Drug Conjugates Using Different Dynamic Covalent Bonds and their Application in Cancer Therapy

Abstract

: Polymer-drug conjugates are polymers with drug molecules chemically attached to polymer side chains through a weak covalent bond (degradable bond) or a dynamic covalent bond. These systems are known as prodrugs in the inactive form of the drug passing into the blood circulation system. When the prodrug reaches to the target organ, tissue or cell, the drug is activated by cleavage of the bond between the drug and polymer under certain conditions existing in the target organ. The advantages of polymer-drug conjugates compared to other controlledrelease carriers and conventional pharmaceutical formulations are the increased drug loading capacity, the prolonged in vivo circulation time, the enhanced intercellular uptake, the better controlled release, the improved therapeutic efficacy and the enhanced permeability and retention effect. The aim of the present review is the investigation of polymer-drug conjugates bearing anticancer drugs. The polymer through its side chains is linked to the anticancer drugs via dynamic covalent bonds such as hydrazone/imine bonds, disulfide bonds and boronate esters. These dynamic covalent bonds are cleaved in conditions existing only in cancer cells and not in healthy ones. Thus, ensures the selective release of the drug to the targeted tissue, reducing in this way the frequent side effects of chemotherapy, leading to a more targeted application, despite the nature of the applied polymer, possessing the ability to aim selectively tumors via incorporation of a relative ligand.

Flower Necklaces of Controllable Length Formed From N-(2-Hydroxypropyl) Methacrylamide-Based Amphiphilic Statistical Copolymers

“…We infer that the structure of the spherical objects may correspond to the flower micelles, − illustrated in Figure . We note that the electron density of the pyrene moiety is almost the same as that of the precursor (see the Supporting Information).…”

“…Therefore, the dynamic covalent bond strategy with statistical copolymers is quite appealing and has an advantage over the conventional strategy of using block copolymer micelles in drug delivery systems. 29,30 In fact, the efficacy of the dynamic covalent bond strategy has been demonstrated in animal experiments. 8−10 However, the aggregate structure of statistical copolymers is much less understood than that of block copolymers, and only a few scattering studies with detailed modeling 11−18 have been performed, despite small-angle scattering being one of the most powerful tools to derive quantitative and statistical information about the structure of nano-objects.…”

“…If drugs are loaded into block copolymer micelles or vesicles with noncovalent interactions, they are gradually released before reaching their target. Therefore, the dynamic covalent bond strategy with statistical copolymers is quite appealing and has an advantage over the conventional strategy of using block copolymer micelles in drug delivery systems. , In fact, the efficacy of the dynamic covalent bond strategy has been demonstrated in animal experiments. − …”

Molecular docking for rationalizing the use of linkers in polymer drug conjugates design for pegylated anti-inflammatory drug delivery

“…All the structures occurrence, were confirmed for their possibility of being synthesized via suitable literatures. (Davaran et al, 2006;Kemisetti & Manda, 2018;Mattheolabakis et al, 2014;Narayanan et al, 2013;Zhao et al, 2016) the various structures of prodrug under current investigation have been listed in Linkers play versatile role in the development and functioning of polymer-drug conjugates, they act as targeting entity (Chang et al, 2016), solubility enhancer (Chang et al, 2016;Ofokansi et al, 2016), Linking ability provider (Theodosis-Nobelos et al, 2020) and releasability definer. (Lawrence et al, 2016;Taghizadeh et al, 2015;Tedeschini et al, 2021) Various linkers have been utilized in the development of polymer drug conjugates (PDC's) of Ibuprofen, here we have constricted to those linkers which have been employed in the conjugation of polyethylene glycol to Ibuprofen to form respective PDC's.…”

Flexible Organic Framework-Based Anthracycline Prodrugs for Enhanced Tumor Growth Inhibition

“…Prodrugs are chemically modified, biologically inert molecular, macromolecular, or supramolecular drugs that are transformed in vivo to release the pharmacologically active drugs. − Prodrug design provides a remarkably useful tool for the increase of the pharmaceutical properties of active agents via simple chemical modifications, which can improve chemical stability, solubility in water or the lipid membrane, oral or local absorption, and brain permeability or reduce presystemic metabolism, toxicity, unacceptable taste, irritation, or pain. , Among different approaches, polymer-derived prodrugs have received considerable attention due to their advantages, which include high drug loading capacity, enhanced intercellular uptake, better controlled release, prolonged in vivo circulation time, enhanced permeability and retention effect, and improved therapeutic efficacy. − By utilizing the dynamic hydrazone bond to conjugate drugs to various polymers, a large number of prodrugs have been prepared, which undergo active agent release through acid-sensitive in vivo hydrolysis of the hydrazone bond. − We envisioned that prodrugs constructed from homogeneous porous polymers would allow for ready hydrolysis of the hydrazone units to the tumor acid microenvironment and consequently promote cleavage of the bond. This strategy, to the best of our knowledge, has not been reported yet.…”