Water-soluble HPMA copolymer—prostaglandin E1conjugates containing a cathepsin K sensitive spacer

In cancer photodynamic therapy (PDT), improved efficiency of photosensitizer delivery to tumors may be obtained by binding them to targetable water soluble polymeric carriers. However, attachment of photosensitizers to Macromolecular carriers may alter their spectral and photosensitizing properties. In this study, a new monosubstituted phthalocyanine derivative, N-glycyl zinc(II) 4,9,16,23-tetraaminophthalocyanine (G-TAPC-Zn) was synthesized by the reaction of zinc(II) 4,9,16,23-tetraaminophthalocyanine (TAPC-Zn) with N-tert-butoxycarbonyl-glycine N'-hydroxybenzotriazole ester followed by deprotection of the tert-butoxycarbonyl (BOC) group. G-TAPC-Zn contains an aliphatic amino group suitable for attachment to water soluble polymeric carriers. By aminolysis of a polymeric precursor, an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer containing oligopeptide (GFLG) side-chains terminated in p-nitrophenyl ester groups, with G-TAPC-Zn a polymeric derivative of the latter (P-GFLGG-TAPC-Zn) was synthesized. Spectral data indicated that in aqueous solutions P-GFLGG-TAPC-Zn formed aggregates. The degree of aggregation decreased with increasing concentration of detergents or organic solvents in buffer solutions. Consequently, the release of the drug from carrier catalyzed by thiol proteinases, papain or cathepsin B, took place only in the presence of detergents or organic solvents, i.e., under conditions with a lower probability of aggregate formation. Binding of G-TAPC-Zn to HPMA copolymers decreased the quantum yield of singlet oxygen generation from 0.24 to 0.063 and significantly increased its resistance to photobleaching.

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Water-soluble HPMA copolymer–wortmannin conjugate retains phosphoinositide 3-kinase inhibitory activity in vitro and in vivo

Journal of Controlled Release ◽

10.1016/s0168-3659(01)00349-2 ◽

2001 ◽

Vol 74 (1-3) ◽

pp. 275-281 ◽

Cited By ~ 20

Author(s):

L. Varticovski ◽

Zheng-Rong Lu ◽

Kahlil Mitchell ◽

Isabel de Aos ◽

Jindrich Kopeček

Keyword(s):

Inhibitory Activity ◽

Water Soluble ◽

Hpma Copolymer ◽

Phosphoinositide 3 Kinase ◽

Kinase Inhibitory Activity

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Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

Endocrine Related Cancer ◽

10.1677/erc.1.01045 ◽

2005 ◽

Vol 12 (Supplement_1) ◽

pp. S189-S199 ◽

Cited By ~ 117

Author(s):

R Duncan ◽

M J Vicent ◽

F Greco ◽

R I Nicholson

Keyword(s):

Clinical Trials ◽

Anticancer Agents ◽

Antitumour Activity ◽

Metastatic Cancer ◽

Clinical Results ◽

Water Soluble ◽

Current Status ◽

Hpma Copolymer ◽

Drug Conjugates

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

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Synthesis of Water-Soluble Star Polymers Based on Cyclodextrins

Physiological Research ◽

10.33549/physiolres.933981 ◽

2018 ◽

pp. S357-S365

Author(s):

L. KOTRCHOVÁ ◽

T. ETRYCH

Keyword(s):

Star Polymers ◽

Water Soluble ◽

Hpma Copolymer ◽

Polymer Carriers ◽

Physico Chemical ◽

Reversible Addition ◽

Degradation Rates ◽

Hpma Copolymers ◽

Hydroxypropyl Methacrylamide ◽

Chain Transfer Polymerization

Novel star polymers based on the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and cyclodextrin were synthesized and the physico-chemical behavior of these precursors was studied. Semitelechelic HPMA copolymers were grafted onto the cyclodextrin core, thus forming star-like structure. Both prepared systems were designed as possible polymer carriers for the controlled release of cytostatic drugs, which after the drug release and degradation will be eliminated from the organism. Two synthesis approaches were used to obtain similar polymer carriers with different degradation rates. All the polymers were prepared by reversible addition-fragmentation chain-transfer polymerization, which guarantees low dispersity of the prepared systems.

