies are nonspecific and ineffectual. In present study, notable cancer therapeutic strategy which combines PEG functionalized poly (3-hydroxybutyric acid-co-hydroxyvaleric acid) (PHBV) nanospheres decorated with folic acid for delivery of paclitaxel (PTX) drug conjugated with copper oxide (CuO) nanoparticles (NPs) is proposed. Moreover, PTX loading with CuO NPs in PHBV nanosphere was done to increase its solubility and analyze its apoptotic effects in human breast cancer (MCF-7) cells. The pH-sensitive CuO-PTX@PHBV-PEG-FA nanosystem was successfully developed, as evidenced by number of characterizations. Resultant CuO-PTX@PHBV-PEG-FA NPs were 148.93 ± 10.5 nm in size, having 0.206 PDI, with −20.3 ± 0.6 mV zeta potential. MTT assay in MCF-7 cells was used to assess cell viability, while anticancer potential of CuO-PTX@PHBV-PEG-FA nanosystem was confirmed through different staining techniques. According to in vitro studies, FA-conjugated PHBV modified CuO-PTX targeted nanoparticles exhibited higher anticancer effect than free PTX probably due to binding interaction of folate receptor with cells that overexpress the target. This nanosystem has the potential to be a promising breast cancer treatment agent.

Evaluation of PEG-b-polycarbonates self-assemblies containing azobenzene or coumarin moieties as nanocarriers using paclitaxel as a model hydrophobic drug

The work assesses the performance of nanocarriers from amphiphilic block copolymers with functional azobenzene or coumarin moieties for delivery of paclitaxel. Placlitaxel was encapsulated by the nanoprecipitation method. Characterisations were performed by DLS, TEM, Zeta potential and HPLC. Cell viability was investigated in HeLa and Huh-5-2-cell lines. Coumarin-containing polymeric micelles (Dh = 26 ± 2 nm, PDI = 0.28, ζ = ‒22.9 ± 3.6 mV) with 11.2 ± 0.5%w/w drug loading showed enhanced cytotoxicity in HeLa cells (IC50 < 0.02 nM) compared to free paclitaxel (IC50 = 0.17 ± 0.02 nM). Azobenzene-containing polymeric vesicles (Dh = 390 ± 20 nm, PDI = 0.24, ζ = ‒33.2 ± 5.0 mV) with a 6.8 ± 0.4%w/w drug loading showed increased cytotoxicity under 530 nm light (IC50 = 0.0114 ± 0.00033 nM) in HeLa cells due to a stimulated delivery of paclitaxel. Effectivity of these block copolymers as paclitaxel nanovectors and light stimulated release has been demonstrated.

Facile Preparation of Paclitaxel Nano-Suspensions to Treat Lung Cancer

Lung cancer is a worldwide issue which account for the death of thousands every year. Paclitaxel (PTX) as the first line chemotherapy drug to treat lung cancer, its clinical applications is largely limited by its poor solubility. The facile preparation of pharmaceutical formulations to increase the solubility as well as targetability of PTX is of vital importance in lung cancer treatment. Herein, we introduced a facile method to prepare PTX nano-suspensions (NSs), which have high drug loading as well as well-dispersed particle size. The in vitro cell experiments revealed its capability to enhance the drug accumulation in A549 cells than free PTX. Moreover, in vivo animal assay suggested its better tumor accumulation and antitumor efficacy than PTX injection (Taxol).

Mucus Penetrating and Cell-Binding Polyzwitterionic Micelles as Potent Oral Nanomedicine for Cancer Drug Delivery.

