PHPMA
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INTRODUCTION: Fine needle aspiration biopsy (FNAB) is an easy method with an option of repetitive withdrawal of cell material. METHODS: First, mice were inoculated with mouse T-lymphoma, after 10 d the samples from tumor, lymph nodes and spleen gained by FNAB and excision were analyzed by flow cytometry. Tumor progression was compared to the control group simultaneously. Then, 10 d after tumor cell inoculation free doxorubicin (DOX) or different PHPMA DOX conjugates were injected. Cell material was analyzed to detect subpopulations of lymphocyte infiltrate, and levels of cytokines in correlation with progression or regression of the disease. RESULTS: FNAB has no influence on the tumor's growth or survival of experimental animals. After treatment with PHPMA conjugates there was a significant increase of T-lymphocyte subpopulations in tumor microenvironment compared to controls or free DOX, but only in mice with confirmed macroscopic regression of tumor within two weeks. Mice treated with conjugates showed significantly lower cancer infiltration of lymph nodes and spleen. CONCLUSION: FNAB provides a great benefit to in vivo monitoring of cell changes directly in the tumor after treatment. The number of infiltrating T-lymphocytes increases in correlation with consecutive tumor eradication after treatment with PHPMA. This proves that not only direct cytotoxic but also imunostimulating effect are necessary for successful treatment.
- MeSH
- doxorubicin aplikace a dávkování chemie terapeutické užití MeSH
- experimentální nádory farmakoterapie patologie MeSH
- jehlová biopsie * MeSH
- kyseliny polymethakrylové chemie MeSH
- metastázy nádorů * MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- proliferace buněk * MeSH
- protinádorové látky aplikace a dávkování chemie terapeutické užití MeSH
- T-lymfocyty patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nanoparticles (NPs) that form by self-assembly of amphiphilic poly(N-(2-hydroxypropyl)-methacrylamide) (pHPMA) copolymers bearing cholesterol side groups are potential drug carriers for solid tumor treatment. Here, we investigate their behavior in solutions of human serum albumin (HSA) in phosphate buffered saline. Mixed solutions of NPs, from polymer conjugates with or without the anticancer drug doxorubicin (Dox) bound to them, and HSA at concentrations up to the physiological value are characterized by synchrotron small-angle X-ray scattering and isothermal titration calorimetry. When Dox is absent, a small amount of HSA molecules bind to the cholesterol groups that form the core of the NPs by diffusing through the loose pHPMA shell or get caught in meshes formed by the pHPMA chains. These interactions are strongly hindered by the presence of Dox, which is distributed in the pHPMA shell, meaning that the delivery of Dox by the NPs in the human body is not affected by the presence of HSA.
- MeSH
- cholesterol chemie farmakokinetika MeSH
- doxorubicin chemie farmakokinetika MeSH
- kyseliny polymethakrylové chemie farmakokinetika MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- lidský sérový albumin chemie farmakokinetika MeSH
- nádory farmakoterapie metabolismus MeSH
- nanočástice chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We report novel pH-reversibly surface-shielded polyplexes with enhanced gene transfer activity upon systemic administration. A four-arm-structured sequence-defined cationic oligomer KK[HK[(H-Sph-K)3HC]2]2 was designed and synthesized on solid-phase, containing additional lysine residues not only for improved pDNA polyplex stability, but also providing attachment points for subsequent polyplex functionalization with amine-reactive shielding polymers. Herein, the surface of polyplexes was shielded with hydrophilic polymers, monovalent PEG or monovalent and multivalent pHPMA, optionally attached to the polyplex via the acid-labile linker AzMMMan. Overall, surface modification with PEG or pHPMA resulted in a decrease in the zeta potential of polyplexes, consistent with the degree of surface shielding. At pH 6.0, only polyplexes modified via the acid-labile linkage showed an increase in zeta potential, consistent with a "deshielding" in acidic environment, expected as beneficial for endosomal escape. Shielding was more efficient for multivalent pHPMA (20kDa, 30kDa) as compared to monovalent pHPMA (10kDa, 20kDa, 30kDa) or PEG (5kDa). In vitro transfection studies revealed higher gene expression by the polyplexes with the acid-labile shield as compared to their irreversibly shielded counterparts. Intravenous administration of AzMMMan-pHPMA modified polyplexes in an in vivo tumor mouse model mediated enhanced gene expression in the subcutaneous tumor and reduced undesirable expression in the liver.
