ABSTRACT
Purpose
To investigate the effects of the particle size and surface coating on the cellular uptake of the polymeric nanoparticles for drug delivery across the physiological drug barrier with ...emphasis on the gastrointestinal (GI) barrier for oral chemotherapy and the blood–brain barrier (BBB) for imaging and therapy of brain cancer.
Methods
Various sizes of commercial fluorescent polystyrene nanoparticles (PS NPs) (
viz
20 50, 100, 200 and 500 nm) were modified with the d-α-tocopheryl polyethylene glycol 1,000 succinate (vitamin E TPGS or TPGS). The size, surface charge and surface morphology of PS NPs before and after TPGS modification were characterized. The Caco-2 and MDCK cells were employed as an
in vitro
model of the GI barrier for oral and the BBB for drug delivery into the central nerve system respectively. The distribution of fluorescent NPs after
i.v.
administration to rats was analyzed by the high performance liquid chromatography (HPLC).
Results
The
in vitro
investigation showed enhanced cellular uptake efficiency for PS NPs in both of Caco-2 and MDCK cells after TPGS surface coating.
In vivo
investigation showed that the particle size and surface coating are the two parameters which can dramatically influence the NPs biodistribution after
intravenous
administration. The TPGS coated NPs of smaller size (< 200 nm) can escape from recognition by the reticuloendothelial system (RES) and thus prolong the half-life of the NPs in the blood system.
Conclusions
TPGS-coated PS NPs of 100 and 200 nm sizes have potential to deliver the drug across the GI barrier and the BBB.
Abstract d -α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate ...with polyethylene glycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers for drug delivery, including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration (CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drug delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance (MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we briefly discuss its physicochemical and pharmaceutical properties and its wide applications in composition of the various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.
Great efforts have been devoted so far to combine nano‐magnetic hyperthermia and nano‐photothermal therapy to achieve encouraging additive therapeutic performance in vitro and in vivo with limitation ...to direct intratumoral injection and no guidance of multimodality molecular imaging. In this study, a novel multifunctional theranostic nanoplatform (MNP@PES‐Cy7/2‐DG) consisting of magnetic nanoparticles (MNPs), poly(3,4‐ethylenedioxythiophene):poly(4‐styrenesulfonate) (PES), Cyanine7 (Cy7), and 2‐deoxyglucose (2‐DG)‐polyethylene glycol is developed. They are then applied to combined photo‐magnetic hyperthermia therapy under intravenous administration that is simultaneously guided by trimodality molecular imaging. Remarkably, nanoparticles are found aggregated mainly in the cytoplasm of tumor cells in vitro and in vivo, and exhibit stealth‐like behavior with a long second‐phase blood circulation half‐life of 20.38 ± 4.18 h. Under the guidance of photoacoustic/near‐infrared fluorescence/magnetic resonance trimodality imaging, tumors can be completely eliminated under intracellular photo‐magnetic hyperthermia therapy with additive therapeutic effect due to precise hyperthermia. This study may promote a further exploration of such a platform for clinical applications.
A novel multifunctional theranostic nanoplatform (MNP@PES‐Cy7/2‐DG) is developed and applied for combined photo‐magnetic hyperthermia therapy under intravenous administration, which is simultaneously guided by multimodality molecular imaging. Under the guidance of photoacoustic imaging/magnetic resonance imaging/fluorescence molecular imaging tumors can be completely eliminated under intracellular inside‐out hyperthermia with additive therapeutic effect due to precise hyperthermia.
Abstract Although high efficacy has been showed, Paclitaxel and Docetaxel cause serious side effects due to the adjuvant used in their clinical formulation Taxol® and Taxotere® . We developed a ...micelle system with a newly synthesized TPGS2k polymer, which shows lower CMC of 0.0219 mg/ml compared with 0.2 mg/ml for traditional micelles with TPGS involved, to achieve sustained and controlled drug delivery with Docetaxel used as a model anti-cancer drug. The TPGS2k micelles were further conjugated to folic acid (FA) for targeted drug delivery. The Docetaxel-loaded TPGS2k micelles with and without FA conjugation were found of desired size and size distribution, high drug encapsulation efficiency and favorable drug release. In vitro studies using MCF-7 cancer cells demonstrated significantly the higher cellular uptake of the formulated drug for TPGS2k micelle formulation than that for Taxotere® . The targeting effects for the FA conjugated TPGS2k micelles are also demonstrated. The IC50 value, which is the drug concentration needed for 50% cell viability in the designated time period, is 103.4, 1.280 and 0.1480 μg/ml for MCF-7 cancer cells after 24, 48, and 72 h treatment respectively, which is greatly decreased to be 0.526, 0.251 and 0.233 μg/ml, i.e . a 99.5%, 80.4% decrease and 57.5% increase for the TPGS2k micelle formulation, and further decreased to be 0.1780, 0.1520 and 0.1140 μg/ml, i.e . a 99.8%, 88.1% and 23.0% decrease for the folic acid conjugated micelles, respectively. A synergistic effect between TPGS2k and Docetaxel is also achieved. The present work represents a new concept in the design of drug delivery systems – the carrier materials of the drug delivery system can also have therapeutic effects, which either modulate the side effects of, or promote a synergistic interaction with the formulated drug.
