Research

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9 pages, 1596 KiB

Open AccessArticle

Molecular Mechanisms of the Interactions of N-(2-Hydroxypropyl)methacrylamide Copolymers Designed for Cancer Therapy with Blood Plasma Proteins

by Larisa Janisova, Andrey Gruzinov, Olga V. Zaborova, Nadiia Velychkivska, Ondřej Vaněk, Petr Chytil, Tomáš Etrych, Olga Janoušková, Xiaohan Zhang, Clement Blanchet, Christine M. Papadakis, Dmitri I. Svergun and Sergey K. Filippov

Pharmaceutics 2020, 12(2), 106; https://doi.org/10.3390/pharmaceutics12020106 - 28 Jan 2020

Cited by 10 | Viewed by 3652

Abstract

The binding of plasma proteins to a drug carrier alters the circulation of nanoparticles (NPs) in the bloodstream, and, as a consequence, the anticancer efficiency of the entire nanoparticle drug delivery system. We investigate the possible interaction and the interaction mechanism of a [...] Read more.

The binding of plasma proteins to a drug carrier alters the circulation of nanoparticles (NPs) in the bloodstream, and, as a consequence, the anticancer efficiency of the entire nanoparticle drug delivery system. We investigate the possible interaction and the interaction mechanism of a polymeric drug delivery system based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers (pHPMA) with the most abundant proteins in human blood plasma—namely, human serum albumin (HSA), immunoglobulin G (IgG), fibrinogen (Fbg), and apolipoprotein (Apo) E4 and A1—using a combination of small-angle X-ray scattering (SAXS), analytical ultracentrifugation (AUC), and nuclear magnetic resonance (NMR). Through rigorous investigation, we present evidence of weak interactions between proteins and polymeric nanomedicine. Such interactions do not result in the formation of the protein corona and do not affect the efficiency of the drug delivery. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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18 pages, 5680 KiB

Open AccessArticle

Polymer Cancerostatics Containing Cell-Penetrating Peptides: Internalization Efficacy Depends on Peptide Type and Spacer Length

by Eliška Böhmová, Robert Pola, Michal Pechar, Jozef Parnica, Daniela Machová, Olga Janoušková and Tomáš Etrych

Pharmaceutics 2020, 12(1), 59; https://doi.org/10.3390/pharmaceutics12010059 - 10 Jan 2020

Cited by 11 | Viewed by 3342

Abstract

Cell-penetrating peptides (CPPs) are commonly used substances enhancing the cellular uptake of various cargoes that do not easily cross the cellular membrane. CPPs can be either covalently bound directly to the cargo or they can be attached to a transporting system such as [...] Read more.

Cell-penetrating peptides (CPPs) are commonly used substances enhancing the cellular uptake of various cargoes that do not easily cross the cellular membrane. CPPs can be either covalently bound directly to the cargo or they can be attached to a transporting system such as a polymer carrier together with the cargo. In this work, several CPP–polymer conjugates based on copolymers of N-(2-hydroxypropyl)methacrylamide (pHPMA) with HIV-1 Tat peptide (TAT), a minimal sequence of penetratin (PEN), IRS-tag (RYIRS), and PTD4 peptide, and the two short hydrophobic peptides VPMLK and PFVYLI were prepared and characterized. Moreover, the biological efficacy of fluorescently labeled polymer carriers decorated with various CPPs was compared. The experiments revealed that the TAT–polymer conjugate and the PEN–polymer conjugate were internalized about 40 times and 15 times more efficiently than the control polymer, respectively. Incorporation of dodeca(ethylene glycol) spacer improved the cell penetration of both studied polymer–peptide conjugates compared to the corresponding spacer-free polymer conjugates, while the shorter tetra(ethylene glycol) spacer improved only the penetration of the TAT conjugate but it did not improve the penetration of the PEN conjugate. Finally, a significantly improved cytotoxic effect of the polymer conjugate containing anticancer drug pirarubicin and TAT attached via a dodeca(ethylene glycol) was observed when compared with the analogous polymer–pirarubicin conjugate without TAT. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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16 pages, 3455 KiB

Open AccessArticle

Targeted Polymer-Based Probes for Fluorescence Guided Visualization and Potential Surgery of EGFR-Positive Head-and-Neck Tumors

by Robert Pola, Eliška Böhmová, Marcela Filipová, Michal Pechar, Jan Pankrác, David Větvička, Tomáš Olejár, Martina Kabešová, Pavla Poučková, Luděk Šefc, Michal Zábrodský, Olga Janoušková, Jan Bouček and Tomáš Etrych

