In this review, we summarize recent advances in crosslinked nanogels for cancer imaging and therapy. The applications of nanogels in drug and gene delivery as well as development of novel cancer therapeutic methods are first introduced, followed by the introduction of applications in optical and multimodal imaging, and imaging-guided cancer therapy. The conclusion and future direction in this field are discussed at the end of this review.
Definition
crosslinked nanogels the structures of which are covalently crosslinked have better physiological stability than micelles and liposomes, making them more suitable for cancer theranostics.
1. Introduction
Cancer is one of the major threats to human lives all over the world [
1]. Traditional cancer treatment process divides diagnosis and therapy into different procedures, which is time consuming and requires high cost [
2,
3]. In contrast, cancer theranostics which combines diagnosis and therapy into one system can overcome such disadvantages, and has shown great potential in the field of cancer treatment [
4,
5,
6]. Recently, phototheranostics, which based on optical imaging, have been widely studied because of their unique advantages such as high safety and sensitivity, low cost and capability of multi-channel imaging [
7,
8,
9,
10,
11]. Numerous phototheranostic systems based on variety of materials such as small molecular dyes [
12,
13], anti-cancer drugs [
14,
15] and biomacromolecules [
16] have been developed. However, as theranostics require the combination of multiple functionalities including imaging and therapy, complicated synthetic procedures are usually inevitable [
17,
18]. Therefore, developing phototheranostic systems based on multifunctional and facile synthesized materials is in high demand.
Among numerous materials for phototheranostics, nanomaterials have shown great promise and been widely applied in the field of cancer imaging and therapy [
19,
20]. Compared with small molecular dyes or drugs, nanomaterials can be easily prepared via nano-based preparation methods such as nanoprecipitation and nanoemulsion [
21,
22,
23]. Some inorganic nanoparticles or 2D nanomaterials have unique optical properties, which can be used as phototheranostics directly [
24,
25,
26,
27]. In addition, different functionalities can be integrated into nanomaterials by simply doping or linking different moieties [
28,
29]. Anti-cancer drugs can also be absorbed or covalently linked onto such nanomaterials, endowing them with the capability for chemotherapy [
30,
31]. For organic nanomaterials, hydrophobic anti-cancer drugs or photosensitizers as well as optical imaging contrast agents can be encapsulated into micelles or liposomes simultaneously, which is a conventional way to construct phototheranostic platforms [
32,
33,
34,
35]. Owing to their relatively good biocompatibility, organic nanoparticles have gained increasing attention in the field of phototheranostics.
Although organic nanoparticles have been widely applied in cancer imaging and therapy, some drawbacks of conventional nanoparticles should be overcome. As most organic nanoparticles are micelles and liposomes, they may dissociate when their concentration decrease lower than the critical micelle concentration [
36]. Such a feature makes nanoparticles unstable in harsh conditions such as blood circulation, which further leads to the burst release of encapsulated drugs or contrast agents [
37,
38]. To overcome such drawbacks, crosslinked nanogels have been chosen in the development of phototheranostic systems. Compared with micelles or liposomes, a crosslinked structure can stabilize the nanogels, leading to the non-dissociable nanostructure [
39,
40,
41,
42]. Such structure makes nanogels keep intact in the circulation, thus resulting in improved biodistribution and better tumor accumulation [
43,
44].
3. Crosslinked Nanogels for Cancer Therapy
Nanomaterials have been widely used as carriers for drug and gene delivery in the field of cancer therapy [
75]. As crosslinked nanogels have the advantages including good stability and environmental responsiveness, nanogels can be good candidates for nanocarriers [
76]. The crosslinked structure may prevent the burst release of loaded drugs. In addition, an activatable drug- or gene-delivery system can be developed by nanogels with environmental responsiveness [
77]. In this section, we summarize applications of nanogels for cancer therapy including chemotherapy, gene therapy and enzyme dynamic therapy. The properties of these nanogels introduced in this section are summarized in . The most commonly used anti-cancer drug was doxorubicin (DOX), and it can be loaded via electrostatic interaction with nanogels. Drugs can be released under specific responsiveness such as pH, glutathione (GSH) and esterase. However, such method sometimes led to low drug loading capacity. To improve the drug-loading capacity, drug-crosslinked nanogels were designed, and the drug loading capacity can reach as high as 60.8%. For gene therapy, therapeutic RNAs were commonly loaded by ionic interaction, and can be released in a tumor-associated microenvironment.
Table 2. Summary of the nanogels for cancer therapy by loaded drug, loading capacity, responsiveness and animal study.
Type |
Loaded Drug |
Loading Capacity |
Responsiveness |
Animal Study |
References |
Chemotherapy |
DOX/GL |
1.2% (DOX) |
pH |
Yes |
[54] |
|
DOX |
5.7% |
- |
No |
[55] |
|
DOX |
54.1% |
pH/GSH/trypsin |
Yes |
[56] |
|
DOX |
18.2% |
pH/GSH |
Yes |
[66] |
|
TAX |
20–30% |
pH/esterase |
Yes |
[49] |
|
Pt(IV) |
60.8% |
GSH/ascorbic acid |
Yes |
[57] |
|
Pt(IV)/TPZ |
8.06% (Pt)/9.12% (TPZ) |
GSH |
Yes |
[58] |
Gene therapy |
siRNA |
- |
RNase H |
Yes |
[51] |
|
siRNA |
- |
pH/RNase H |
Yes |
[59] |
|
siBcl2 |
- |
DTT |
Yes |
[60] |
|
RNase |
23.5% |
NTR |
Yes |
[61] |
Enzyme dynamic therapy |
- |
- |
·O2−/H2O2 |
Yes |
[53] |
|
- |
- |
H2O2 |
Yes |
[50] |
This entry is adapted from the peer-reviewed paper 10.3390/polym12091902