Solution properties of drug carriers based on poly[<i>N</i>‐(2‐hydroxypropyl)methacrylamide] containing biodegradable bonds

Ulbrich, Karel; Koňák, Čestmı́r; Tuzar, Zdeněk; Kopeček, Jindřich

doi:10.1002/macp.1987.021880604

Cited by 97 publications

(39 citation statements)

References 10 publications

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“…Perhaps micellar aggregates are formed in aqueous solutions as the hydrophobic Mce6 molecules are repelled by the water forming a hydrophobic core with the hydrophilic copolymer forming the outer micellar shell in contact with the water. This phenomenon has been shown with other HPMA copolymers containing side chains terminated with hydrophobic molecules [44,46] as well as with adriamycin-poly(glutamic acid) conjugates [45]. A study in which the quantum yield of oxygen uptake was measured for the P-G-F-L-G-Mce6 reaction mixture after both 48 h and 1 week incubation periods with cathepsin B showed a marked increase in this value with time of cleavage ( Table 2).…”

Section: Discussionsupporting

confidence: 67%

A polymeric drug delivery system for the simultaneous delivery of drugs activatable by enzymes and/or light

Krinick¹,

Sun²,

Joyner³

et al. 1994

Journal of Biomaterials Science, Polymer Edition

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Three water soluble copolymers based on N-(2-hydroxypropyl)methacrylamide were prepared. Copolymer I contains adriamycin, a chemotherapeutic agent, attached via enzymatically degradable oligopeptide (glycylphenylalanylleucylglycine; G-F-L-G) side chains. The other two copolymers contained the photosensitizer, meso-chlorin e6 monoethylene diamine disodium salt (Mce6). In Copolymer II, the chlorin is attached via the degradable G-F-L-G sequence, and it was bound by the nondegradable glycyl spacer in Copolymer III. Initially, the copolymers were characterized separately in vitro and in vivo. Combinations of the copolymer bound chemotherapeutic agent and each of the copolymer bound photosensitizers were then assessed for antitumor effect in vivo. Localization/retention studies (A/J mice; Neuro 2A neuroblastoma solid tumor) were performed with the two copolymers containing Mce6 as well as the free drug. Results of these experiments demonstrated a very different tumor uptake profile for the two copolymers. While the free drug was rapidly cleared from tumor tissue, the copolymer containing Mce6 attached via the non-degradable bond was retained for an extended period; drug concentrations in the tumor were high even after 5 days. On the other hand, a high concentration of the copolymer containing Mce6 bound via the degradable sequence was taken up by the tumor, yet its concentration in the tumor was substantially diminished at 48 h after administration. This shows indirect evidence of in vivo cleavage of Mce6 from the copolymer in the lysosomal compartment which is supported by direct evidence of cleavage by cathepsin B (a lysosomal enzyme) in vitro. Antitumor effects were assessed on Neuro 2A neuroblastoma induced in A/J mice for all three copolymers. Photodynamic therapy (PDT) proved the copolymer with Mce6 bound via the degradable oligopeptide sequence to be a more effective photosensitizer in vivo than the other chlorin containing copolymer. The difference in activity was consistent with the results obtained by photophysical analyses in which the free drug had a higher quantum yield of singlet oxygen generation than the polymer bound drug in buffer. The quantum yield of singlet oxygen generation increased with the enzymatic cleavage of the chlorin from the copolymer. Conditions were subsequently determined for which chemotherapy or PDT would show some antitumor effect, yet be incapable of curing tumors. Finally, combination therapy experiments were performed in which the copolymer bound adriamycin was mixed with either of the copolymer bound chlorin compounds and injected intravenously (i.v.) into the tail veins of mice.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionsupporting

confidence: 67%

A polymeric drug delivery system for the simultaneous delivery of drugs activatable by enzymes and/or light

Krinick¹,

Sun²,

Joyner³

et al. 1994

Journal of Biomaterials Science, Polymer Edition

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“…This process was found to be reversible (by lowering the temperature) and was probably due to formation of aggregates of polymer chains. These polymer-polymer (or polymerprotein) interactions are currently being investigated further (Ulbrich et al, 1986). Problems of solubility were not observed during incubation of puromycin-containing polymers.…”

