Research progress of self-assembled nanogel and hybrid hydrogel systems based on pullulan derivatives

Figures & data

Figure 1. Chemical structures of (A) pullulan, (A) cholesterol-bearing pullulan (CHP), (B) CHPNH2, and (C) CHPOA-PEGSH; (D) Pullulan-based nanogels and hybrid hydrogels; and (E, F) schematic representation of chaperone-assisted refolding.

Table 1. Summary of recent studies of CHP nanogels.

Loaded objects	Types	Applications	References
Doxorubicin	Antitumor drug	Sustained-release	(Akiyoshi & Sunamoto, 1996)
Methacrylate random copolymer	Antimicrobial agent	Tunable activity	(Takahashi et al., 2015)
Prostaglandin E1	Anabolic agent	Wood healing	(Kobayashi et al., 2009)
Prostaglandin E2	Anabolic agent	Bone repair	(Kato et al., 2007)
Green fluorescent protein	Protein	Tunable release	(Asayama et al., 2008; Sasaki et al., 2010)
Bovine serum albumin	Protein	Tunable release	(Nishikawa et al., 1996)
Insulin	Protein	Enhanced stability	(Akiyoshi et al., 1998)
Oncogene erbB-2/neu/HER2	Protein	Induced cellular and humoral immune responses	(Gu et al., 1998)
amyloid β-protein	Protein	Alzheimer’s disease therapy	(Ikeda et al., 2006)
Truncated HER2 protein 1-146	Protein	Specific T cell immune responses	(Kitano et al., 2006)
NY-ESO-1 protein	Protein	T cell immunomonitoring and tumor responses	(Uenaka et al., 2007)
146HER2/Recombinant human granulocyte-macrophage colony-stimulating factor	Protein	Humoral immune responses	(Kageyama et al., 2008)
Melanoma antigen gene-A4 protein	Protein	Clinical cancer vaccination therapy	(Kyogoku et al., 2016)
Carbonic anhydrase B, Citrate synthase, Horseradish peroxidase	Enzyme	Molecular chaperone	(Nomura et al., 2005; Sawada et al., 2006, 2011)
α-Chymotrypsin	Enzyme	Tunable activity and thermal stability	(Nishikawa et al., 1994)
Lipase	Enzyme	Colloidal and thermal stabilization	(Sawada & Akiyoshi, 2010)
Synthetic long peptide antigen	Antigen	Antitumor vaccine of targeting macrophages	(Muraoka et al., 2014)
Interleukin-12	Cytokine	Sustained-release for tumor immune therapy	(Shimizu et al., 2008)
Tumor necrosis factor (TNF)-α	Cytokine	Protecting bone resorption	(Nagano et al., 2011)
Tumor necrosis factor (TNF)-α	Cytokine	Vaccine adjuvant against influenza virus	(Nagatomo et al., 2015)
9-mer HER2p63-71 peptide	Peptide	Tumor immune therapy	(Ikuta et al., 2002)
DNA	DNA	DNA separation	(Kondo et al., 2010)
Dex	Dye	Reduced cytotoxicity	(Gupta & Gupta, 2004)

Table 2. Summary of recent studies of nanogel crosslinked hydrogels.

Hybrid hydrogels	Nanogel/crosslinkers	Loaded objects	Applications	References
CHPOA-PEGSH	CHPOA: R: H or Cholesteryl group or AOI^(1); PEGSH^(2)	Liposome	Dually controlled-release	(Sekine et al., 2012)
CHPOA-PEGSH		BMP2 protein, FGF18 protein	Multidrug delivery for bone repair	(Fujioka-Kobayashi et al., 2012)
CHPOA-PEGSH		Insulin	hydrolysis mechanism and exchange reactions	(Shimoda et al., 2012b)
CHPOA-PEGSH		sFGFR2^S525W	cytokine therapy	(Yokota et al., 2014)
CHPOA-PEGSH		W9 peptide	Bone repair, sustained-release	(Sato et al., 2015)
CHPOA-PEGSH		Vitronectin, mouse embryo fibroblast cells	Artificial extracellular matrices	(Hashimoto et al., 2016)
CHPOA-PEGSH		Insulin	Longer elimination half-life	(Shimoda et al., 2012a)
CHPOA-PEGSH		Silicone sheet	Wound healing	(Maeda et al., 2017)
CHPA-PEGSH	CHPA: R: H or Cholesteryl group or − COCH = CH2; PEGSH^(2)	Prostaglandin E2, BMPprotein, PDGF protein	Bone repair	(Kato et al., 2007; Hayashi et al., 2009; Kamolratanakul et al., 2011; Miyahara et al., 2012)
CHPA-PEGSH		Interleukin-12	Long-term stability	(Hasegawa et al., 2009)
CHPOA-PEGDA	CHPOA; PEGDA^(3)	Insulin	Tunable activity	(Tahara et al., 2013)
CHPOA-P(MAA-g-EG)	CHPOA; P(MAA-g-EG)	Pregabalin	pH-responsive release	(Cinay et al., 2017)
CHPMA-MPC	CHPMA: R: H or Cholesteryl group or − COC(CH3)=CH2; MPC^(4)	Insulin, Carbonicanhydrase B	Molecular chaperone	(Morimoto et al., 2005a,b)
CHP-HA	CHP: R: H or Cholesteryl group; HA^(5)	Peptide-1, insulin, erythropoietin	Molecular chaperone, sustained-release	(Hirakura et al., 2010)
PHD	Pullulan-collagen; 1,2,7,8-diepoxyoctane	1,2,7,8-diepoxyoctane	Tissue filler materials	(Ma et al., 2017)