Pharmaceutics 2020, 12(1), 31; https://doi.org/10.3390/pharmaceutics12010031 - 01 Jan 2020

Cited by 12 | Viewed by 3606

Abstract

This report describes the design, synthesis and evaluation of tumor-targeted polymer probes to visualize epidermal growth factor receptor (EGFR)-positive malignant tumors for successful resection via fluorescence guided endoscopic surgery. Fluorescent polymer probes of various molecular weights enabling passive accumulation in tumors via enhanced [...] Read more.

This report describes the design, synthesis and evaluation of tumor-targeted polymer probes to visualize epidermal growth factor receptor (EGFR)-positive malignant tumors for successful resection via fluorescence guided endoscopic surgery. Fluorescent polymer probes of various molecular weights enabling passive accumulation in tumors via enhanced permeability and retention were prepared and evaluated, showing an optimal molecular weight of 200,000 g/mol for passive tumor targeting. Moreover, poly(N-(2-hydroxypropyl)methacrylamide)-based copolymers labeled with fluorescent dyes were targeted with the EGFR-binding oligopeptide GE-11 (YHWYGYTPQNVI), human EGF or anti-EGFR monoclonal antibody cetuximab were all able to actively target the surface of EGFR-positive tumor cells. Nanoprobes targeted with GE-11 and cetuximab showed the best targeting profile but differed in their tumor accumulation kinetics. Cetuximab increased tumor accumulation after 15 min, whereas GE 11 needed at least 4 h. Interestingly, after 4 h, there were no significant differences in tumor targeting, indicating the potential of oligopeptide targeting for fluorescence-navigated surgery. In conclusion, fluorescent polymer probes targeted by oligopeptide GE-11 or whole antibody are excellent tools for surgical navigation during oncological surgery of head and neck squamous cell carcinoma, due to their relatively simple design, synthesis and cost, as well as optimal pharmacokinetics and accumulation in tumors. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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21 pages, 6836 KiB

Open AccessArticle

Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship

by Alena Braunová, Martin Kaňa, Júlia Kudláčová, Libor Kostka, Jan Bouček, Jan Betka, Milada Šírová and Tomáš Etrych

Pharmaceutics 2019, 11(11), 579; https://doi.org/10.3390/pharmaceutics11110579 - 05 Nov 2019

Cited by 12 | Viewed by 2946

Abstract

Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacrylamide) (PHPMA) [...] Read more.

Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacrylamide) (PHPMA) as potential macromolecular inhibitors of P-gp, and concurrently, carriers of drugs, passively targeting solid tumors by the enhanced permeability and retention (EPR) effect. Interestingly, there were significant differences between the effects of di- and tri- block polymer-based micelles, with the former being significantly more thermodynamically stable and showing much higher P-gp inhibition ability. The presence of Boc-protected hydrazide groups or the Boc-deprotection method did not affect the physico-chemical or biological properties of the block copolymers. Moreover, diblock polymer micelles could be loaded with free PPO containing 5–40 wt % of free PPO, which showed increased P-gp inhibition in comparison to the unloaded micelles. Loaded polymer micelles containing more than 20 wt % free PPO showed a significant increase in toxicity; thus, loaded diblock polymer micelles containing 5–15 wt % free PPO are potential candidates for in vitro and in vivo application as potent MDR inhibitors and drug carriers. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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19 pages, 5461 KiB

Open AccessArticle

Oxidation- and Temperature-Responsive Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) Micelle as a Potential Anticancer Drug Carrier

by Tae Hoon Kim, Madhusudhan Alle and Jin-Chul Kim

Pharmaceutics 2019, 11(9), 462; https://doi.org/10.3390/pharmaceutics11090462 - 06 Sep 2019

Cited by 13 | Viewed by 3810

Abstract

Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) (P(HEA-co-PVS)), as an oxidizable amphiphilic polymer, was prepared for the fabrication of an oxidation- and temperature-responsive micelle for the delivery of doxorubicin (DOX). The interfacial activity of H₂O₂-treated P(HEA-co-PVS) [...] Read more.

Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) (P(HEA-co-PVS)), as an oxidizable amphiphilic polymer, was prepared for the fabrication of an oxidation- and temperature-responsive micelle for the delivery of doxorubicin (DOX). The interfacial activity of H₂O₂-treated P(HEA-co-PVS) was significantly lower than that of the untreated variety, possibly because of the oxidization of PVS. P(HEA-co-PVS) exhibited a lower critical solution temperature (LCST) behavior and the LCST increased upon H₂O₂ treatment. The copolymer micelles, prepared by the dialysis method, were found to be round particles (less than 100 nm) on TEM micrograph. The release degree of Nile red loaded in the micelles was higher when the H₂O₂ concentration was higher, possibly because the micelles could be solubilized more readily at a higher H₂O₂ concentration. The release degree was more strongly dependent on the oxidizing agent concentration when the temperature was higher. DOX loaded in the micelles suppressed the in vitro growth of KB cells (a human cancer cell type originating from the cervix) much more effectively than DOX loaded in an unoxidizable control micelle and free DOX, possibly because the copolymer would undergo an increase in its LCST, lose its amphiphilic property, and the micelles would be disassembled. The DOX-loaded micelles were readily internalized into KB cells, as evidenced by flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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11 pages, 4109 KiB

Open AccessArticle

Hydroxyurea-Loaded Albumin Nanoparticles: Preparation, Characterization, and In Vitro Studies

by Yerkeblan Tazhbayev, Olzhas Mukashev, Meiram Burkeev and Jörg Kreuter

Pharmaceutics 2019, 11(8), 410; https://doi.org/10.3390/pharmaceutics11080410 - 12 Aug 2019

Cited by 21 | Viewed by 4093

Abstract

Human serum albumin nanoparticles (HSA-NPs) have been widely used as drug delivery systems. In most cases, HSA-NPs are formed by the method of desolvation in the presence of glutaraldehyde as a crosslinking agent. In the present study, we showed the possibility of crosslinking [...] Read more.

Human serum albumin nanoparticles (HSA-NPs) have been widely used as drug delivery systems. In most cases, HSA-NPs are formed by the method of desolvation in the presence of glutaraldehyde as a crosslinking agent. In the present study, we showed the possibility of crosslinking human serum albumin (HSA) molecules with natural agents, urea, and cysteine at the nanoparticle level under mild conditions (at room temperature of 20–25 °C). Optimal concentrations of the interacting components (HSA, urea, and cysteine) were found to produce nanoparticles with optimal physico-chemical parameters (particle size, polydispersity, zeta potential, yield, etc.) for application as drug carriers. We used hydroxyurea (HU), a simple organic compound currently used as a cancer chemotherapeutic agent. The results indicated sizes of 196 ± 5 nm and 288 ± 10 nm with a surface charge of −22 ± 3.4 mV and −17.4 ± 0.5 mV for HSA-NPs (20 mg/mL of HSA, 0.01 mg/mL of cysteine, and 10 mg/mL of urea) and HSA–HU-NPs (2 mg/mL of HU), respectively. The yield of the HSA–HU-NPs was ~93% with an encapsulation efficiency of ~77%. Thus, the particles created (immobilized with HU) were stable over time and able to prolong the effect of the drug. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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13 pages, 6252 KiB

Open AccessArticle

Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents

by Jun Fang, Rayhanul Islam, Waliul Islam, Hongzhuan Yin, Vladimir Subr, Tomas Etrych, Karel Ulbrich and Hiroshi Maeda

Pharmaceutics 2019, 11(7), 343; https://doi.org/10.3390/pharmaceutics11070343 - 16 Jul 2019

Cited by 46 | Viewed by 4433

Abstract

One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory [...] Read more.

One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory anticancer nanomedicine. In this study, we focused on one vascular mediator involved in the EPR effect, carbon monoxide (CO), and utilized two CO generating agents, one is an extrinsic CO donor (SMA/CORM2 micelle) and another is an inducer of endogenous CO generation via heme oxygenase-1 (HO-1) induction that is carried out using pegylated hemin. Both agents generated CO selectively in solid tumors, which resulted in an enhanced EPR effect and a two- to three-folds increased tumor accumulation of nanodrugs. An increase in drug accumulation in the normal tissue did not occur with the treatment of CO generators. In vivo imaging also clearly indicated a more intensified fluorescence of macromolecular nanoprobe in solid tumors when combined with these CO generators. Consequently, the combination of CO generators with anticancer nanodrugs resulted in an increased anticancer effect in the different transplanted solid tumor models. These findings strongly warrant the potential application of these CO generators as EPR enhancers in order to enhance tumor detection and therapy using nanodrugs. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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25 pages, 9954 KiB

