Polymer conjugates with anticancer activity

Putnam, David; Kopeček, Jindřich

doi:10.1007/3540587888_14

Cited by 297 publications

(156 citation statements)

References 259 publications

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“…Another possibility is to further extend the incubation period to allow more extensive lysosomal breakdown of the PIC, which could yield more optimal dequenching of the PIC and permit photosensitizer redistribution from the endosomes and lysosomes to other more critically photosensitive subcellular sites. PIC degradation could also be further enhanced by incorporating lysosomal enzyme-cleavable linkers (54,55) between the MAb and photosensitizer.…”

Section: Discussionmentioning

confidence: 99%

Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study

Savellano

Hasan

2005

Clinical Cancer Research

113

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Purpose: Photoimmunotherapy may allow target-specific photodynamic destruction of malignancies and may also potentiate anticancer antibody therapies. However, clinical use of either of the two modalities is limited for different reasons. Antibody therapies suffer from being primarily cytostatic and the need for prolonged administration with consequent side effects. In the case of photoimmunotherapy, a major impediment has been the absence of well-characterized photosensitizer immunoconjugates (PIC). In this investigation, we suggest a strategy to overcome these limitations and present the successful targeting of epidermal growth factor receptor (EGFR) using a well-characterized PIC. Experimental Design: The PIC consisted of the EGFR-recognizing chimeric monoclonal antibody, C225, conjugated with a two-branched polyethylene glycol and benzoporphyrin derivative (BPD, Verteporfin). Mechanistic studies included photophysics, phototoxicity, cellular uptake, and catabolism experiments to yield dosimetric parameters. Target cells included two EGFR-overexpressing human cancer cell lines, OVCAR-5 and A-431. Nontarget cells included an EGFR-negative fibroblast cell line, 3T3-NR6, and a monocyte-macrophage cell line, J774. Results: BPD-C225 PICs targeted and photodynamically killed EGFR-overexpressing cells, whereas free BPD exhibited no specificity. On a per mole basis, PICs were less phototoxic than free BPD, but PICs were very selective for target cells, whereas free BPD was not. Phototoxicity of the PICs increased at prolonged incubations. Photodynamic dose calculations indicated that PIC photophysics, photochemistry, catabolism, and subcellular localization were important determinants of PIC phototoxic potency. Conclusions: This study shows the efficacy of EGFR targeting with PIC constructs and suggests approaches to improve PIC designs and targeting strategies for in vivo photoimmunotherapy. The approach offers the possibility of dual effects via antibody-mediated cytostasis and photoimmunotherapy-based cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study

Savellano

Hasan

2005

Clinical Cancer Research

113

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“…When a drug is administered systemically, the compound will accumulate at the site of action, but will also accumulate in healthy tissue, and may concurrently be cleared through the reticuloendothelial system (RES). Low MW drugs will readily diffuse from the bloodstream into healthy tissues, as suggested by studies that reveal uniform distribution throughout the body [110]. This homogeneous localization of the drug leads to low concentrations of the drug at the tumor site and causes most of the negative side effects associated with systemic therapy.…”

Section: Controlled Drug Deliverymentioning

confidence: 99%

“…have recently gained attention as macromolecular carriers that are capable of overcoming transport barriers that limit drug delivery to tumors [106,110,116,117]. Polymer conjugates for drug delivery are typically large hydrophilic molecules linked to a therapeutic agent.…”

Section: Soluble Carriers-polymersmentioning

confidence: 99%

Peptide-based biopolymers in biomedicine and biotechnology

Chow

Nunalee

Lim

et al. 2008

Materials Science and Engineering: R: Reports

286

231

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Peptides are emerging as a new class of biomaterials due to their unique chemical, physical, and biological properties. The development of peptide-based biomaterials is driven by the convergence of protein engineering and macromolecular self-assembly. This review covers the basic principles, applications, and prospects of peptide-based biomaterials. We focus on both chemically synthesized and genetically encoded peptides, including poly-amino acids, elastin-like polypeptides, silk-like polymers and other biopolymers based on repetitive peptide motifs. Applications of these engineered biomolecules in protein purification, controlled drug delivery, tissue engineering, and biosurface engineering are discussed.

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“…Conjugation of drugs to the macromolecular carrier increases their circulating time in the bloodstream, decreases systemic toxicity, allows its passive accumulation in tumor tissue due to enhanced permeability and retention (EPR) effect [3] and intracellular uptake by endocytosis (reviewed in [4]). The incorporation of peptide linkers, which are degradable in the lysosomal compartment, is one of the critical aspects for the design of macromolecular therapeutics.…”

Section: Introductionmentioning

confidence: 99%

“…The incorporation of peptide linkers, which are degradable in the lysosomal compartment, is one of the critical aspects for the design of macromolecular therapeutics. Detailed studies performed previously in our group have provided the theoretical basis and experimental evidence for drug release following enzymatic degradation in lysosomes of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates containing boidegradable tetrapeptide linker (P-GFLG-DOX) [4,5].…”

Section: Introductionmentioning

confidence: 99%

Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells

Malugin

Kopečková

Kopeček

2007

Journal of Controlled Release

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Despite intensive study, the molecular mechanism for cell toxicity of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-bound doxorubicin remains unclear. Moreover, the ability of the released drug to accumulate in the nucleus has also been questioned. We have hypothesized that the pattern of cell cycle progression is a useful indicator for the presence of free doxorubicin in the nucleus and its interaction with nuclear DNA. The effects of HPMA copolymer-bound doxorubicin on cell cycle progression were evaluated in this study in cultured human ovarian cancer A2780 cells. We determined that P-GFLG-DOX, but not P-GG-DOX, initiates cell cycle arrest and nuclear fragmentation in the same manner as free DOX, but with a time-delay. Our data indicate that drug release from the conjugate is required for the apoptotic activity associated with the conjugate.

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Polymer conjugates with anticancer activity

Cited by 297 publications

References 259 publications

Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study

Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study

Peptide-based biopolymers in biomedicine and biotechnology

Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells

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