Water-soluble Polymer Carrier Research Articles

Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical applications of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering.To address the limitation, we developed N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WDCLDNRIGRRQCVKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as PH-cDR5 (high valence), PM-cDR5 (medium valence) and PL-cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells PM-cDR5 exhibited an IC50 of 94 pM, while PH-cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC50 for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy.

Improved drug transfer into brain tissue via the “nose-to-brain” approach using suspension or powder formulations based on the amorphous solid dispersion technique

Intranasal administration has attracted increasing attention as a drug delivery approach based on nose-to-brain drug delivery from the nasal cavity to brain tissue directly, bypassing the blood–brain barrier. However, application of the method to poorly water-soluble drugs is potentially limited due to low aqueous solubility and dissolution, which can hinder drug transfer to brain tissue. In the present study, we focused on an amorphous solid dispersion (ASD) technique to improve drug dissolution. A carbamazepine-loaded ASD model drug was prepared using the solvent evaporation method (ASD-1). After screening six water-soluble polymer carriers, polyvinyl alcohol (PVA)-based ASD-1 formulation exhibited the most rapid and highest drug dissolution under experimental conditions in the nasal cavity (pH 6.0). A carbamazepine suspension dispersed with a PVA-ASD-1 formulation exhibited enhanced drug delivery into plasma and brain tissue of rats in vivo. A spray-dried powder formulation of PVA-ASD (PVA-ASD-2) exhibited improved drug dissolution and in vivo drug transfer. Our key finding is that the spray-dried PVA-ASD-2 formulation exhibited higher brain/plasma ratios than the PVA-ASD-1 suspension formulation. Our physical characterization data and demonstration of improved drug transfer suggest that ASD-based intranasal formulations hold promise for drug delivery to the brain.

Laccase-catalyzed surface oxidation of poly(2-hydroxyethyl methacrylate) contact lens hydrogel using polyvinylamine-graft-TEMPO as mediator

Surface oxidation is a commonly used surface modification method for macromolecular biomaterials, which can increase the surface hydrophilicity and biocompatibility, and provide active sites for subsequent functional modifications. The nitroxyl radical, as represented by TEMPO, could act as an electron transfer mediator in the catalytic oxidation reaction in aqueous phase. By immobilizing TEMPO on a water-soluble polymer carrier polyvinylamine (PVAm) and using laccase as a catalyst, the surface of poly(2-hydroxyethyl methacrylate) (pHEMA) contact lens hydrogel can be selectively oxidized. Herein, polyvinylamine-graft-TEMPO was used as a polymeric electron transfer mediator to confine the oxidation reaction within the surface of the pHEMA hydrogel. The oxidized hydrogel with surface aldehydes was subsequently coated with hyaluronic acid, which gained low rate of water loss and low protein adsorption. This surface oxidation method can provide new ways for the activation, modification, and function expansion for the surface of polymeric biomaterials especially contact lens hydrogels.

PH-Responsive Water-Soluble Polymer Carriers for Cell-Selective Metabolic Sialylation Labeling.

Cell-surface sialic acids can be metabolically labeled and subsequently modified using bioorthogonal chemistry. The method has great potential for targeted therapy and imaging; however, distinguishing the sialylation of specific cells remains a major challenge. Here, we described a cell-selective metabolic sialylation labeling strategy based on water-soluble polymer carriers presented with pH-responsive N-azidoacetylmannosamine (ManNAz) release. 2-Methacryloyloxyethyl phosphorylcholine contributed to increased water solubility and reduced nonspecific attachment to cells. Lactobionic acid residues, used for cell selectivity, recognized overexpressed receptors on target hepatoma cells and mediated cellular internalization. ManNAz caged by acidic pH-responsive carbonated ester linkage on the polymer was released inside target cells and expressed as azido sialic acid. Additionally, longer copolymer carriers enhanced the metabolic labeling efficiency of sialylation. This approach provides a platform for cell-selective labeling of sialylation and can be applied to high-resolution bioimaging and targeted therapy.

HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery.

