HPMA Copolymer–Drug Conjugates with Controlled Tumor‐Specific Drug Release

Abstract

Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water‐soluble polymer carriers of low‐molecular‐weight drugs and compounds, e.g., cytostatic agents, anti‐inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N‐(2‐hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity.

GRP78‐Targeted HPMA Copolymer‐Photosensitizer Conjugate for Hyperthermia‐Induced Enhanced Uptake and Cytotoxicity in MCF‐7 Breast Cancer Cells

“…[8,[23][24][25] The advantage of the HPMA copolymer system is its good water solubility, its lack of toxicity and immunogenicity, and the ability to incorporate various functionalized monomers. [26][27][28] In hyperthermia conditions, heat shock receptor glucose regulated protein 78 (GRP78) is known to be overexpressed on MCF-7 cancer cells. [29,30] In this study, we sought to synthesize and characterize HPMA copolymer-HPPH conjugates containing heat shock receptor-targeting peptides in the side chain and improve their cellular uptake by MCF-7 cancer cells under mild hyperthermia and further enhance therapeutic efficacy.…”

Ribonuclease A modification with poly[N‐(2‐hydroxypropyl)methacrylamide] copolymers: new route of synthesis and purification

“…Therefore, when a polymer is conjugated with a protein, it presents better chemical stability, increases the hydrodynamic radius allowing long intravascular half‐life, and reduces the immunogenicity. Furthermore, the polymer confers protection against proteolytic degradation and stabilizes the active site of enzymes …”

“…HPMA is a highly hydrophilic, non‐immunogenic, non‐toxic and biocompatible polymer whose α‐carbon substitution and N‐substituted amide bond ensure the hydrolytic stability of the side chains . The research on HPMA homopolymers and copolymers began in the early 1970s with the first synthesis and polymerization of HPMA . HPMA‐copolymers were initially designed as blood plasma expanders .…”

“…HPMA‐copolymers were initially designed as blood plasma expanders . Afterwards, HPMA‐copolymers, containing functional groups suitable for the attachment of biologically active molecules (proteins, enzymes, hormones, drugs), were designed to develop a polymer–drug carrier system . HPMA‐copolymers have great chemical versatility and therefore, have been employed to synthesize novel conjugates.…”

“…HPMA‐copolymers have great chemical versatility and therefore, have been employed to synthesize novel conjugates. Copolymers of HPMA have suitable reactive groups that allow the conjugation with drugs containing appropriate functional groups …”