Section: Discussionmentioning

confidence: 99%

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Duncan¹,

Kopečkova-Rejmanová²,

Strohalm³

et al. 1987

Br J Cancer

166

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Summary During recent years N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been developed as targetable drug carriers. These soluble synthetic polymers are internalized by cells by pinocytosis and they can be tailor-made to include peptidyl side-chains degradable intracellularly by specific lysosomal enzymes. Thus they provide the opportunity fo achieve controlled intracellular delivery of anticancer agents. The anthracycline antibiotic daunomycin, and protein synthesis inhibitor puromycin, were bound to HPMA copolymers via several different peptide side-chains, including Gly-Gly, Gly-Phe-Leu-Gly and Gly-Phe-PheLeu. Incubation of polymer-drug conjugates with isolated lysosomal enzymes (either a mixture of rat liver lysosomal enzymes or purified thiol-dependent lysosomal proteinases, cathepsins L and B) showed that significant release of drug occurred over 20h, more than 20% of daunomycin and more than 80% of puromycin being liberated. To test their pharmacological activity conjugates were incubated with either the mouse leukaemia L1210, or the human lymphoblastoid leukaemia CCRF in vitro. The conjugates tested were all less effective than free daunomycin, but they showed differential toxicity against L1210 depending on the aminoacid sequence of their drug-polymer linkage. Inclusion of fucosylamine-terminating side-chains into the HPMA copolymer structure increased the affinity of conjugates for the L1210 cell membrane and resulted in increased toxicity. In contrast HPMA-daunomycin conjugates with or without fucosylamine affected CCRF cells equally, but this cell line was more sensitive than the mouse leukaemia to both free and polymer-bound daunomycin. Incubation of L1210 cells in polymer-bound daunomycin for 72h, followed by plating cells out in low density in drug-free medium, showed that a concentration of polymer-bound drug (184,ugml-1) could be selected to achieve a cytotoxic effect.

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“…These polymers include the tailored oligopeptide side chains to be degradable by extra-or intra-cellular enzymes at target sites, followed by drug release [5][6][7][8]. However, such a system was still limited in terms of the responsiveness of drug release via degradation when hydrophobic drugs were used [9]. Further, if the polymeric prodrug systems were degraded at target sites and subsequent polymer-bound drugs were released, the concentrations and activities of released drugs at the target sites will be dependent on enzyme concentrations or their activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of biodegradable polyrotaxane as a novel supramolecular-structured drug carrier

Ooya

Yui

1997

Journal of Biomaterials Science, Polymer Edition

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Polyrotaxanes were synthesized as novel biodegradable polymers with supramolecular assembly and their properties evaluated in vitro. The synthesis of biodegradable polyrotaxanes consists of three steps: preparation of an inclusion complex consisting of alpha-cyclodextrins (alpha-CDs) and amino-terminated poly(ethylene glycol) (PEG); introduction of L-phenylalanine (L-Phc) at each complex terminal via peptide linkages: and hydroxypropylation of alpha-CDs in the polyrotaxanes. Succinimide ester of benzyloxycarbonyl-L-Phe was condensed with the terminal amino groups of the inclusion complex. 1H-NMR and GPC results showed that alpha-CDs were threaded onto a PEG chain and L-Phe moieties were introduced at each terminal of the PEG chain. Further, the amount of threaded alpha-CDs was found to be governed by the molecular weight of PEG. The hydroxypropylation of alpha-CDs improved the solubility of the polyrotaxanes in PBS (pH 7.4). The hydroxypropylated (HP-) polyrotaxanes were characterized by terminal peptide cleavage using papain. In vitro degradation of HP-polyrotaxanes revealed that HP-alpha-CDs threaded onto a PEG chain were released only when terminal peptide linkages were cleaved. Moreover, threaded HP-alpha-CDs onto a PEG chain was found to be completely released. Kinetics of terminal peptide cleavage were also evaluated by catalytic efficiency (kcat/K(m)). The kcat/K(m) values were found to be independent of the molecular weight of HP-polyrotaxanes but to be affected by terminal hydrophobic moieties. It is proposed that our designed polyrotaxanes are feasible as novel drug carriers.

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Solution properties of drug carriers based on poly[N‐(2‐hydroxypropyl)methacrylamide] containing biodegradable bonds

Cited by 97 publications

References 10 publications

A polymeric drug delivery system for the simultaneous delivery of drugs activatable by enzymes and/or light

A polymeric drug delivery system for the simultaneous delivery of drugs activatable by enzymes and/or light

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Synthesis and characterization of biodegradable polyrotaxane as a novel supramolecular-structured drug carrier

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