HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

Abstract

Recently, numerous polymer materials have been employed as drug carrier systems in medicinal research, and their detailed properties have been thoroughly evaluated. Water-soluble polymer carriers play a significant role between these studied polymer systems as they are advantageously applied as carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, antimicrobial molecules, or multidrug resistance inhibitors. Covalent attachment of carried molecules using a biodegradable spacer is strongly preferred, as such design ensures the controlled release of the drug in the place of a desired pharmacological effect in a reasonable time-dependent manner. Importantly, the synthetic polymer biomaterials based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are recognized drug carriers with unique properties that nominate them among the most serious nanomedicines candidates for human clinical trials. This review focuses on advances in the development of HPMA copolymer-based nanomedicines within the passive and active targeting into the place of desired pharmacological effect, tumors, inflammation or bacterial infection sites. Specifically, this review highlights the safety issues of HPMA polymer-based drug carriers concerning the structure of nanomedicines. The main impact consists of the improvement of targeting ability, especially concerning the enhanced and permeability retention (EPR) effect.

Keywords: EPR effect; HPMA copolymers; controlled release; drug delivery; nanomedicines.

Figure 1

In vivo positron emission tomography (PET) imaging and biodistribution study: (a) serial maximum intensity projection (MIP) images, (b) time–activity curves, (c) and comparison of radioactivity retained in liver, blood, tumor and muscle of ⁸⁹Zr-labeled linear pHPMAs; HD-P + Def (M_w = 27,800 g/mol, Ð = 1.74), ⁸⁹Zr-LD-P-30 + Def (M_w = 33,300 g/mol, Ð = 1.06) and ⁸⁹Zr-LD-P-45 + Def (M_w = 45,200 g/mol, Ð = 1.07). Reprinted with permission from [39]. Copyright (2017) The Royal Society of Chemistry.

Figure 2

Synthesis of multiblock biodegradable N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer (pHPMA)–drug conjugates. Reprinted with permission from [62]. Copyright (2017) American Chemical Society.

Figure 3

Schematic description of pHPMA-based star-like nanomedicine synthesis. The grafting-to approach is based on the covalent one-point attachment of semitelechelic polymer precursors (the light blue dot is reactive group on main chain end of polymer) onto the core (green star) containing functional groups. The grafting-from approach is employing the reversible addition–fragmentation transfer (RAFT) polymerization using the core containing several chain-transfer agents (violet dots) leading to the growth of the polymer chain from monomers (small violet dots) directly on the core.

Figure 4

Schematic sketch of the formation of adjustable star-shaped nanomedicine based on semitelechelic pHPMAs and polyester-based core. Green stars are bisMPA cores, light and dark blue lines are polymers, violet dots represent drugs.

Figure 5

Schematic structure of amphiphilic pHPMA−doxorubicin (Dox) conjugates P1–P3 differing in the hydrophobic moiety (A) and star pHPMA−Dox conjugate (B). Release of cholesterol moieties from copolymers P1−P3 at pH 7.4 and 37 °C, mimicking the bloodstream environment (C). Reprinted with permission from [82]. Copyright© American Chemical Society (2018).

Figure 6

Schematic description of the enhanced and permeability retention (EPR) effect and application of EPR effect enhancers for the solution of heterogenicity of tumor tissue. Reprinted with permission from [101]. Copyright (2020) Elsevier B.V. (Amsterdam, Netherlands).

Figure 7

Synthesis of polymer-bound nitric oxide (NO) donors. Reprinted with permission from [110]. Copyright (2018) Elsevier B.V. (Amsterdam, Netherlands).