Self-Assembly of pH-Labile Polymer Nanoparticles for Paclitaxel Prodrug Delivery: Formulation, Characterization, and Evaluation

The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to α-tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro); this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC50) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC50 concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency.

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Decreased cytotoxic effects of doxorubicin in a human ovarian cancer-cell line expressing wild-typep53 andWAF1/CIP1 genes

International Journal of Cancer ◽

10.1002/ijc.2910610320 ◽

1995 ◽

Vol 61 (3) ◽

pp. 397-401 ◽

Cited By ~ 22

Author(s):

Faina Vikhanskaya ◽

Maurizio D'Incalcimassimo Broggini

Keyword(s):

Ovarian Cancer ◽

Cell Line ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Human Ovarian Cancer ◽

Human Ovarian Cancer Cell ◽

Cytotoxic Effects

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DIFFERENTIAL EXPRESSION OF MTOR COMPONENTS IN ENDOMETRIOSIS AND ENDOMETRIOID OVARIAN CANCER CELL LINE: EFFECTS OF RAPAMYCIN, RESVERATROL AND BEZ-235

10.26226/morressier.597eedbbd462b80296ca1bb1 ◽

2017 ◽

Author(s):

Chatterjee Jayanta

Keyword(s):

Ovarian Cancer ◽

Cell Line ◽

Differential Expression ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Endometrioid Ovarian Cancer

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Cytotoxic Effect of 5-Fluorouracil-loaded Polymer-coated Magnetite Nanographene Oxide Combined with Radiofrequency

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180404151218 ◽

2018 ◽

Vol 18 (8) ◽

pp. 1148-1155 ◽

Cited By ~ 6

Author(s):

Leili Asadi ◽

Sakine Shirvalilou ◽

Sepideh Khoee ◽

Samideh Khoei

Keyword(s):

Cellular Uptake ◽

Cancer Cell Line ◽

Superparamagnetic Iron Oxide ◽

Colon Cancer Cell Line ◽

Cytotoxic Effects ◽

Proliferation Capacity ◽

Capacity Level ◽

Colony Number ◽

Nano Graphene ◽

Dialysis Bag

Background: Despite the development of conventional therapies including surgery, radiotherapy, chemotherapy and hyperthermia, the prognosis remains very poor. Recently, integration of conventional therapy and multifunctional nanoparticles have attracted a lot of attention because it produces a synergistic effect and better diagnostic and therapeutic efficiency. Objective: This study aimed to investigate the uptake and cytotoxic effects of Polycaprolactone (PCL)/chitosan (CHI)-coated Superparamagnetic Iron Oxide Nano-Graphene Oxide (SPION-NGO) as a carrier of 5-fluorouracil (5-Fu) and Radiofrequency (RF) hyperthermia using an Alternate Magnetic Field (AMF) with 13.56 MHz frequency on the proliferation capacity level of CT26 colon cancer cell line in a monolayer culture. Method: The release of the newly synthesised 5-Fu-loaded PCL/CHI-SPION-NGO was measured in Phosphate Buffered Saline (PBS) using the dialysis bag method. The cellular uptake of 5-Fu-loaded PCL/CHI-SPIONNGO was measured using Atomic Absorption Spectroscopy (AAS). The cytotoxic effects of 5-Fu, 5-Fu- PCL/CHI-SPION-NGO and PCL/CHI-SPION-NGO with and without RF hyperthermia were determined using the colony formation assay. Results: Particle size and zeta potential of 5-Fu-PCL/CHI-SPION-NGO and PCL/CHI-SPION-NGO were 61.2 nm and -1.87 mV and 43.4 nm and -10.19 mV, respectively. Spectroscopy results demonstrated that the cellular uptake of 5-Fu-PCL/CHI-SPION-NGO increased with elevated nanostructure concentrations. The results revealed that the proliferation capacity of the cells decreased with 5-Fu or 5-Fu-PCL/CHI-SPION-NGO in combination with RF hyperthermia. Furthermore, extent of reduction in colony number following treatment with 5-Fu-PCL/CHI-SPION-NGO in combination with AMF was significantly more than 5-Fu + hyperthermia. Conclusion: Therefore, PCL/CHI-SPION-NGO can deliver 5-Fu more efficiently into the CT26 cells.