Orally administrable anticancer nanomedicines are highly desirable due to their easy and repeatable administration, but are not yet feasible because the current nanomedicine cannot simultaneously overcome the strong mucus and villi barriers and thus have very low bioavailability (BA). Herein, this work presents the first polymeric micelle capable of fast mucus permeation and villi absorption and delivering paclitaxel (PTX) efficiently to tumors with therapeutic efficacy even better than intravenously administered polyethylene glycol based counterpart or free PTX. Poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), a water-soluble polyzwitterion, is highly nonfouling to proteins and other biomacromolecules such as mucin but can weakly bind to phospholipids. Therefore, the micelle of its block copolymer with poly(ε-caprolactone) (OPDEA-PCL) can efficiently permeate through the viscous mucus and bind to villi, which triggers transcytosis-mediated transepithelial transport into blood circulation for tumor accumulation. The orally administered micelles deliver PTX to tumors, efficiently inhibiting the growth of HepG2 and patient-derived hepatocellular carcinoma xenografts and triple-negative breast tumors. These results demonstrate that OPDEA-based micelles may serve as an efficient oral nanomedicine for delivering other small molecules or even large molecules.

Nanosized paclitaxel-loaded niosomes: formulation, in vitro cytotoxicity, and apoptosis gene expression in breast cancer cell lines.

In this study, the optimized niosomal formulation containing paclitaxel using non-ionic surfactants and cholesterol was designed and its cytotoxic effects against different breast cancer cell lines and apoptosis gene expression analysis were also investigated. Due to enhancing equation variables, the Box-Behnken method has been applied. Lipid/drug molar ratio, the amounts of Span 60, and cholesterol were selected as the target for optimization. The particle size of niosome loaded paclitaxel and entrapment efficiency proportion have been considered in the role of dependent variables. Then the cytotoxic activity of the optimized formulation was evaluated using an MTT assay against different breast cancer cell lines including MCF-7, T-47D, SkBr3, and MDA-MB-231. The expression level of Bax and Bcl-2 apoptosis genes was determined by Real-Time PCR. In this study, the optimized niosomal formulation revealed that the synthesized niosomes had a spherical appearance and had an average size of 192.73 ± 5.50nm so that the percentage of drug loading was 94.71 ± 1.56%. Moreover, this formulation showed a controlled and slowed release of paclitaxel at different pH (7.4, 6.5, and 5.4). The cytotoxicity results demonstrated that cell viability in all concentrations of niosome loaded paclitaxel had profound cytotoxic effects on all studied breast cancer cell lines compared to the free paclitaxel (p < 0.05). In addition, the expression of apoptosis genes was much higher than that of free paclitaxel indicating the susceptibility of cells to apoptosis. As a result, niosomal formulations containing paclitaxel can be used as a new drug delivery system to increase cytotoxicity and treatment of breast cancer in the upcoming future.

Targeted delivery of cancer drug paclitaxel to chordomas tumor cells via an RNA nanoparticle harboring an EGFR aptamer

Paclitaxel has been extensively used in clinics for cancer treatment. However, its limited solubility in aqueous solution and high occurrence of side effects have also been widely reported. In this study, we constructed a biocompatible RNA nanoparticle delivery system (3WJ-EGFRapt) that includes 3WJ (3-way junction) nanoparticle with a size of 4.85 ± 0.59 nm as a backbone and an EGFR (epidermal growth factor receptor) aptamer for specific targeting to chordomas cells, which owns the encapsulation ability of drug paclitaxel (PTX) for cancer therapy. Confocal microscopy and flow cytometry results confirmed 3WJ-EGFRapt nanoparticle exhibited excellent specific targeting to chordomas cell U-CH2 which is an EGFR(+) cell line; while the 3WJ nanoparticle lose the targeted ability. Both of the two nanoparticles own no sensitivity to lung cancer cell H520 which is an EGFR(-) cell line. Moreover, the 3WJ-EGFRapt nanoparticle encapsulated drug PTX could enhance the inhibition efficiency of chordomas tumor cells U-CH2 as compared to free PTX alone. This work demonstrates that RNA-3WJ constructed with a targeting aptamer provides a compromising targeted drug delivery ability on chordomas cells for therapeutics.

