The therapeutic efficacy of antitumor nanomedicines is influenced by numerous factors, with the most critical being the selection of an appropriate biomaterial and the use of suitable stimulus-responsive linkers. The chosen biomaterial must be biocompatible and capable of binding the drug via a linker that facilitates selective release and activation of the therapeutic effect, specifically within tumor tissue. In this study, we designed, synthesized, and compared the physicochemical and biological properties of various polymer nanomedicines, each bearing pirarubicin conjugated to water-soluble and biocompatible methacrylamide-based copolymers through pH-sensitive hydrazone bonds. Our findings indicate that the hydrophobicity and length of the linker near the hydrazone bond are crucial factors influencing the treatment efficacy of the nanomedicines. Conjugates with aminohexanoyl linkers exhibited superior drug release and enhanced antitumor activity compared with those with shorter linkers. Overall, our study highlights that the rate of drug release, governed by the linker structure, plays a pivotal role in therapeutic efficacy, while the hydrophilicity of the polymer backbone has a lesser impact.

Department of Gastrointestinal Surgery Shengjing Hospital of China Medical University No 36 Sanhao Street Shenyang 110004 Liaoning China

Department of General Surgery Shengjing Hospital of China Medical University No 36 Sanhao Street Shenyang 110004 Liaoning China

Faculty of Pharmaceutical Sciences Sojo University Kumamoto 860 0082 Japan

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského nám 2 Prague 6 162 00 Czech Republic

Zobrazit více v PubMed

Ulbrich K., Holá K., Šubr V., Bakandritsos A., Tuček J., Zbořil R.. Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies. Chem. Rev. 2016;116(9):5338–5431. doi: 10.1021/acs.chemrev.5b00589. PubMed DOI

Kopeček J., Yang J.. Polymer Nanomedicines. Adv. Drug Delivery Rev. 2020;156:40–64. doi: 10.1016/j.addr.2020.07.020. PubMed DOI PMC

Maeda H., Nakamura H., Fang J.. The EPR Effect for Macromolecular Drug Delivery to Solid Tumors: Improvement of Tumor Uptake, Lowering of Systemic Toxicity, and Distinct Tumor Imaging in Vivo. Adv. Drug Delivery Rev. 2013;65(1):71–79. doi: 10.1016/j.addr.2012.10.002. PubMed DOI

Kopeček J., Kopečková P.. HPMA Copolymers: Origins, Early Developments, Present, and Future. Adv. Drug Delivery Rev. 2010;62(2):122–149. doi: 10.1016/j.addr.2009.10.004. PubMed DOI PMC

Chen X., Parelkar S. S., Henchey E., Schneider S., Emrick T.. PolyMPC–Doxorubicin Prodrugs. Bioconjugate Chem. 2012;23(9):1753–1763. doi: 10.1021/bc200667s. PubMed DOI

Chen K., Liao S., Guo S., Zheng X., Wang B., Duan Z., Zhang H., Gong Q., Luo K.. Multistimuli-Responsive PEGylated Polymeric Bioconjugate-Based Nano-Aggregate for Cancer Therapy. Chem. Eng. J. 2020;391(August 2019):123543. doi: 10.1016/j.cej.2019.123543. DOI

Pytlíková S., Pechar M., Chytil P., Studenovský M., Pola R., Kotrchová L., Konefał R., Čtveráčková L., Laga R., Pankrác J., Gao S., Jiang B., Yang K., Fang J., Filipová M., Etrych T.. Highly Hydrophilic Methacrylamide-Based Copolymers as Precursors for Polymeric Nanomedicines Containing Anthracyclines. Eur. Polym. J. 2024;205(January):112756. doi: 10.1016/j.eurpolymj.2024.112756. DOI

Krakovičová H., Etrych T., Ulbrich K.. HPMA-Based Polymer Conjugates with Drug Combination. Eur. J. Pharm. Sci. 2009;37:405. doi: 10.1016/j.ejps.2009.03.011. PubMed DOI

Wang Y., Gu Z., Wang W., Liu S. L.. Progress in Researches for PH-Sensitive Polymer with Ketal (Acetal) Bonds Used as Drug Carriers. Chin. J. New Drugs. 2015;24:782.

Zhai Y., Zhou X., Zhang Z., Zhang L., Wang D., Wang X., Sun W.. Design, Synthesis, and Characterization of Schiffbase Bond-Linked PH-Responsive Doxorubicin Prodrug Based on Functionalized MPEG-PCL for Targeted Cancer Therapy. Polymers. 2018;10:1127. doi: 10.3390/polym10101127. PubMed DOI PMC

Zhang P., Wu J., Xiao F., Zhao D., Luan Y.. Disulfide Bond Based Polymeric Drug Carriers for Cancer Chemotherapy and Relevant Redox Environments in Mammals. Med. Res. Rev. 2018;38:1485. doi: 10.1002/med.21485. PubMed DOI

Pechar M., Pola R., Studenovský M., Bláhová M., Grosmanová E., Dydowiczová A., Filipová M., Islam R., Gao S., Fang J., Etrych T.. Polymer Nanomedicines with Enzymatically Triggered Activation: A Comparative Study of in Vitro and in Vivo Anti-Cancer Efficacy Related to the Spacer Structure. Nanomedicine. 2022;46:102597. doi: 10.1016/j.nano.2022.102597. PubMed DOI

Yi X., Zhang Q., Dong H., Zhao D., Xu J. Q., Zhuo R., Li F.. One-Pot Synthesis of Crosslinked Amphiphilic Polycarbonates as Stable but Reduction-Sensitive Carriers for Doxorubicin Delivery. Nanotechnology. 2015;26:395602. doi: 10.1088/0957-4484/26/39/395602. PubMed DOI