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Designing polymer conjugates as lysosomotropic nanomedicines

Biochemical Society Transactions ◽

10.1042/bst0350056 ◽

2007 ◽

Vol 35 (1) ◽

pp. 56-60 ◽

Cited By ~ 80

Author(s):

R. Duncan

Keyword(s):

Drug Delivery ◽

Clinical Trials ◽

Molecular Mass ◽

Anticancer Agents ◽

Synthetic Polymer ◽

Water Soluble ◽

Hpma Copolymer ◽

Polymer Conjugates ◽

Drug Conjugates ◽

Polymer Drug Conjugates

Marriage of cell biology (the concept of ‘lysosomotropic drug delivery’) and the realization that water-soluble synthetic polymers might provide an ideal platform for targeted drug delivery led to the first synthetic polymer–drug conjugates that entered clinical trials as anticancer agents. Conceptually, polymer conjugates share many features with other macromolecular drugs, but they have the added advantage of the versatility of synthetic chemistry that allows tailoring of molecular mass and addition of biomimetic features. Conjugate characteristics must be optimized carefully to ensure that the polymeric carrier is biocompatible and that the polymer molecular mass enables tumour-selective targeting followed by endocytic internalization. The polymer–drug linker must be stable in transit, but be degraded at an optimal rate intracellularly to liberate active drug. Our early studies designed two HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer conjugates containing doxorubicin that became the first synthetic polymer–drug conjugates to be tested in phase I/II clinical trials. Since, a further four HPMA copolymer–anticancer drug conjugates (most recently polymer platinates) and the first polymer-based γ-camera imaging agents followed. Polymer–drug linkers cleaved by lysosomal thiol-dependent proteases and the reduced pH of endosomes and lysosomes have been used widely to facilitate drug liberation. It is becoming clear that inappropriate trafficking and/or malfunction of enzymatic activation can lead to new mechanisms of clinical resistance. Recent studies have described HPMA copolymer conjugates carrying a combination of both endocrine and chemotherapy that are markedly more active than individual conjugates carrying a single drug. Moreover, current research is investigating novel dendritic polymer architectures and novel biodegradable polymers as drug carriers that will provide improved drug delivery and imaging probes in the future. The present paper reviews the clinical status of polymeric anticancer agents, the rationale for the design of polymer therapeutics and discusses the benefits and challenges of lysosomotropic delivery.

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HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

Journal of Personalized Medicine ◽

10.3390/jpm11020115 ◽

2021 ◽

Vol 11 (2) ◽

pp. 115

Author(s):

Petr Chytil ◽

Libor Kostka ◽

Tomáš Etrych

Keyword(s):

Drug Carrier ◽

Drug Carriers ◽

Water Soluble ◽

Pharmacological Effect ◽

Polymer Materials ◽

Covalent Attachment ◽

Dependent Manner ◽

Hpma Copolymer ◽

Water Soluble Polymer ◽

Safety Issues

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.

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A Resorcinol-Formaldehyde Resin as an Embedding Material for Electron Microscopy of Membranes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010006355x ◽

1969 ◽

Vol 27 ◽

pp. 328-329 ◽

Cited By ~ 1

Author(s):

J. G. Robertson ◽

D. F. Parsons

Keyword(s):

Electron Microscopy ◽

Osmium Tetroxide ◽

Neutral Lipids ◽

Lipid Extraction ◽

Water Soluble ◽

Formaldehyde Resin ◽

Electron Microscope Autoradiography ◽

Resorcinol Formaldehyde ◽

Major Disadvantage ◽

Cell Organization

The extraction of lipids from tissues during fixation and embedding for electron microscopy is widely recognized as a source of possible artifact, especially at the membrane level of cell organization. Lipid extraction is also a major disadvantage in electron microscope autoradiography of radioactive lipids, as in studies of the uptake of radioactive fatty acids by intestinal slices. Retention of lipids by fixation with osmium tetroxide is generally limited to glycolipids, phospholipids and highly unsaturated neutral lipids. Saturated neutral lipids and sterols tend to be easily extracted by organic dehydrating reagents prior to embedding. Retention of the more saturated lipids in embedded tissue might be achieved by developing new cross-linking reagents, by the use of highly water soluble embedding materials or by working at very low temperatures.