Tissue-reactive drugs enable materials-free local depots

Local, sustained drug delivery of potent therapeutics holds promise for the treatment of a myriad of localized diseases while eliminating systemic side effects. However, introduction of drug delivery depots such as viscous hydrogels or polymer-based implants is highly limited in stiff tissues such as desmoplastic tumors. Here, we present a method to create materials-free intratumoral drug depots through Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs diffuse into tissue and attach locally for sustained drug release. In TRAPs, potent drugs are modified with ECM-reactive groups and then locally injected to quickly react with accessible amines within the ECM, creating local drug depots. We demonstrate that locally injected TRAPs create dispersed, stable intratumoral depots deep within mouse and human pancreatic tumor tissues. TRAPs depots based on ECM-reactive paclitaxel (TRAP paclitaxel) had better solubility than free paclitaxel and enabled sustained in vitro and in vivo drug release. TRAP paclitaxel induced higher tumoral apoptosis and sustained better antitumor efficacy than the free drug. By providing continuous drug access to tumor cells, this material-free approach to sustained drug delivery of potent therapeutics has the potential in a wide variety of diseases where current injectable depots fall short.

Targeted killing of CD133+ lung cancer stem cells using paclitaxel-loaded PLGA-PEG nanoparticles with CD133 aptamers

To construct a polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) nanocarrier (N-Pac-CD133) coupled with a CD133 nucleic acid aptamer carrying paclitaxel for eliminating lung cancer stem cells (CSCs). Paclitaxel-loaded N-Pac-CD133 was prepared using the emulsion/solvent evaporation method and characterized. CD133+ lung CSCs were separated by magnetic bead separation and identified for their biological behaviors and gene expression profile. The efficiency of paclitaxel-loaded N-Pac-CD133 for targeted killing of lung cancer cells was assessed in vitro. SCID mice were inoculated with A549 cells and received injections of normal saline, empty nanocarrier linked with CD133 aptamer (N-CD133), paclitaxel, paclitaxel-loaded nanocarrier (N-Pac) or paclitaxel-loaded N-Pac-CD133 (n=8, 5 mg/kg paclitaxel) on days 10, 15 and 20, and the tumor weight and body weight of the mice were measured on day 40. Paclitaxel-loaded N-Pac-CD133 showed a particle size of about 100 nm with a high encapsulation efficiency (>80%) and drug loading rate (>8%), and was capable of sustained drug release within 48 h. The CD133+ cell population in lung cancer cells showed the characteristic features of lung CSCs, including faster growth rate (30 days, P=0.001) and high expressions of tumor stem cell markers OV6(P < 0.001), CD133 (P=0.001), OCT3/4 (P=0.002), EpCAM (P=0.04), NANOG (P=0.005) and CD44 (P=0.02). Compared with N-Pac and free paclitaxel, paclitaxel-loaded N-Pac-CD133 showed significantly enhanced targeting ability and cytotoxicity against lung CSCs in vitro (P < 0.001) and significantly reduced the formation of tumor spheres (P < 0.001). In the tumor-bearing mice, paclitaxel-loaded N-Pac-CD133 showed the strongest effects in reducing the tumor mass among all the treatments (P < 0.001). CD133 aptamer can promote targeted delivery of paclitaxel to allow targeted killing of CD133+ lung CSCs. N-Pac-CD133 loaded with paclitaxel may provide an effective treatment for lung cancer by targeting the lung cancer stem cells.

Evaluation of poly (lactic-co-glycolic acid) nanoparticles to improve the therapeutic efficacy of paclitaxel in breast cancer.