Recently, numerous polymer materials have been employed as drug carrier systems in medicinal research, and their detailed properties have been thoroughly evaluated. Water-soluble polymer carriers play a significant role between these studied polymer systems as they are advantageously applied as carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, antimicrobial molecules, or multidrug resistance inhibitors. Covalent attachment of carried molecules using a biodegradable spacer is strongly preferred, as such design ensures the controlled release of the drug in the place of a desired pharmacological effect in a reasonable time-dependent manner. Importantly, the synthetic polymer biomaterials based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are recognized drug carriers with unique properties that nominate them among the most serious nanomedicines candidates for human clinical trials. This review focuses on advances in the development of HPMA copolymer-based nanomedicines within the passive and active targeting into the place of desired pharmacological effect, tumors, inflammation or bacterial infection sites. Specifically, this review highlights the safety issues of HPMA polymer-based drug carriers concerning the structure of nanomedicines. The main impact consists of the improvement of targeting ability, especially concerning the enhanced and permeability retention (EPR) effect.

Polymer Derivatives of Anticancer Drugs: Features of Synthesis and Biological Activity

The state of the development of polymeric derivatives of anticancer agents for selective delivery is assessed, and relevant directions for further development and improvement in this field are identified. As part of the work, the available data on polymeric derivatives of anticancer preparations was analyzed, and the relevant unsolved problems in this direction were determined. Polymer systems for the selective delivery of anticancer agents, such as polymer micelles, polymer conjugates, polymer complexes, and nanohydrogels, are considered. The analysis was performed with respect to first-line therapy preparations (doxorubicin, cisplatin, 5-fluorouracil). The features of the synthesis of polymer systems for selective delivery are considered. The main directions of binding of the drug to the polymer carrier are determined. The advantage of polymeric carriers is their high molecular weight, which ensures the best pharmacokinetic parameters. The use of water-soluble carriers makes it possible to obtain simple injection systems, and the presence of functional groups in the polymer chain enables the polymer to be modified with various drugs and vectors for tumor cells. Such systems may also contain components (vectors) that “recognize” tumor cells, which increases the level of specific drug interactions with the target cell. Folic acid can be such a vector, since the expression of its receptors is higher for some tumor cells than for normal ones. Another example is steroid hormone residue; there are a sufficient number of its receptors on the surface of cancer cells. These compounds, which are used as cancer cell vectors, are poorly soluble in water. These substances become chemically attached to a water-soluble polymer carrier at a specific concentration. The system then becomes water-soluble. There are practically no studies on the search for and use of carrier polymers with their own pharmacological activity, including antitumor and immunostimulating. Polymethacrylates are a class of anionic polymers with their own potential pharmacological activity, which is associated with activation of the immune system. There are promising areas of research in this field: the determination of the optimal conditions for the synthesis of a water-soluble anionic polymer carrier based on methacrylic acid with the characteristics of a given molecular weight; the determination of the cytotoxicity of potential polymeric carriers in an in vitro cell culture and of the dependence of the cytotoxic effect on the molecular-weight characteristics of the polymer; the production of polymeric conjugates of doxorubicin, 5-fluorouracil, cisplatin, and their combinations; the study of the effect of molecular-weight characteristics, the structure of the polymer chain, and the degree of chemical modification of (co)polymers on the release of drugs from the polymer system under conditions simulating biosystems and on the cytotoxicity of polymer conjugates in vitro and in vitro; and the determination of their own immunostimulating properties (the study of the activation of macrophages under the action of polymers) of polymeric carriers with respect to the molecular weight, polydispersity, and the presence of hydrophilic anionic groups.