AOI: 2-(acryloyloxy)ethyl isocyanate; PEGSH: pentaerythritol tetra (mercaptoethyl)polyoxyethylene; PEGDA: polyrthylene glycol diacrylate; MPC: 2-methacryloyloxyethyl phosphorylcholine; HA: chemically cross-linked Haluronan.

Important structures marked with consecutive numbers (1)–(5) are redrawn within the Supplemental File ‘Numbered Structures’.

Table 3. Summary of recent studies of responsive pullulan nanogels.

Nanogel	Typical structures	Loaded objects	Applications	References
CHPNH2	R: H or Cholesteryl group or − CONH(CH2)2NH2	Quantum dots, Bovine serum albumin	Live cell imaging	(Hasegawa et al., 2005; Toita et al., 2008)
CHPNH2		β-galactosidase, amyloid β-protein, green fluorescent protein, TAT-GFP protein, Bcl-xL protein	Intracelluar protein delivery, inhibition of Aβ aggregation, cancer therapy and immune regulation	(Ikeda et al., 2006; Ayame et al., 2008; Watanabe et al., 2011)
RGD-cCHP		Bovine serum albumin	Targeted protein delivery	(Shimoda et al., 2011)
cCHP		Pneumococcal surfaceprotein A	Nasal vaccine	(Kong et al., 2013; Fukuyama et al., 2015)
HA/DPNG	R: H or − COCH3 or PEI^(6)	Paclitaxel	Treatment of heterogeneous tumor	(Yim et al., 2013)
PA/SDM	R: H or − CH3COCH3 or Succinylated sulfadimethoxine group	Doxorubicin	pH-responsive for targeted tumor	(Na & Bae, 2002; Na et al., 2003a)
PUL-DO/bHis	R: H or Deoxycholic acid group or N-Boc-l-histidine group	Doxorubicin	pH-responsive for targeted tumor	(Na et al., 2007)
acL-CHP	R: H or acid-labile group^(7)	Bovine serum albumin	pH-sensitive for tunable release	(Morimoto et al., 2013)
CMP-PNIPAM	CMP: Carboxymethyl pullulan; PNIPAM^(8)	Diphenhydramine hydrochloride	Thermo- and pH-responsive release	(Asmarandei et al., 2013)
PLP	R: H or Poly(l-lactide)^(9)	Doxorubicin	Thermo-responsive for long-term release	(Seo et al., 2012)
SPL	R: H or Succinyl group or Poly(l-lactide)^(9)	Lysozyme, etanercept	Thermo-responsive forlong-term release	(Jung et al., 2013, 2014)
SpP	R: H or Spiro form or Merocyanine form^(10)	Citrate synthase, pyrene	Photo-responsive for protein delivery	(Hirakura et al., 2004; Wang et al., 2014)
PL/phA	R: H or phA^(11)	–	Photodynamic therapy	(Bae et al., 2010)
PFP	R: H or phA or Folic acid group	–	Photodynamic therapy	(Bae & Na, 2010)
CHP-o-NB	R: H or o-NB^(12)	Insulin	Patterned film	(Nishimura et al., 2016)
NIR-PNG	R: H or NG^(13)	IRDye800	Lymph node mapping	(Noh et al., 2012; Kong et al., 2015)
Gd-CHPOA	R: H or Cholesteryl group or Acryloyl-moiety^(14); Gd-chelating crosslinker^(15)	–	Tumor imaging	(Chan et al., 2015)
ImCHP	R: H or Cholesteryl group or Imidazolyl group^(16)	–	Redox sensitivity	(Sasaki et al., 2011)
PulSTS-PNIPAM	R: H or STS^(17) or PNIPAM^(8)	–	Thermo- and redox-responsive system	(Morimoto et al., 2008b,c)
PA	R: H or –COCH3	Clonazepam	Sustained release	(Jung et al., 2003)
BPA	R: H or –COCH3 or Vitamin H group	Doxorubicin	Targeted tumor	(Na et al., 2003b; Park et al., 2006)
PUL/DOCA	R: H or Deoxycholic acid group	Doxorubicin	Sustained release	(Na et al., 2006)
PUL/FA	R: H or Folic acid group	Doxorubicin	Anticancer	(Kim et al., 2008)
PUL/LLA	R: H or l-lactic acid oligomer^(18)	Carmofur; Peostaglandin E2	Antitumor; Induced immunological tolerance	(Miyazaki & Tabata, 2009; Okamoto et al., 2011)
CAP	R: H or Modified carborane^(19)	Carborane	Boron neutron capture therapy	(Kawasaki et al., 2017)