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Ferritin Labeled Antibody Staining of Thin Sections

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100064013 ◽

1969 ◽

Vol 27 ◽

pp. 420-421

Author(s):

J. D. McLean ◽

S. J. Singer

Keyword(s):

Biological Material ◽

Water Soluble ◽

Thin Sections ◽

Antibody Staining ◽

Thin Sectioning ◽

Ultrathin Sections

The successful application of ferritin labeled antibodies (F-A) to ultrathin sections of biological material has been hampered by two main difficulties. Firstly the normally used procedures for the preparation of material for thin sectioning often result in a loss of antigenicity. Secondly the polymers employed for embedding may non-specifically absorb the F-A. Our earlier use of cross-linked polyampholytes as embedding media partially overcame these problems. However the water-soluble monomers used for this method still extract many lipids from the material.

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The Effect of Benzene on Bluegill Olfactory Lamellae

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010011965x ◽

1985 ◽

Vol 43 ◽

pp. 574-575

Author(s):

D.R. Mattie ◽

J.W. Fisher

Keyword(s):

Surface Morphology ◽

Soluble Fraction ◽

Lepomis Macrochirus ◽

Sublethal Concentration ◽

Water Soluble ◽

Major Constituent ◽

Jet Fuels ◽

Aquatic Biota ◽

Normal Surface ◽

Cacodylate Buffer

Jet fuels such as JP-4 can be introduced into the environment and come in contact with aquatic biota in several ways. Studies in this laboratory have demonstrated JP-4 toxicity to fish. Benzene is the major constituent of the water soluble fraction of JP-4. The normal surface morphology of bluegill olfactory lamellae was examined in conjunction with electrophysiology experiments. There was no information regarding the ultrastructural and physiological responses of the olfactory epithelium of bluegills to acute benzene exposure.The purpose of this investigation was to determine the effects of benzene on the surface morphology of the nasal rosettes of the bluegill sunfish (Lepomis macrochirus). Bluegills were exposed to a sublethal concentration of 7.7±0.2ppm (+S.E.M.) benzene for five, ten or fourteen days. Nasal rosettes were fixed in 2.5% glutaraldehyde and 2.0% paraformaldehyde in 0.1M cacodylate buffer (pH 7.4) containing 1.25mM calcium chloride. Specimens were processed for scanning electron microscopy.

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An SEM study of raphide crystal initials in the leaves of vitis (grape)

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141299 ◽

1995 ◽

Vol 53 ◽

pp. 984-985

Author(s):

H. J. Arnott ◽

M. A. Webb ◽

L. E. Lopez

Keyword(s):

Calcium Oxalate ◽

Water Soluble ◽

Calcium Oxalate Crystals ◽

Calcium Oxalate Crystal ◽

Oxalate Crystals ◽

Large Numbers ◽

Sem Study ◽

The Matrix ◽

Crystal Cells ◽

Crystal Idioblast

Many papers have been published on the structure of calcium oxalate crystals in plants, however, few deal with the early development of crystals. Large numbers of idioblastic calcium oxalate crystal cells are found in the leaves of Vitis mustangensis, V. labrusca and V. vulpina. A crystal idioblast, or raphide cell, will produce 150-300 needle-like calcium oxalate crystals within a central vacuole. Each raphide crystal is autonomous, having been produced in a separate membrane-defined crystal chamber; the idioblast''s crystal complement is collectively embedded in a water soluble glycoprotein matrix which fills the vacuole. The crystals are twins, each having a pointed and a bidentate end (Fig 1); when mature they are about 0.5-1.2 μn in diameter and 30-70 μm in length. Crystal bundles, i.e., crystals and their matrix, can be isolated from leaves using 100% ETOH. If the bundles are treated with H2O the matrix surrounding the crystals rapidly disperses.

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