Gao S.-Q., Lu Z.-R., Petri B., Kopečková P., Kopeček J., Kopecková P., Kopecek J.. Colon-Specific 9-Aminocamptothecin-HPMA Copolymer Conjugates Containing a 1,6-Elimination Spacer. J. Controlled Release. 2006;110(2):323–331. doi: 10.1016/j.jconrel.2005.10.004. PubMed DOI

Pola R., Pokorná E., Vočková P., Böhmová E., Pechar M., Karolová J., Pankrác J., Šefc L., Helman K., Trněný M., Etrych T., Klener P.. Cytarabine Nanotherapeutics with Increased Stability and Enhanced Lymphoma Uptake for Tailored Highly Effective Therapy of Mantle Cell Lymphoma. Acta Biomater. 2021;119:349–359. doi: 10.1016/j.actbio.2020.11.014. PubMed DOI

Ulbrich K., Šubr V., Strohalm J., Plocová D., Jelínková M., Říhová B.. Polymeric Drugs Based on Conjugates of Synthetic and Natural Macromolecules. J. Controlled Release. 2000;64(1–3):63–79. doi: 10.1016/S0168-3659(99)00141-8. PubMed DOI

Huang X., Du F., Ju R., Li Z.. Novel Acid-Labile, Thermoresponsive Poly­(Methacrylamide)­s with Pendent Ortho Ester Moieties. Macromol. Rapid Commun. 2007;28(5):597–603. doi: 10.1002/marc.200600798. DOI

Ulbrich K., Etrych T., Chytil P., Jelínková M., Říhová B.. Antibody-Targeted Polymer-Doxorubicin Conjugates with PH-Controlled Activation. J. Drug Targeting. 2004;12:477. doi: 10.1080/10611860400011869. PubMed DOI

Koziolová E., Kostka L., Kotrchová L., Šubr V., Konefal R., Nottelet B., Etrych T.. N -(2-Hydroxypropyl)­Methacrylamide-Based Linear, Diblock, and Starlike Polymer Drug Carriers: Advanced Process for Their Simple Production. Biomacromolecules. 2018;19(10):4003–4013. doi: 10.1021/acs.biomac.8b00973. PubMed DOI

Luo X., Liu J., Liu G., Wang R., Liu Z., Li A.. Manipulation of the Bioactivity of Glucose Oxidase via Raft-controlled Surface Modification. J. Polym. Sci., Part A: Polym. Chem. 2012;50(14):2786–2793. doi: 10.1002/pola.26067. DOI

Ishitake K., Satoh K., Kamigaito M., Okamoto Y.. Stereogradient Polymers Formed by Controlled/Living Radical Polymerization of Bulky Methacrylate Monomers. Angew. Chem., Int. Ed. 2009;48:1991. doi: 10.1002/anie.200805168. PubMed DOI

Rejmanová P., Labský J., Kopeček J.. Aminolyses of Monomeric and Polymeric 4-nitrophenyl Esters of N -methacryloylamino Acids. Die Makromol. Chem. 1977;178(8):2159–2168. doi: 10.1002/macp.1977.021780803. DOI

Drobník J., Kopeček J., Labský J., Rejmanová P., Exner J., Saudek V., Kálal J.. Enzymatic Cleavage of Side Chains of Synthetic Water-soluble Polymers. Die Makromol. Chem. 1976;177(10):2833–2848. doi: 10.1002/macp.1976.021771003. DOI

Perrier S., Takolpuckdee P., Mars C. A.. Reversible Addition-Fragmentation Chain Transfer Polymerization: End Group Modification for Functionalized Polymers and Chain Transfer Agent Recovery. Macromolecules. 2005;38(6):2033–2036. doi: 10.1021/ma047611m. DOI

Kracíková L., Ziółkowska N., Androvič L., Klimánková I., Červený D., Vít M., Pompach P., Konefał R., Janoušková O., Hrubý M., Jirák D., Laga R.. Phosphorus-Containing Polymeric Zwitterion: A Pioneering Bioresponsive Probe for 31P-Magnetic Resonance Imaging. Macromol. Biosci. 2022;22:2100523. doi: 10.1002/mabi.202100523. PubMed DOI

Nakamura H., Etrych T., Chytil P., Ohkubo M., Fang J., Ulbrich K., Maeda H.. Two Step Mechanisms of Tumor Selective Delivery of N-(2-Hydroxypropyl) Methacrylamide Copolymer Conjugated with Pirarubicin via an Acid-Cleavable Linkage. J. Controlled Release. 2014;174(1):81–87. doi: 10.1016/j.jconrel.2013.11.011. PubMed DOI

Cayot P., Tainturier G.. The Quantification of Protein Amino Groups by the Trinitrobenzenesulfonic Acid Method: A Reexamination. Anal. Biochem. 1997;249:184. doi: 10.1006/abio.1997.2161. PubMed DOI

Ren J., Jepson C. E., Nealy S. L., Kuhlmann C. J., Osuka S., Azolibe S. U., Blucas M. T., Nagaoka-Kamata Y., Kharlampieva E., Kamata M.. Site-Oriented Conjugation of Poly­(2-Methacryloyloxyethyl Phosphorylcholine) for Enhanced Brain Delivery of Antibody. Front. Cell Dev. Biol. 2023;11:1214118. doi: 10.3389/fcell.2023.1214118. PubMed DOI PMC

Iwasaki Y., Ishihara K.. Cell Membrane-Inspired Phospholipid Polymers for Developing Medical Devices with Excellent Biointerfaces. Sci. Technol. Adv. Mater. 2012;13:064101. doi: 10.1088/1468-6996/13/6/064101. PubMed DOI PMC