PEI: polyethyleneimine; PNIPAM: poly-N-isopropylacrylamide; phA: pheophorbides-A group; o-NB: ortho-Nitrobenzyl-substituted cholesteryl group; STS: sulfanylthiocarbonylsulfanyl group.

Important structures marked with consecutive numbers (6)–(19) are redrawn within the Supplemental File ‘Numbered Structures’.

Figure 2. (A) Schematic illustration showing the composition of the degradable deep penetrating cationic nanoparticle (HA/DpNG-PTX, Table 3), and how it can be used to penetrate into tissue; (B) temperature-induced changes in the morphology and association of CHPMA-PNIPAM nanogels and SPL complexes; swollen nanogels formed by the association of a few CHPMA nanogels, shrunken nanogels, and botryoidal nanogels are shown; (C) aqueous condition at 4 °C but hydrogel condition at 37.5 °C is shown; (D) schematic illustration of SpS nanogel under UV–Vis light. HA/DpNG-PTX: hyaluronic acid-coated degradable cationic nanogel–paclitaxel; CHPMA-PNIPAM: methacryloyl-substituted CHP-poly-N-isopropylacrylamide; SPL: succinated pullulan-poly(l-lactide).

Table 4. Clinical studies of CHP nanogels.

Loaded objects	Cancer type and clinical cases	References
HER2	Solid tumors; well tolerated, CD4^+ T-cell response in 5/9 patients, CD8^+ T-cell responses in 4/9 patients	(Kitano et al., 2006)
HER2 plus GM-CSF	146HER2-specific IgG antibody response in 14 patients; fastly reached plateau levels vaccinated with CHP-HER2 plus GM-CSF	(Kageyama et al., 2008)
NY-ESO-1	NY-ESO-1 antibody response in all 9 patients	(Kawabata et al., 2007)
	CD4^+ T-cell response in 7 including 3 esophageal cancer, 1 malignant melanoma and 3 prostate cancer of 9 patients	(Uenaka et al., 2007)
	Melanoma cell; CD4^+ and CD8^+ T-cell responses, detecting CD4^+CD25^+ Foxp3^+ Tregs and CD68^+ immunoregulatory macrophages	(Tsuji et al., 2008)
	Esophageal cancer; antibody, CD4^+ and CD8^+ T-cell responses in 7,7 and 6 of 8 patients	(Wada et al., 2008)
	Lung adenocarcinoma; antibody, CD4^+ and CD8^+ T-cell responses	(Isobe et al., 2009)
	Non-small cell lung cancer; spontaneously remission for one patient	(Nakamura et al., 2009)
	Esophageal and prostate cancer; antibody responses in 8/9 patients	(Kawada et al., 2012)
	Advanced/metastatic esophageal cancer; 100-μg cohort inducing antibody responses in 3/13 patients and 200-μg cohort in 7/12 patients	(Kageyama et al., 2013)
NY-ESO-1 plus HER2	Esophageal cancer; comparable antibody response with CHP/NY-ESO-1 and CHP/HER2	(Aoki et al., 2009)
MAGE-A4	Advanced esophageal, stomach or lung cancer; MAGE-A4-specific humoral immune response in 4/20 patients, CD4^+ and CD8^+ T-cell responses in 3/20 and 6/20 patients	(Saito et al., 2014)
MAGE-A4	5 colon, 1 esophageal, 1 papilla of Vater, 1 breast, 1 pancreatic cancer; IgG response in 7/9 patients, IgE response in 4/7 patients	(Kyogoku et al., 2016)

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