N-(2-Hydroxypropyl)methacrylamide copolymer containing hydrazide groups (PHPMA) conjugated with pirarubicin (THP) via a hydrazone bond (PHPMA-hyd-THP) is a drug conjugate that releases THP in the acidic milieu of a tumor. PHPMA-hyd-THP has an apparent Mw of 40,000 and a hydrodynamic diameter of 8.2±1.7nm but no apparent plasma protein binding. PHPMA-hyd-THP possesses two mechanisms of selectivity toward solid tumors and has potent antitumor action. The first one is drug accumulation in tumors that depends on the enhanced permeability and retention (EPR) effect, which results in a 4-20 times higher concentration of drug in the tumor than in normal tissues such as the heart, lung, and intestine. This accumulation in tumor tissue is in great contrast to that of conventional low-Mw THP. The second one is pH-dependent release of drug from PHPMA-hyd-THP: this conjugate released free THP more efficiently at a lower pH, which exists in tumors, and exerts cytotoxic activity. Free THP is known for its much faster uptake into tumor cells compared with doxorubicin. Thus, in our in vitro study, PHPMA-hyd-THP showed a higher cytotoxicity at the lower pH of tumor tissue than at the neutral pH of normal tissue. Furthermore, much more THP was liberated from the conjugate in acidic tumor tissue than in normal tissue. The EPR effect-dependent accumulation of PHPMA-hyd-THP and tumor-selective THP release in the tumor tissues led to highly tumor-selective drug accumulation, which continued for more than 72h, whereas the lowest free drug concentration was detected in normal tissues at 24h and no longer at a later time. In conclusion, we determined in our study here that the acid-cleavable PHPMA-hyd-THP conjugate had an excellent antitumor effect without appreciable adverse effects.

• Klíčová slova
• Acid-cleavable linkage, EPR effect, HPMA polymer conjugate, Hydrazone, Pirarubicin (THP), Tumor selectivity,
• MeSH
• akrylamidy aplikace a dávkování   chemie   farmakokinetika   MeSH
• doxorubicin aplikace a dávkování   analogy a deriváty   chemie   farmakokinetika   MeSH
• HeLa buňky MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• nosiče léků aplikace a dávkování   chemie   farmakokinetika   MeSH
• polymery aplikace a dávkování   chemie   farmakokinetika   MeSH
• protinádorové látky aplikace a dávkování   chemie   farmakokinetika   MeSH
• tkáňová distribuce MeSH
• tumor burden účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• doxorubicin MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• pirarubicin MeSH Prohlížeč
• polymery MeSH
• protinádorové látky MeSH

Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon.

• Klíčová slova
• Acid-cleavable linkage, Chemical carcinogenesis, Controlled drug release, Dendrimer-derived polymer conjugate, EPR effect, HPMA polymer conjugate, Pirarubicin (THP),
• MeSH
• berberinové alkaloidy chemie   farmakokinetika   MeSH
• dendrimery chemie   farmakokinetika   MeSH
• doxorubicin analogy a deriváty   chemie   farmakokinetika   farmakologie   MeSH
• HeLa buňky MeSH
• lidé MeSH
• melanom experimentální MeSH
• methakryláty chemie   farmakokinetika   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• nosiče léků chemie   farmakokinetika   MeSH
• polymery chemie   farmakokinetika   MeSH
• protinádorové látky chemie   farmakokinetika   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2,3,10,11-tetrahydroxytetrahydroprotoberberine MeSH Prohlížeč
• berberinové alkaloidy MeSH
• dendrimery MeSH
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• nosiče léků MeSH
• PAMAM Starburst MeSH Prohlížeč
• pirarubicin MeSH Prohlížeč
• polymery MeSH
• protinádorové látky MeSH

Many conjugates of water-soluble polymers with biologically active molecules were developed during the last two decades. Although, therapeutic effects of these conjugates are affected by the properties of carriers, the properties of the attached drugs appear more important than the same carrier polymer in this case. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX. Here, we conjugated the THP or DOX to N-(2-hydroxypropyl)methacrylamide copolymer via a hydrazone bond. The polymeric prodrug conjugates, P-THP and P-DOX, respectively, had comparable hydrodynamic sizes and drug loading. Compared with P-DOX, P-THP showed approximately 10 times greater cellular uptake during a 240 min incubation and a cytotoxicity that was more than 10 times higher during a 72-h incubation. A marginal difference was seen in P-THP and P-DOX accumulation in the liver and kidney at 6 h after drug administration, but no significant difference occurred in the tumor drug concentration during 6-24 h after drug administration. Antitumor activity against xenograft human pancreatic tumor (SUIT2) in mice was greater for P-THP than for P-DOX. To sum up, the present study compared the biological behavior of two different drugs, each attached to an N-(2-hydroxypropyl)methacrylamide copolymer carrier, with regard to their uptake by tumor cells, body distribution, accumulation in tumors, cytotoxicity, and antitumor activity in vitro and in vivo. No differences in the tumor cell uptake of the polymer-drug conjugates, P-THP and P-DOX, were observed. In contrast, the intracellular uptake of free THP liberated from the P-THP was 25-30 times higher than that of DOX liberated from P-DOX. This finding indicates that proper selection of the carrier, and especially conjugated active pharmaceutical ingredient (API) are most critical for anticancer activity of the polymer-drug conjugates. THP, in this respect, was found to be a more preferable API for polymer conjugation than DOX. Hence the treatment based on enhanced permeability and retention (EPR) effect that targets more selectively to solid tumors can be best achieved with THP, although both polymer conjugates of DOX and THP exhibited the EPR effects and drug release profiles in acidic pH similarly.

