Exploring the Potential of Nanogels: From Drug Carriers to Radiopharmaceutical Agents

Abstract

Nanogels open up access to a wide range of applications and offer among others hopeful approaches for use in the field of biomedicine. This review provides a brief overview of current developments of nanogels in general, particularly in the fields of drug delivery, therapeutic applications, tissue engineering, and sensor systems. Specifically, cyclodextrin (CD)-based nanogels are important because they have exceptional complexation properties and are highly biocompatible. Nanogels as a whole and CD-based nanogels in particular can be customized in a wide range of sizes and equipped with a desired surface charge as well as containing additional molecules inside and outside, such as dyes, solubility-mediating groups or even biological vector molecules for pharmaceutical targeting. Currently, biological investigations are mainly carried out in vitro, but more and more in vivo applications are gaining importance. Modern molecular imaging methods are increasingly being used for the latter. Due to an extremely high sensitivity and the possibility of obtaining quantitative data on pharmacokinetic and pharmacodynamic properties, nuclear methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) using radiolabeled compounds are particularly suitable here. The use of radiolabeled nanogels for imaging, but also for therapy, is being discussed.

Keywords: cyclodextrin; drug delivery; molecular imaging; nanogels; radiolabeling; theranostics.

Figure 1

Examples of gels.

Figure 2

Cartoon illustration of CD structure.

Figure 3

Cartoon illustrations of CD nanogels and their preparation methods.

Figure 4

a) Illustration of host–guest complexation‐based nanogels and structures of typical cross‐linkers. b) Illustration of the synthesis of nanogels cross‐linked by six‐arm isocyanate‐terminated linkers, together with Cryo‐FESEM images of swollen nanogels. Reproduced with permission.^{[ 116 ]} Copyright 2012, American Chemical Society.

Figure 5

a) Schematic illustration of the synthesis and TEM image of CD‐based EGDE nanogel. Reproduced with permission.^{[ 117 ]} Copyright 2012, Elsevier. b) Schematic illustration of the synthesis and TEM image of ultrasmall γ‐CD nanogel. Reproduced with permission.^{[ 122 ]} Copyright 2023, the Royal Society of Chemistry.

Figure 6

a) Illustration of host–guest complexation‐based nanogels and structures of typical guest units. b) Illustration of the synthesis of CD‐adamantane nanogels.^{[ 131 ]} Reproduced with permission.^{[ 131 ]} Copyright 2009, Wiley‐VCH GmbH.

Scheme 1

Different drug loading mechanisms in CD‐based nanogels, electrostatic interactions (top); host–guest interactions (bottom).

Scheme 2

Different drug release mechanisms: change of the binding constant (top); functionalization of nanogels with biological entities for the recognition of diseased cells (middle); temporal swelling or permanent degradation of nanogels (bottom).

Figure 7

Supramolecular gels prepared applying a host–guest macromer (HGM) approach, consisting in the assembly of adamantane‐modified hyaluronic acid and monocrylated β‐CD followed by photo‐crosslinking. The gels exhibited self‐healing and ability to be remolded into freestanding 3D constructs. Reproduced with permission.^{[ 168 ]} Copyright, 2016 American Chemical Society.

Figure 8

Chemical structures of various compounds used to radiolabel nanogels discussed in this review. A) Structures of metal‐based chelators (and their respective radionuclide(s) in purple) that are attached to the monomer or polymer chains. B) Common radioiodination strategy using different mediators such as chloramine‐T, iodobeads or iodogen. C) Nanogel radiolabeling strategies using chelator‐based or non‐metal radiolabeling approaches.

Scheme 3

Cartoon is highlighting challenges in nanomedicine and solutions nanogels may offer to improve multimodal imaging and combinational therapy. For successful clinical translation, specific challenges in synthesis, design and delivery of nanoparticles such as functionalization of nanoparticles, toxicity, stability in vivo, nonspecific distribution, efficacy for desired application (highlighted in red text) could be addressed through the use of functionalized nanogels carrying certain properties (highlighted in green).

Figure 9

In vivo behavior of intravenously administered large and small radiolabeled nanogels in animal models: Target (cancer) and non‐target (liver, spleen) accumulation of A) µ‐PET measurements and biodistribution studies of [⁶⁸Ga]Ga‐malDOTA‐TATE‐sPEG nanogels (black) and [⁶⁸Ga]Ga‐NOTAsPEG nanogels (red) in Balb/c AR42J tumor‐bearing nude mice. Reproduced with permission.^{[ 218 ]} Copyright 2017, American Chemical Society. B) PET/CT images at 4, 24, and 48 h after intravenous injection of [⁶⁴Cu]Cu‐DOTA‐PAA (2) and [⁶⁴Cu]Cu‐NOTA‐PAA (3) in 4T1 mice bearing murine mammary carcinoma tumor (white arrow indicates the tumor). Reproduced with permission.^{[ 216 ]} Copyright 2015, Ivyspring International Publisher. C) Table highlighting the importance of targeting mechanism for above mentioned large and small nanogels which leads to an understanding that both RES accumulation and renal clearance can be achieved with large sized nanogels via active targeting of the nanogels and allowing their degradation (e.g., GSH induced in A) into smaller sized particles in the extracellular environment.

Figure 10

A) Synthesis scheme of [¹³¹I]I‐PBA‐PHP nanogels. B) Biodistribution data (% ID) of [¹³¹I]‐PHP and [¹³¹I]I‐PBA‐PHP nanogels at 16 hours post‐injection in 4T1 tumor‐bearing mice. Tumor inhibition efficacy with various treatments (NS = normal saline; PHP = non‐radiolabeled nanogels; PBA‐PHP = non‐radiolabeled phenylboronic acid nanogels; ¹³¹I‐PHP = radiolabeled nanogels; ¹³¹I‐PBA‐PHP = radiolabeled phenylboronic acid nanogels) showing C) relative tumor volume, D) body weight and E) survival rate of 4T1 tumor‐bearing mice within 47 d. Reproduced with permission.^{[ 231 ]} Copyright 2022, Frontiers.

Figure 11

Schematic illustration of dual‐labeled (Cy5 and ^99mTc) PIBMA (poly(isobutylene‐alt‐maleic‐anhydride) nanogels containing CD units as a complementary system to recognize adamantane‐functionalized micro albumin aggregates (MAA‐Ad). Reproduced with permission.^{[ 221 ]} Copyright 2018, Ivyspring International Publisher.