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Inhibition of MMP2-PEX by a novel ester of dihydroxy cinnamic and linoleic acid from the seagrass Cymodocea serrulata

Scientific Reports ◽

10.1038/s41598-021-90845-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

V. S. Christina ◽

R. Lakshmi Sundaram ◽

V. Sivamurugan ◽

D. Thirumal Kumar ◽

C. D. Mohanapriya ◽

...

Keyword(s):

Cancer Cell ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Md Simulations ◽

Cell Types ◽

Structural Details ◽

M Phase ◽

Ft Ir ◽

Target Binding ◽

Cymodocea Serrulata

AbstractMatrix metalloproteinases (MMPs) are pivotal for cancer cell migration and metastasis which are generally over-expressed in such cell types. Many drugs targeting MMPs do so by binding to the conserved catalytic domains and thus exhibit poor selectivity due to domain-similarities with other proteases. We report herein the binding of a novel compound [3-(E-3,4-dihydroxycinnamaoyloxyl)-2-hydroxypropyl 9Z, 12Z-octadeca-9, 12-dienoate; Mol. wt: 516.67 Da], (C1), isolated from a seagrass, Cymodocea serrulata to the unconserved hemopexin-like (PEX) domain of MMP2 (− 9.258 kcal/mol). MD simulations for 25 ns, suggest stable ligand-target binding. In addition, C1 killed an ovarian cancer cell line, PA1 at IC50: 5.8 μM (lesser than Doxorubicin: 8.6 µM) and formed micronuclei, apoptotic bodies and nucleoplasmic bridges whilst causing DNA laddering, S and G2/M phase dual arrests and MMP disturbance, suggesting intrinsic apoptosis. The molecule increased mRNA transcripts of BAX and BAD and down-regulated cell survival genes, Bcl-xL, Bcl-2, MMP2 and MMP9. The chemical and structural details of C1 were deduced through FT-IR, GC–MS, ESI–MS, 1H and 13C NMR [both 1D and 2D] spectra.

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The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-09979-x ◽

2021 ◽

Author(s):

Kalyani Patil ◽

Farheen B. Khan ◽

Sabah Akhtar ◽

Aamir Ahmad ◽

Shahab Uddin

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Disease Recurrence ◽

Resistance Mechanisms ◽

Cytotoxic Agents ◽

Plastic State ◽

Metastatic Progression ◽

Acquired Drug Resistance ◽

Natural Agents

AbstractThe ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

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Extracellular Matrix Proteins Expression Profiling in Chemoresistant Variants of the A2780 Ovarian Cancer Cell Line

BioMed Research International ◽

10.1155/2014/365867 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 38

Author(s):

Radosław Januchowski ◽

Piotr Zawierucha ◽

Marcin Ruciński ◽

Michał Nowicki ◽

Maciej Zabel

Keyword(s):

Ovarian Cancer ◽

Extracellular Matrix ◽

Drug Resistance ◽

Cell Line ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Altered Expression ◽

Expression Levels

Ovarian cancer is the leading cause of death among gynaecological malignancies. Extracellular matrix (ECM) can affect drug resistance by preventing the penetration of the drug into cancer cells and increased resistance to apoptosis. This study demonstrates alterations in the expression levels of ECM components and related genes in cisplatin-, doxorubicin-, topotecan-, and paclitaxel-resistant variants of the A2780 ovarian cancer cell line. Affymetrix Gene Chip Human Genome Array Strips were used for hybridisations. The genes that had altered expression levels in drug-resistant sublines were selected and filtered by scatter plots. The genes that were up- or downregulated more than fivefold were selected and listed. Among the investigated genes, 28 genes were upregulated, 10 genes were downregulated, and two genes were down- or upregulated depending on the cell line. Between upregulated genes 12 were upregulated very significantly—over 20-fold. These genes included COL1A2, COL12A1, COL21A1, LOX, TGFBI, LAMB1, EFEMP1, GPC3, SDC2, MGP, MMP3, and TIMP3. Four genes were very significantly downregulated: COL11A1, LAMA2, GPC6, and LUM. The expression profiles of investigated genes provide a preliminary insight into the relationship between drug resistance and the expression of ECM components. Identifying correlations between investigated genes and drug resistance will require further analysis.

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