• Klíčová slova
• EPR effect, HPMA polymer conjugate, acid-cleavable linkage, doxorubicin (DOX), pirarubicin (THP),
• MeSH
• akrylamidy chemie   MeSH
• doxorubicin analogy a deriváty   chemie   farmakologie   MeSH
• experimentální sarkom farmakoterapie   metabolismus   patologie   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nosiče léků aplikace a dávkování   chemie   MeSH
• polymery aplikace a dávkování   chemie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorová antibiotika chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• akrylamidy MeSH
• doxorubicin MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nosiče léků MeSH
• pirarubicin MeSH Prohlížeč
• polymery MeSH
• protinádorová antibiotika MeSH
• protinádorové látky MeSH

Polyurethane (PU) foams are classified as physically nonrecyclable thermosets. The current effort of sustainable and eco-friendly production makes it essential to explore methods of better waste management, for instance by modifying the structure of these frequently used polymers to enhance their microbial degradability. The presence of ester links is known to be a crucial prerequisite for the biodegradability of PU foams. However, the impact of other hydrolysable groups (urethane, urea and amide) occurred in PU materials, as well as the supramolecular structure of the PU network and the cellular morphology of PU foams, is still relatively unexplored. In this work, fully aliphatic PU foams with and without hydrolyzable amide linkages were prepared and their aerobic biodegradation was investigated using a six-month soil burial test. Besides the variable chemical composition of the PU foams, the influence of their different supramolecular arrangement and cellular morphologies on the extent of biodegradation was also evaluated. Throughout the soil burial test, the release of carbon dioxide, and enzyme activities of proteases, esterases, and ureases were measured. At the same time, phospho-lipid fatty acids (PLFA) analysis was conducted together with an assessment of microbial community composition achieved by analysing the genetic information from the 16S rRNA gene and ITS2 region sequencing. The results revealed a mineralization rate of 30-50 % for the PU foams, indicating a significant level of degradation as well as indicating that PU foams can be utilized by soil microorganisms as a source of both energy and nutrients. Importantly, microbial biomass remained unaffected, suggesting that there was no toxicity associated with the degradation products of the PU foams. It was further confirmed that ester linkages in PU foam structure were easily enzymatically cleavable, while amide linkages were not prone to degradation by soil microorganisms. In addition, it was shown that the presence of amide linkages in PU foam leads to a change in the supramolecular network arrangement due to increased content of hard segments, which in turn reduces the biodegradability of PU foam. These findings show that it is important to consider both chemical composition and supramolecular/macroscopic structure when designing new PU materials in an effort to develop environmentally friendly alternatives.

• Klíčová slova
• Amide bond, Biodegradation, Enzymatic activity, Microbial composition, Polyurethane foam, Soil burial, Supramolecular structure,
• MeSH
• amidy * MeSH
• estery MeSH
• polyurethany * chemie   MeSH
• půda MeSH
• RNA ribozomální 16S MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amidy * MeSH
• estery MeSH
• polyurethane foam MeSH Prohlížeč
• polyurethany * MeSH
• půda MeSH
• RNA ribozomální 16S MeSH

Truncation of a peptide substrate in the N-terminus and replacement of its scissile amide bond with a non-cleavable reduced bond results in a potent inhibitor of HIV-1 protease. A series of such inhibitors has been synthesized, and S2-S3' subsites of the protease binding cleft mapped. The S2 pocket requires bulky Boc or PIV groups, large aromatic Phe residues are preferred in P1 and P1' and Glu in P2'. The S3' pocket prefers Phe over small Ala or Val. Introduction of a Glu residue into the P2' position yields a tight-binding inhibitor of HIV-1 protease, Boc-Phe-[CH2-NH]-Phe-Glu-Phe-OMe, with a subnanomolar inhibition constant. The relevant peptide derived from the same amino acid sequence binds to the protease with a Ki of 110 nM, thus still demonstrating a good fit of the amino acid residues into the protease binding pockets and also the importance of the flexibility of P1-P1' linkage for proper binding. A new type of peptide bond mimetic, N-hydroxylamine -CH2-N(OH)-, has been synthesized. Binding of hydroxylamino inhibitor of HIV-1 protease is further improved with respect to reduced-bond inhibitor.

• MeSH
• inhibitory HIV-proteasy * MeSH
• inhibitory proteas chemická syntéza   farmakologie   MeSH
• molekulární sekvence - údaje MeSH
• peptidy chemická syntéza   farmakologie   MeSH
• sekvence aminokyselin MeSH
• substrátová specifita MeSH
• vazebná místa účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory HIV-proteasy * MeSH
• inhibitory proteas MeSH
• peptidy MeSH