Introduction: Paclitaxel (PTX) is a cornerstone in the treatment of breast cancer, the most common type of cancer in women. However, this drug has serious limitations, including lack of tissue-specificity, poor water solubility, and the development of drug resistance. The transport of PTX in a polymeric nanoformulation could overcome these limitations. Methods: In this study, PLGA-PTX nanoparticles (NPs) were assayed in breast cancer cell lines, breast cancer stem cells (CSCs) and multicellular tumor spheroids (MTSs) analyzing cell cycle, cell uptake (Nile Red-NR-) and α-tubulin expression. In addition, PLGA-PTX NPs were tested in vivo using C57BL/6 mice, including a biodistribution assay. Results: PTX-PLGA NPs induced a significant decrease in the PTX IC50 of cancer cell lines (1.31 and 3.03-fold reduction in MDA-MB-231 and E0771 cells, respectively) and CSCs. In addition, MTSs treated with PTX-PLGA exhibited a more disorganized surface and significantly higher cell death rates compared to free PTX (27.9% and 16.3% less in MTSs from MCF-7 and E0771, respectively). PTX-PLGA nanoformulation preserved PTX's mechanism of action and increased its cell internalization. Interestingly, PTX-PLGA NPs not only reduced the tumor volume of treated mice but also increased the antineoplastic drug accumulation in their lungs, liver, and spleen. In addition, mice treated with PTX-loaded NPs showed blood parameters similar to the control mice, in contrast with free PTX. Conclusion: These results suggest that our PTX-PLGA NPs could be a suitable strategy for breast cancer therapy, improving antitumor drug efficiency and reducing systemic toxicity without altering its mechanism of action.

Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)-conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.

Manganese-based multifunctional nanoplatform for dual-modal imaging and synergistic therapy of breast cancer

Manganese has recently been exploited for cancer immunotherapy, fenton-like reaction-mediated chemo-dynamic therapy, and magnetic resonance imaging. The integration of multiple roles of manganese into one platform is of great significance for cancer theranostics and tumor inhibition. Here, we designed a multifunctional nanoplatform based on manganese, which consisted of a manganese-containing inner core and a phospholipid bilayer shell co-loaded with glucose oxidase (GOx), paclitaxel (PTX), and a NIR fluorescent dye (NanoMn-GOx-PTX). In a pH-dependent manner, the nanoplatform released manganese ions and payloads inside the tumor cells. In vitro characterization and cellular experiments indicated that NanoMn-GOx-PTX could catalyze the conversion of glucose into reactive oxygen species (ROS) through a cascade Fenton-like reaction as well as release free PTX. The consumption of glucose, ROS production, and the chemotherapeutic effect of PTX contributed to the superior cytotoxicity and apoptosis of 4T1 cancer cells. Moreover, NanoMn-GOx-PTX effectively induced the production of large amounts of type I interferon and pro-inflammatory cytokines in vivo, activating the innate immune response. Through the synergistic functions of the above components, NanoMn-GOx-PTX exerted the strongest anti-tumor effect in 4T1 tumor-bearing models. Therefore, the manganese-based nanoplatform could serve as a promising theranostic tool for breast cancer therapy. Statement of significance1) This nanoplatform can be used as a universal tool for delivering proteins and anticancer drugs into cells; 2) The PEG-modified phospholipid bilayer shell plays a significant role in retarding the release of overloaded manganese ions and drugs in a pH-sensitive manner; 3) The released Mn2+ has the ability to enhance T1 contrast in magnetic resonance imaging; 4) The released Mn2+ can function as nanoadjuvants to activate the cGAS-STING pathway and effectively induce the natural immune response;5) The overloaded manganese ions are combined with glucose oxidase to form a cascade reaction system, indirectly converting glucose into ROS to induce oxidative damage of tumor tissue.

Novel polysaccharide building hybrid nanoparticles: remodelling TAMs to target ERα-positive breast cancer

With the increasing number of oncology patients and the use of chemotherapeutic agents, tumour multidrug resistance is becoming more and more prevalent. The search for new tumour treatment strategies to overcome tumour multidrug resistance is urgent. In this study, we designed GSH and ROS dual-responsive tumour-associated macrophages (TAMs)-targeted nanoparticles (NPs) for the co-delivery of the clinical first-line anti-breast cancer chemotherapy drug paclitaxel (PTX) and baicalin (Bai), which re-educates TAMs to alter their phenotype. We synthesised oligohyaluronic acid-mannose-folic acid (oHA-Man-FA, HMF) and astragalus polysaccharide-dithiodipropionic acid-paeoniflorol (APS-S-Pae, ASP), two hybrid materials that can self-assemble in water to form hybrid nanoparticles (HP-NPs) co-loaded with paclitaxel and baicalin (HP-NPs@PTX/Bai). The experimental results show that our designed hybrid nanoparticles can be specifically released in the tumour microenvironment and deliver the antitumor drug PTX as well as Bai, which reshapes the phenotype of TAMs, to the tumour site. The hybrid nanoparticles not only effectively re-educated TAMs from M2 TAM to M1 TAM, but also ameliorated the cytotoxic side effects caused by free PTX and provided better tumour suppression than free PTX and HP.