Open AccessArticle

Paclitaxel Magnetic Core–Shell Nanoparticles Based on Poly(lactic acid) Semitelechelic Novel Block Copolymers for Combined Hyperthermia and Chemotherapy Treatment of Cancer

by Evi Christodoulou, Maria Nerantzaki, Stavroula Nanaki, Panagiotis Barmpalexis, Kleoniki Giannousi, Catherine Dendrinou-Samara, Makis Angelakeris, Eleni Gounari, Antonis D. Anastasiou and Dimitrios N. Bikiaris

Pharmaceutics 2019, 11(5), 213; https://doi.org/10.3390/pharmaceutics11050213 - 03 May 2019

Cited by 19 | Viewed by 4005

Abstract

Magnetic hybrid inorganic/organic nanocarriers are promising alternatives for targeted cancer treatment. The present study evaluates the preparation of manganese ferrite magnetic nanoparticles (MnFe₂O₄ MNPs) encapsulated within Paclitaxel (PTX) loaded thioether-containing ω-hydroxyacid-co-poly(d,l-lactic acid) (TEHA-co-PDLLA) polymeric nanoparticles, for [...] Read more.

Magnetic hybrid inorganic/organic nanocarriers are promising alternatives for targeted cancer treatment. The present study evaluates the preparation of manganese ferrite magnetic nanoparticles (MnFe₂O₄ MNPs) encapsulated within Paclitaxel (PTX) loaded thioether-containing ω-hydroxyacid-co-poly(d,l-lactic acid) (TEHA-co-PDLLA) polymeric nanoparticles, for the combined hyperthermia and chemotherapy treatment of cancer. Initially, TEHA-co-PDLLA semitelechelic block copolymers were synthesized and characterized by ¹H-NMR, FTIR, DSC, and XRD. FTIR analysis showed the formation of an ester bond between the two compounds, while DSC and XRD analysis showed that the prepared copolymers were amorphous. MnFe₂O₄ MNPs of relatively small crystallite size (12 nm) and moderate saturation magnetization (64 emu·g⁻¹) were solvothermally synthesized in the sole presence of octadecylamine (ODA). PTX was amorphously dispersed within the polymeric matrix using emulsification/solvent evaporation method. Scanning electron microscopy along with energy-dispersive X-ray spectroscopy and transmission electron microscopy showed that the MnFe₂O₄ nanoparticles were effectively encapsulated within the drug-loaded polymeric nanoparticles. Dynamic light scattering measurements showed that the prepared nanoparticles had an average particle size of less than 160 nm with satisfactory yield and encapsulation efficiency. Diphasic PTX in vitro release over 18 days was observed while PTX dissolution rate was mainly controlled by the TEHA content. Finally, hyperthermia measurements and cytotoxicity studies were performed to evaluate the magnetic response, as well as the anticancer activity and the biocompatibility of the prepared nanocarriers. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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Review

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28 pages, 7970 KiB

Open AccessReview

Fluorescence Imaging as a Tool in Preclinical Evaluation of Polymer-Based Nano-DDS Systems Intended for Cancer Treatment

by Tomáš Etrych, Olga Janoušková and Petr Chytil

Pharmaceutics 2019, 11(9), 471; https://doi.org/10.3390/pharmaceutics11090471 - 12 Sep 2019

Cited by 24 | Viewed by 4659

Abstract

Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and [...] Read more.

Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and structure of the nano-sized carrier is crucial for the successful transition of targeted drug delivery nanomedicines into clinical practice. In preclinical research in particular, fluorescence imaging has become one of the most commonly used powerful imaging tools. Increasing numbers of suitable fluorescent dyes that are excitable in the visible to near-infrared (NIR) wavelengths of the spectrum and the non-invasive nature of the method have significantly expanded the applicability of fluorescence imaging. This chapter summarizes non-invasive fluorescence-based imaging methods and discusses their potential advantages and limitations in the field of drug delivery, especially in anticancer therapy. This chapter focuses on fluorescent imaging from the cellular level up to the highly sophisticated three-dimensional imaging modality at a systemic level. Moreover, we describe the possibility for simultaneous treatment and imaging using fluorescence theranostics and the combination of different imaging techniques, e.g., fluorescence imaging with computed tomography. Full article

(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)

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