New drug formulations are sought for poorly water-soluble substances because there is a risk of compromised bioavailability if such substances are administered orally. Such active pharmaceutical ingredients can be reformulated as solid dispersions with suitable water-soluble polymers. In this contribution, formulation of a novel and physically stable dispersion of Simvastatin in poly(2-hydroxypropyl) methacrylamide (pHPMA) is demonstrated. Due to the limited water sorption of pHPMA and a high Tg, the prepared dispersion is more suited for oral administration and storage compared with neat amorphous Simvastatin. Surprisingly, the rate of global reorientation and the internal motion of Simvastatin molecules were enhanced and exhibited dynamical heterogeneities when incorporated into the pHPMA matrix. As revealed by solid-state nuclear magnetic resonance combined with Raman spectroscopy exploiting the fluorescence phenomenon the mobility of the ester and lactone components increased considerably, whereas the naphthalene ring remained rigid. Furthermore, the solid dispersion was found to be nano-heterogeneous with nanometer-sized Simvastatin domains. The presence of these clusters had no impact on the dynamics of the rigid pHPMA chains. Thus, the diffusion of Simvastatin molecules through the glassy pHPMA walls and the subsequent transformation of the clusters into larger crystallites were prevented. No crystallization was detected for more than two years.
- MeSH
- adsorpce MeSH
- diferenciální skenovací kalorimetrie MeSH
- kyseliny polymethakrylové chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární struktura MeSH
- Ramanova spektroskopie MeSH
- simvastatin chemie MeSH
- stabilita léku MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- 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
In the past decades, nanosized drug delivery systems based on N-(2-hydroxypropyl)methacrylamide copolymers (pHPMA) have gained increasing attention in nanomedicine field due to their hydrophilicity, versatility, biocompatibility, non-toxicity, and non-immunogenicity. Indeed, pHPMA nanosystems with various controlled drug release capabilities inside targeted tissues or cells have been intensively studied. This paper summarizes recent advances in the design and application of pHPMA conjugates with specific antibodies or their fragments, focusing predominantly on the systems for the cancer therapy, particularly, the mechanisms of action of therapeutic antibodies, the approaches of their modification and subsequent attachment of pHPMA and their conjugates with diverse active moieties. Finally, we highlight the major biomedical applications of these antibody-polymer-drug conjugates and consider directions of possible development over the coming decade.
This paper describes the synthesis and biological evaluation of a conjugate of the highly cytotoxic drug 2-pyrrolinodoxorubicin (p-DOX) with an N-(2-hydroxypropyl)methacrylamide copolymer (PHPMA) as a water-soluble biocompatible polymer carrier, utilizing the advantageous concept of polymer-drug conjugates. The conjugate of p-DOX with HPMA copolymer (PHPMA/p-DOX) was prepared by reacting the PHPMA/DOX conjugate, where the DOX was bound via a hydrazone bond, with 4-iodobutyraldehyde. The hydrazone bond between the polymer and drug is susceptible to pH-controlled hydrolysis, enabling prolonged stability in circulation and fast p-DOX release under conditions mimicking the intracellular environment. The in vitro cytostatic activity of free p-DOX was in accordance with literature, whereas its PHPMA conjugate exhibited a 1.3- to 5-fold lower cytotoxicity, depending on the cancer cell line, when compared to the free p-DOX. This is in qualitative agreement with the data obtained for DOX and its HPMA copolymer conjugates. On mice bearing T-cell EL4 lymphoma, no tumor suppression was observed from the free p-DOX at a subtoxic dose of 0.1 mg/kg, whereas the PHPMA/p-DOX conjugate significantly inhibited the initial tumor growth at approximately equitoxic doses of 0.4 and 0.8 mg p-DOX eq/kg. However, moderately elevated doses of the p-DOX equivalent in the conjugate caused toxic effects, making accurate dosage setting essential.
- MeSH
- doxorubicin aplikace a dávkování škodlivé účinky analogy a deriváty chemická syntéza chemie terapeutické užití MeSH
- kyseliny polymethakrylové chemická syntéza chemie MeSH
- lidé MeSH
- lymfom T-buněčný farmakoterapie patologie MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemická syntéza chemie MeSH
- proliferace buněk účinky léků MeSH
- protinádorová antibiotika aplikace a dávkování škodlivé účinky chemická syntéza chemie terapeutické užití MeSH
- pyrroly aplikace a dávkování škodlivé účinky chemická syntéza chemie terapeutické užití MeSH
- rozpustnost MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