Solid dispersions to enhance the delivery of a potential drug candidate LPSF/FZ4 for the treatment of schistosomiasis

Drug candidate LPSF/FZ4 with promising schistosomicidal properties in vitro was previously synthesized. However, LPSF/FZ4 has limited aqueous solubility (<1 μg/mL), leading to ineffective dissolution and, therefore, no meaningful in vivo comparative studies could be pursued. This study was aimed to develop a proper amorphous solid dispersion (SD) to enhance the solubility and dissolution rate of LPSF/FZ4 such that its biological activity could be investigated. To better understand its physiological behavior, the pKa of LPSF/FZ4, a monoprotic weak acid with NH group at the imidazolidine ring, was first determined to be 8.13 using an automated SiriusT3. The development of SD systems for LPSF/FZ4 involved the evaluation of various water-soluble polymer carriers such as PVP K-29/32, PVP K-90, HPMC K4M, PVPVA 64 and SOLUPLUS®. The most promising SD systems were selected through in vitro dissolution studies under nonsink conditions, together with physicochemical characterization as well as accelerated stability study. It was shown that SD of 10% LPSF/FZ4 in SOLUPLUS® and PVP K-90 could significantly increase the area-under-the-curve value of the nonsink dissolution profile (AUC values of the SD in SOLUPLUS® and PVP K-90 were 1381.03 and 1342.34 μL/mL·min, respectively, and that of the pure crystalline drug was 0.02 μL/mL·min), a useful surrogate for the in vivo bioavailability. Cmax values for the SD in SOLUPLUS® (12.50 μL/mL) and PVP K-90 (25.86 μL/mL) were also higher than the one of the crystalline drug (0.02 μL/mL). The SD system of LPSF/FZ4 in SOLUPLUS® showed a significant increase in schistosomicidal activity in an animal model as compared with the conventional treatment using crystalline drug, consistent with the AUC trend from the nonsink dissolution. Thus this SD system of LPSF/FZ4 could be useful as a potential formulation for treating schistosomiasis.

HPMA Copolymer-Drug Conjugates with Controlled Tumor-Specific Drug Release.

Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water-soluble polymer carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity.

Seven years of radionuclide laboratory at IMC - important achievements.

For many important research topics in polymer science the use of radionuclides brings significant benefits concerning nanotechnology, polymer drug delivery systems, tissue engineering etc. This contribution describes important achievements of the radionuclide laboratory at Institute of Macromolecular Chemistry of the Academy of Sciences of the Czech Republic (IMC) in the area of polymers for biomedical applications. Particular emphasis will be given to water-soluble polymer carriers of radionuclides, thermoresponsive polymer radionuclide carriers, thermoresponsive polymers for local brachytherapy, polymer scaffolds modified with (radiolabeled) peptides and polymer copper chelators for the therapy of Wilson´s disease.

Synthesis of pH-sensitive, water-soluble paclitaxel prodrugs based on norbornene-functional polylactide by copper-free click chemistry

ABSTRACTIn this study, a novel polymeric prodrug based on norbornene-functional polylactide with functionalized paclitaxels (LEV-PTXL) covalently conjugated to water-soluble polymer carrier via a pH-sensitive hydrazone bond was developed. A series of water-soluble PTXL prodrugs with decent drug contents of 17.3 and 24.7 wt% (denoted as PTXL prodrugs 1 and 2) were prepared. The molecular structures and characteristics were confirmed by 1H NMR, Fourier transform infrared, and gel permeation chromatography. In vitro release studies showed that PTXL release rate from polymeric prodrug were significantly accelerated under acidic medium, due to the acid-cleavable hydrazone linkage. As illustrated by cytotoxicity study, while the corresponding polymer carrier was nontoxic, the polymeric prodrug exhibited higher therapeutic efficacy toward MCF-7 and A549 (IC50 = 0.19 and 4.94 µg PTXL equiv/mL, respectively) cancer cells. The norbornene-functional polylactide-based polymeric prodrug has appeared as a novel anticancer nanomedicine for cancer therapy.

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH).

Water-soluble polymer carriers. Ionically bonded substances with physiological activity

The preparation of water-soluble polymers with physiological activity via ion bonding of low molecular weight physiologically active substances to a polymer carrier has been studied. The conditions for obtaining polymer salts of physiologically active substances with acid properties and amino-containing polymer carrier have been established. The maximum conversion degree has been determined. The polymer salts have been characterized by potentiometric titration, 31P-NMR and IR spectroscopy, and elemental analysis. The stability of the salts and the immobilization rate of the low molecular weight physiologically active substances have been investigated. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 1933–1938, 1997