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Ovarian cancer (OC) is the most lethal gynecologic cancer. Survival statistics have show no significant developments over the last three decades, highlighting the fact that current therapeutic strategies require substantial improvements. In this study, we designed a novel folic acid-PEG-conjugated p-phosphonated calix[4]arene nanoparticle (Fp-PCN) for the simultaneous delivery of paclitaxel (PAC) and carboplatin (CAR) at an optimal ratio (5 : 1, mol : mol) to utilize their potential synergistic effect against OC cells. The Fp-PCNs loaded with PAC and CAR (Fp-PCN PAC+CAR ) resulted in a remarkable efficacy in the suppression of OC, both in vitro and in vivo. Compared to free drugs, Fp-PCN PAC+CAR showed stronger apoptosis induction as well as invasion and self-renewal capacity suppression in SKOV-3 cells. The molecular mechanism to address the synergism is that Fp-PCN PAC+CAR downregulated JMJD3 expression to modulate the H3K27me3 epigenetic mark of the promoters of HER2 and MYCN. Furthermore, the expressions of JMJD3 and HER2 were significantly associated with poor outcomes for ovarian patients. Our study demonstrates that co-delivery of PAC and CAR can be achieved with the Fp-PCNs, and reveals a previously unrecognized and unexpected role of the JMJD3-HER2 signaling axis in PAC and CAR treatment of OC.

A modular p-phosphonated calix[4]arene vesicle (PCV) loaded with paclitaxel (PTX) and conjugated with folic acid as a cancer targeting ligand has been prepared using a thin film-sonication method. It has a pH-responsive capacity to trigger the release of the encapsulated PTX payload under mildly acidic conditions. PTX-loaded PCV conjugated with alkyne-modified PEG-folic acid ligands prepared via click ligation (fP-PCVPTX) has enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumour cells over FR-negative A549 lung tumour cells. Moreover, fP-PCVPTX is also four times more potent than the non-targeting PCVPTX platform towards SKOV-3 cells. Overall, as a delivery platform the PCVs have the potential to enhance efficacy of anticancer drugs by targeting a chemotherapeutic payload specifically to tumours and triggering the release of the encapsulated drug in the vicinity of cancer cells.

Carboplatin and paclitaxel co-loaded nanovesicles (CPT-PTX-CLV), a novel intravenous formulation void of cremophor EL, may have significant advantages over conventional carboplatin and paclitaxel formulations with respect to tumor targeting, sustained drug release, reduced toxicity, and synergistic efficacy profiles. The aim of this study was to develop and validate a rapid, specific, sensitive, and reliable liquid chromatography-time of flight-mass spectrometry (LC/TOF MS)-based bioanalytical method for the simultaneous quantification of CPT and PTX in a fetal bovine serum (FBS) vehicle containing the dispersed nanovesicles. The analytes were extracted from FBS by simple protein precipitation, with subsequent separation of CPT and PTX on a Waters HPLC SunFire C18 column at a flow rate of 0.25 ml/min using gradient elution mode. The total analytical time was only 12 min. Detection and quantitation was performed by electrospray ionization (ESI) in the positive ionization mode with selective ion monitoring (SIM) at m/z 310.0152 for CPT and 876.3224 for PTX. The calibration curves were linear over the concentration range of 10-4,000 ng/ml for CPT and 5-2,000 ng/ml for PTX (r (2)  > 0.99), with the respective lower limit of quantification (LLOQ) at 10 and 5 ng/ml. The intra- and inter-day precision and accuracy of analysis of the quality control samples at low, medium, and high concentration levels were ≤13.6 % relative standard deviation (RSD) and ≤14.6 % relative errors (RE). The rapid, sensitive, and reproducible LC/TOF MS method may be used to support preclinical and clinical pharmacological studies of the CPT-PTX-CLV administered by injection in animal and human cancer models.

Objectives: This paper describes the development and optimization of a nanoparticle delivery platform for the anticancer agent, paclitaxel, using a novel amphiphilic carrier, tetrahexyloxy-tetra-p-aminocalix[4]arene (A4C(6) )., Methods: Nanoparticles were successfully prepared at pH4 by an emulsion evaporation method whereby an organic phase containing paclitaxel: A4C(6) (molar ratio 1:10) was dispersed by probe sonication into an aqueous phase containing 0.5% w/v polyvinyl alcohol as stabilizer., Key Findings: The drug-loaded nanoparticles had a mean size of 78.7±20.7nm, surface potential of 38.3±7.67mV, and paclitaxel loading and encapsulation efficiencies of 69.1±5.3µg drug/mg carrier and 50.4±3.2%, respectively. Transmission electron micrographs showed discrete particles with no evidence of agglomeration. In-vitro dissolution into phosphate buffered saline supplemented with 4% bovine serum albumin showed 32.7±3.9%, 82.6±5.3% and 91.0±6.0% of the encapsulated paclitaxel load was released at 5, 72 and 120h, respectively., Conclusions: This is the first report on the use of amino-substituted amphiphilic calixarenes for the encapsulation of anticancer agents. The nanoparticles produced were significantly smaller than, but had comparable drug loads to the Abraxane nanoparticles, and have the potential to achieve targeted delivery of paclitaxel to tumour tissues., (© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.)