Engineering biocompatible hydrogels using functional nanoparticles has attracted considerable attention because of their uniquely appealing cooperative effects that can enable multimodality imaging ...and treatment with improved efficacy against serious diseases. However, the effects of high‐content nanoparticle dopants on the rheological properties of hydrogels frequently lead to an unsatisfactory therapeutic result, which is particularly notable in the design of magnetic hydrogel formulations for cancer therapy. Herein is reported a novel magnetic hydrogel functionalized by ferromagnetic vortex‐domain iron oxide (FVIOs) with optimally adaptive functions for prevention of breast cancer recurrence. The FVIOs can perfectly incorporate into the dynamic hydrogel networks with an extremely low concentration (0.6 mg mL−1), 17 times lower than that of conventional superparamagnetic iron oxide nanoparticles with sufficient heating capacity. Such magnetic hydrogels exhibit high inductive heating and remarkable rheological properties simultaneously. Moreover, the self‐healing, self‐conformal ability, controlled release of loaded doxorubicin, biodegradation, and pH‐responsiveness of the magnetic hydrogel project their efficient sustainable therapeutic ability. In vivo postoperative treatment has further demonstrated the high efficacy of FVIO‐based magnetic hydrogels, as evidenced by the significant suppression of the local tumor recurrences compared to chemotherapy or hyperthermia alone. This unique magnetic hydrogel formulation with optimally adaptive functions shows strong potential in preventing relapses of various cancers.
A magnetic hydrogel with optimal adaptive functions is reported for the prevention of breast cancer postoperative recurrence. It overcomes the possible side effects of traditional magnetic hydrogels, exhibiting high inductive heating and remarkable rheological properties simultaneously. The utilization of unique properties of nanoscale materials to construct hydrogel formulation is critical for developing high‐efficient therapeutic approaches for postoperative recurrence and metastasis.
Nanotheranostics is to apply and further develop nanomedicine strategies for advanced theranostics. This review summarizes the various nanocarriers developed so far in the literature for ...nanotheranostics, which include polymer conjugations, dendrimers, micelles, liposomes, metal and inorganic nanoparticles, carbon nanotubes, and nanoparticles of biodegradable polymers for sustained, controlled and targeted co-delivery of diagnostic and therapeutic agents for better theranostic effects with fewer side effects. The theranostic nanomedicine can achieve systemic circulation, evade host defenses and deliver the drug and diagnostic agents at the targeted site to diagnose and treat the disease at cellular and molecular level. The therapeutic and diagnostic agents are formulated in nanomedicine as a single theranostic platform, which can then be further conjugated to biological ligand for targeting. Nanotheranostics can also promote stimuli-responsive release, synergetic and combinatory therapy, siRNA co-delivery, multimodality therapies, oral delivery, delivery across the blood-brain barrier as well as escape from intracellular autophagy. The fruition of nanotheranostics will be able to provide personalized therapy with bright prognosis, which makes even the fatal diseases curable or at least treatable at the earliest stage.
We developed a nanocarrier system of herceptin-conjugated nanoparticles of d-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate (TPGS)-cisplatin prodrug (HTCP NPs) for targeted co-delivery of ...cisplatin, docetaxel and herceptin for multimodality treatment of breast cancer of high human epidermal growth factor receptor 2 (HER2) overexpression. Co-polymers poly(lactic acid)-TPGS (PLA-TPGS) and carboxyl group-terminated TPGS (TPGS-COOH) were also added in the polymeric matrix to stabilize the prodrug nanoparticles and to facilitate herceptin conjugation. The HTCP NPs of high, moderate and low docetaxel versus cisplatin ratio were prepared by the nanoprecipitation method, which showed a pH-sensitive release for both anticancer drugs. The therapeutic effects of HTCP NPs were evaluated in vitro and compared with Taxotere® and cisplatin. The HTCP NPs of high docetaxel versus cisplatin ratio were found to have better efficacy than those of moderate and low docetaxel versus cisplatin ratio. The targeting effects of the HTCP NPs were demonstrated by a much lower IC50 value of 0.0201+0.00780+0.1629μg/mL of docetaxel+cisplatin+herceptin for SK-BR-3 cells, which are of high HER2 overexpression, than that of 0.225+0.0875+1.827μg/mL for NIH3T3 cells, which are of low HER2 overexpression, after 24h incubation. The same design of TPGS prodrug nanoparticles can also be applied for targeted co-delivery of other hydrophilic and hydrophobic drugs.
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A major problem in cancer treatment is the multidrug resistance. siRNA inhibitors have great advantages to solve the problem, if the bottleneck of their delivery could be well addressed by the ...various nanocarriers. Moreover, co-delivery of siRNA together with the various anticancer agents in one nanocarrier may maximize their additive or synergistic effect. This review provides a comprehensive summary on the state-of-the-art of the nanocarriers, which may include prodrugs, micelles, liposomes, dendrimers, nanohydrogels, solid lipid nanoparticles, nanoparticles of biodegradable polymers and nucleic acid nanocarriers for delivery of siRNA and co-delivery of siRNA together with anticancer agents with focus on synthesis of the nanocarrier materials, design and characterization, in vitro and in vivo evaluation, and prospect and challenges of nanocarriers.
Plant hormones modulate plant growth, development, and defense. However, many aspects of the origin and evolution of plant hormone signaling pathways remain obscure. Here, we use a comparative ...genomic and phylogenetic approach to investigate the origin and evolution of nine major plant hormone (abscisic acid, auxin, brassinosteroid, cytokinin, ethylene, gibberellin, jasmonate, salicylic acid, and strigolactone) signaling pathways. Our multispecies genome-wide analysis reveals that: (1) auxin, cytokinin, and strigolactone signaling pathways originated in charophyte lineages; (2) abscisic acid, jasmonate, and salicylic acid signaling pathways arose in the last common ancestor of land plants; (3) gibberellin signaling evolved after the divergence of bryophytes from land plants; (4) the canonical brassinosteroid signaling originated before the emergence of angiosperms but likely after the split of gymnosperms and angiosperms; and (5) the origin of the canonical ethylene signaling pathway postdates shortly the emergence of angiosperms. Our findings might have important implications in understanding the molecular mechanisms underlying the emergence of land plants.
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