Basic concepts and recent advances in nanogels as carriers for medical applications

Figures & data

Figure 1. Schematic illustration of potential advantages of nanogel formulations.

Figure 2. The schematic of drug release from the nanogel network (adapted from Yallapu et al., 2007).

Figure 3. Schematic illustration of the nanogel network created by: (a) direct polymerization of monomers; (b) assembling of a polymer precursor (adapted from Chacko et al., 2012).

Table 1. Uncontrolled free-radical polymerization techniques for nanogel synthesis.

Reaction	Details	Advantages//limitations	References
Miniemulsion	Nanodroplets formation through high shear stress (ultrasonication) of the mixture of monomers and surfactants	Narrow size distributions for diameters in the 50–500 nm range.Allows in situ encapsulation//Surfactant and co-stabilizer required.Special equipment necessary (ultrasonic device).	^a
Microemulsion	Absence of high shear stressUse of a critical concentration of surfactantMonomer molecules are in micelles	Usually nanogel sizes between 10 and 150 nm can be achievedNo shear stress necessary//High surfactant concentration needed.Co-surfactant necessary.	^b
Dispersion	Initially all the reaction ingredients are soluble in the reaction mediumPolymerization occurs in a homogeneous phaseThe polymers are insoluble and form a stable dispersion with an aid of colloidal stabilizers	Simple batch synthesis.Particle size adjusted by monomer and dispersant concentration in the range of 0.1–15 mmPreferably for core–shell particles synthesis//Preferably for vinylic functionalized monomers	^c
Precipitation	Initiation of reaction occurs in homogeneous solution of the monomers in the reaction medium.Polymer is soluble in the reaction medium.Particles separation by crosslinking	Batch synthesisNo surfactant requiredParticle size adjusted by monomer concentration in the range of 100–600 nm//Frequently irregular shape and high polydispersity	^d

^a(Landfester, 2003; Karasulu, 2008; Crespy & Landfester, 2010; Landfester et al., 2010; Weiss & Landfester, 2010; Landfester & Musyanovych, 2011; Asadian-Birjand et al., 2012; Khoee & Asadi, 2016).

^b (Landfester & Musyanovych, 2011; Asadian-Birjand et al., 2012; Khoee & Asadi, 2016).

^c (Asadian-Birjand et al., 2012; Khoee & Asadi, 2016).

^d (Asadian-Birjand et al., 2012; Khoee & Asadi, 2016).

Table 2. Main techniques for nanogel obtainment from polymeric precursors.

Reaction	Details	Particle size (nm)	References
Disulfide crosslinking	– Reacting groups: thiol and disulfide, at pH > 8, mild reaction conditions, ease of further functionalization– Self-crosslinking amphiphilic random copolymers (PEG hydrophilic unit and pyridyl disulfide hydro-phobic and crosslinkable unit)	40–60	Zhang et al. (2015)
Amide crosslinking	– Reacting groups: amino and carboxylic, esters, iodides– No additive needed– Adjustable crosslinking degree	50	Zhang et al. (2015)
Imine crosslinking	– Schiff-base reaction– Aldehyde and amine or hydrazide– No catalyst– Mild reaction conditions	6.3–50 function of Mw of PEG	Tan et al. (2012)
Copper-free click  chemistry crosslinking	– Reacting groups: alkyl units with amino groups immobilized to the particle shell via amidation of hydrophilic polymer micelle– With/without catalyst, slow/fast reaction depending on pH	∼40	Zhang et al. (2015)
Photo-induced crosslinking	– Technique used to stabilize polymers with functional groups that can polymerize– Reacting groups: coumarin or alkene– UV irradiation, photo initiator– Highly efficient, cytotoxicity concern	80–250	Zhang et al. (2015)

Table 3. Types of physical crosslinked nanogels.

Nanogels	Examples	References
Liposome modified	– Liposomes bearing succinylated polyglycidol undergo chain shrinking below pH 5.5 and deliver calcein to the cytoplasm.– Liposomes modified with poly(N-isopropylacrylamide) create temperature and pH sensitive nanogels, investigated for transdermal drug delivery.	(Kono et al., 1997; Roux et al., 2002)
Micellar	– Obtained by supramolecular self-assembly of amphiphilic block or graft copolymers in aqueous solutions.– Core–shell morphological structures obtained through hydrogen bonds, with core hydrophobic block segment surrounded by shell hydrophilic polymer block, that stabilizes the entire micelle.– Micelles’ core provides enough space for drugs/biomacromolecules encapsulation. The drug molecules in the hydrophobic core are protected from hydrolysis and enzymatic degradation.– N-isopropylacrylamide based micelle systems, evaluated as drug delivery devices.	(Rosler et al., 2001)
Hybrid	– Composite of nanogel particles dispersed in organic or inorganic matrices.– Ability to form complexes with various proteins, drugs and DNA; may coat the surface of liposomes, particles and solid surfaces including cells.– Able to deliver insulin and anticancer drugs.– Cholesterol-bearing pullulan composed of pullulan backbone and cholesterol branches. The molecules self aggregate and form stable nanogels through physical crosslinking points by the association of hydrophobic groups.– Nanogel in aqueous medium by self-assembly or aggregation of pullulan–poly(N-isopropylacrylamide), hydrophobized polysaccharides and hydrophobized pullulan.	(Akiyoshi et al., 2000; Kuroda et al., 2002; Lee & Akiyoshi, 2004)

Figure 4. Complementary effect of synthetic and biological polymers in bioconjugation (adapted from Lutz & Börner, 2008).

Figure 5. Intracellular delivery stages of biological macromolecules from nanogels (adapted from Keles et al., 2016).

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