In vitro and in vivo anticancer effect of pH-responsive paclitaxel-loaded niosomes

In this study, paclitaxel (PTX)-loaded pH-responsive niosomes modified with ergosterol were developed. This new formulation was characterized in terms of size, morphology, encapsulation efficiency (EE), and in vitro release at pH 5.2 and 7.4. The in vitro efficacy of free PTX and niosome/PTX was assessed using MCF7, Hela, and HUVEC cell lines. In order to evaluate the in vivo efficacy of niosomal PTX in rats as compared to free PTX, the animals were intraperitoneally administered with 2.5 mg/kg and 5 mg/kg niosomal PTX for two weeks. Results showed that the pH-responsive niosomes had a nanometric size, spherical morphology, 77% EE, and pH-responsive release in pH 5.2 and 7.4. Compared with free PTX, we found markedly lower IC50s when cancer cells were treated for 48 h with niosomal PTX, which also showed high efficacy against human cancers derived from cervix and breast tumors. Moreover, niosomal PTX induced evident morphological changes in these cell lines. In vivo administration of free PTX at the dose of 2.5 mg/kg significantly increased serum biochemical parameters and liver lipid peroxidation in rats compared to the control rats. The situation was different when niosomal PTX was administered to the rats: the 5 mg/kg dosage of niosomal PTX significantly increased serum biochemical parameters, but the group treated with the 2.5 mg/kg dose of niosomal PTX showed fewer toxic effects than the group treated with free PTX at the same dosage. Overall, our results provide proof of concept for encapsulating PTX in niosomal formulation to enhance its therapeutic efficacy.

Glutathione-responsive prodrug conjugates for image-guided combination in cancer therapy.

Theranostic prodrug was highly desirable for precise diagnosis and anti-cancer therapy to decrease side effects. However, it is difficult to conjugate chemo-drug and molecular probe for combined therapy due to the complex pharmacokinetics of different molecules. Here, a novel anticancer theranostic prodrug (BTMP-SS-PTX) had been designed and synthesized by conjugating paclitaxel (PTX) with 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol (BTMP) through a disulphide (-S-S-) linkage, which was redox-sensitive to the high concentration of glutathione in tumors. Upon activation with glutathione in weakly acid media, the BTMP-SS-PTX can be dissociated to release free PTX and visible BTMP, which realized the visual tracking of free drug. The cytotoxicity study demonstrated that soluble prodrug BTMP-SS-PTX displayed more outstanding anticancer activity in HepG2, MCF-7 and HeLa cells, lower toxicity to non-cancer cells (293T) than free drugs. Furthermore, BTMP-SS-PTX was still able to induce apoptosis of HeLa cells and significantly inhibited tumor growth in HeLa-xenograft mouse model. On the basis of these findings, BTMP-SS-PTX could play a potential role in cancer diagnosis and therapy.

Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics.