The purpose of this study was to investigate the potentiation of the anticancer activity and enhanced cellular retention of paclitaxel-loaded PLGA nanoparticles after surface conjugation with wheat germ agglutinin (WGA) against colon cancer cells. Glycosylation patterns of representative colon cancer cells confirmed the higher expression levels of WGA-binding glycoproteins in the Caco-2 and HT-29 cells, than in the CCD-18Co cells. Cellular uptake and in vitro cytotoxicity of WNP (final formulation) against colon cell lines was evaluated alongside control formulations. Confocal microscopy and quantitative analysis of intracellular paclitaxel were used to monitor the endocytosis and retention of nanoparticles inside the cells. WNP showed enhanced anti-proliferative activity against Caco-2 and HT-29 cells compared to corresponding nanoparticles without WGA conjugation (PNP). The greater efficacy of WNP was associated with higher cellular uptake and sustained intracellular retention of paclitaxel, which in turn was attributed to the over-expression of N-acetyl-D-glucosamine-containing glycoprotein on the colon cell membrane. WNP also demonstrated increased intracellular retention in the Caco-2 (30% of uptake) and HT-29 (40% of uptake) cells, following post-uptake incubation with fresh medium, compared to the unconjugated PNP nanoparticles (18% in Caco-2) and (27% in HT-29), respectively. Cellular trafficking study of WNP showed endocytosed WNP could successful escape from the endo-lysosome compartment and release into the cytosol with increasing incubation time. It may be concluded that WNP has the potential to be applied as a targeted delivery platform for paclitaxel in the treatment of colon cancer., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Purpose: To potentiate the anticancer activity of paclitaxel-loaded PLGA nanoparticles through surface conjugation with wheat germ agglutinin (WGA)., Methods: PLGA nanoparticles loaded with paclitaxel and isopropyl myristate (IPM) as release modifier were prepared by a solvent evaporation method. WGA was conjugated to the nanoparticle surface to give novel WIT-NP of 330+/-3 nm. In vitro cytotoxicity of WIT-NP against malignant (A549 and H1299) and normal (CCL-186) pulmonary cell lines was evaluated alongside control formulations. IC50 doses were determined by the MTT assay, while cellular apoptosis was detected by cell nuclei staining and DeadEndtrade mark Fluorometric TUNEL assay. Cell cycle arrest was confirmed by flow cytometry. Cellular uptake of 3[H]-paclitaxel from the test and control formulations was also quantified. In vivo anticancer efficacy was evaluated in the SCID mice model engrafted with the A549 tumor nodule., Results: WIT-NP had superior anti-proliferation activity against the A549 and H1299 cell lines compared with conventional paclitaxel formulations as measured by IC50 doses. This was attributed to a more efficient intracellular accumulation of paclitaxel via WGA-receptor-mediated endocytosis and IPM-facilitated intracellular paclitaxel release. WIT-NP activity was associated with paclitaxel-induced apoptosis and cell arrest in the G2/M phase. A single intratumoral injection of WIT-NP at paclitaxel dose of 10 mg/kg inhibited the growth of A549 tumor nodules without inducing significant weight loss in the SCID mice over a period of 25 days. Tumor doubling time was greater than 25 days, compared with 11 days for nodules treated with conventional paclitaxel formulation., Conclusion: The formulation of WIT-NP, in which WGA is conjugated to the surface of paclitaxel and IPM-loaded PLGA nanoparticles, significantly potentiates the anticancer activity of paclitaxel.

The purpose of this study was to develop a novel lectin-conjugated isopropyl myristate (IPM)-incorporated PLGA nanoparticle system (NP) for the local delivery of paclitaxel to the lungs. Wheat germ agglutinin (WGA) was conjugated onto preformed IPM- and paclitaxel-loaded PLGA NPs by a two-step carbodiimide method following comparative uptake studies of Concanavalin A, Ricinus communis-120 and WGA on A549, H1299 and CCL-186 cells. WIT-NP with mean diameter of 331 nm and zeta potential of -4.3 mV were prepared with yield of 66% and paclitaxel encapsulation efficiency of 61%. Particle size was expanded by surface conjugation with WGA, while zeta potential was reduced by the addition of IPM and WGA. In vitro paclitaxel release profile was not affected by WGA but initial drug release was enhanced by adding IPM into the formulation. The WIT-NP showed a burst-release of about 32% of the paclitaxel load within the first 5 h followed by a slow zero-order release of another 7% of the drug load in the next 115 h. Compared with the clinical paclitaxel formulation, paclitaxel-loaded nanoparticles without IPM or WGA, or paclitaxel-loaded nanoparticles with only IPM or WGA, the WIT-NP had superior in vitro cytotoxicity against A549 and H1299 cells. IC50 for WIT-NP after 5 and 24 h incubation with A549 cells were not significantly different (15.5 and 15 microM, respectively) whereas the clinical formulation was not cytotoxic after 5 h but had IC50 of 14 microM after 24 h incubation. WIT-NP exhibited stronger cell-killing effect because of more efficient cellular uptake via WGA-receptor-mediated endocytosis and IPM-facilitated release of paclitaxel from the NPs.