This contribution describes the design and synthesis of multifunctional micelles based on amphiphilic brush block copolymers (BBCPs) for imaging and selective drug delivery of natural anticancer compounds. Well-defined BBCPs were synthesized via one-pot multi-step sequential grafting-through ring-opening metathesis polymerization (ROMP) of norbornene-based macroinitiators. The norbornenes employed contain a poly(ethylene glycol) methyl ether chain, an alkyl bromide chain, and/or a near-infrared (NIR) fluorescent cyanine dye. After block copolymerization, post-polymerization transformations using bromide-azide substitution, followed by the strain-promoted azide-alkyne cycloaddition (SPAAC) allowed for the functionalization of the BBCPs with the piplartine (PPT) moiety, a natural product with well-documented cytotoxicity against cancer cell lines, via an ester linker between the drug and the polymer side chain. The amphiphilic BBCPs self-assembled in aqueous media into nano-sized spherical micelles with neutral surface charges, as confirmed by dynamic light scattering analysis and transmission electron microscopy. During self-assembly, paclitaxel (PTX) could be effectively encapsulated into the hydrophobic core to form stable PTX-loaded micelles with high loading capacities and encapsulation efficiencies. The NIR fluorescent dye-containing micelles exhibited remarkable photophysical properties, excellent colloidal stability under physiological conditions, and a pH-induced disassembly under slightly acidic conditions, allowing for the release of the drug in a controlled manner. The in vitro studies demonstrated that the micelles without the drug (blank micelles) are biocompatible at concentrations of up to 1 mg mL-1 and present a high cellular internalization capacity toward MCF-7 cancer cells. The drug-functionalized micelles showed in vitro cytotoxicity comparable to free PPT and PTX against MCF-7 and PC3 cancer cells, confirming efficient drug release into the tumor environment upon cellular internalization. Furthermore, the drug-functionalized micelles exhibited higher selectivity than the pristine drugs and preferential cellular uptake in human cancer cell lines (MCF-7 and PC3) when compared to the normal breast cell line (MCF10A). This study provides an efficient strategy for the development of versatile polymeric nanosystems for drug delivery and image-guided diagnostics. Notably, the easy functionalization of BBCP side chains via SPAAC opens up the possibility for the preparation of a library of multifunctional systems containing other drugs or functionalities, such as target groups for recognition.

In Vivo Antitumor and Antimetastatic Efficacy of a Polyacetal-Based Paclitaxel Conjugate for Prostate Cancer Therapy.

Prostate cancer (PCa), one of the leading causes of cancer-related deaths, currently lacks effective treatment for advanced-stage disease. Paclitaxel (PTX) is a highly active chemotherapeutic drug and the first-line treatment for PCa; however, conventional PTX formulation causes severe hypersensitivity reactions and limits PTX use at high concentrations. In the pursuit of high molecular weight, biodegradable, and pH-responsive polymeric carriers, one conjugates PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over 2 weeks in a pH-responsive manner while also obtaining a degree of epimerization of PTX to 7-epi-PTX. Serum proteins stabilize tert-Ser-PTX, with enhanced stability in human serum versus PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrate IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrate that tert-Ser-PTX significantly reduces the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibits primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as confirmed by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice carrying orthotopic LNCaP tumors. Overall, the results suggest the application of tert-Ser-PTX as a robust antitumor/antimetastatic treatment for PCa.

Hyaluronic acid coated Pluronic F127/Pluronic P123 mixed micelle for targeted delivery of Paclitaxel and Curcumin

The hydrophobicity of most of the anticancer drugs offers a great challenge in selecting a system for their effective transport. Here comes the importance of micelles that offers a hydrophobic core for incorporating these drugs. In this study, Hyaluronic Acid coated Pluronic mixed micelle loaded with Paclitaxel and Curcumin was designed and evaluated its anticancer activity in MCF-7 cells. Pluronic F127 (PF127) and Pluronic P123 (PP123) were taken for preparing the mixed micelles. The targeting ligand folic acid (FA) was conjugated to one end of PP123 forming FA-PP. The end hydroxyl groups of PF127 were oxidized to aldehyde groups resulted in PF-CHO. Mixed micelles were prepared from PF-CHO and FA-PP and the end aldehyde groups were used for coating the micelles with hyaluronic acid. The material was characterized using FTIR, H1NMR, DLS, FE-SEM and TEM. The coated micelles showed spherical shape with drug loading efficiency of 50.15 and 65.05% for Paclitaxel and Curcumin, respectively. In vitro drug release was studied at pH 5.5 and 7.4. Dual drug-loaded material showed higher in-vitro anticancer activity than free Paclitaxel and Curcumin. The results suggested that synthesized mixed micelle with dual drugs showed great potential for targeted delivery to MCF-7 cells.