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. 2022 Aug 15;14(8):1700. doi: 10.3390/pharmaceutics14081700

Table 4.

Strategies to overcome the limitations related to the application of polymeric micelles.

Limitations Strategies References
Toxicity and Immunogenicity PEGylation approach;
Use pH-sensitive micelles;
High affinity targeting ligands;
Use biodegradable and biocompatible PMs.		 [169,170,171,172,173,174,175]
Low Stability PEGylation approach;
Covalent cross-linking strategies: Shell cross-linked micelles, core cross-linked micelles.
Covalent cross-linking methods: Photo/ultraviolet-induced dimerization, di-functional cross-linkers, click cross-linking method, silicon chemistry method, reversible boronate ester bond;
Non-covalent cross-linking strategies: Complexation of micelle cores, macrocyclic host-guest complexation;
Altering hydrophilic/hydrophobic block ratios of the micelles;
Increase of the crystallinity of hydrophobic segments;
Introduction of inorganic materials into the core or shell of micelles to act as structural stabilizers.		 [176,177,178,179,180,181,182,183,184,185,186,187]
Non-biodegradable and non-biocompatible Use biodegradable PMs such as: poly(ethylene glycol) (PEG), polylactic acid (PLA), poly(caprolactone) (PCL),
polyglycolic acid (PGA), monomethoxy poly (ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA), poly(L-histidine), poly(L-lactic acid) (PLLA), PEG-poly(S-(2-nitrobenzyl)-l-cysteine),
phospholipid, such as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).		 [188,189,190]
Low drug loading Improving the compatibility between drug and polymer;
Polymeric prodrugs;
Electrostatic interactions;
Cross-linking of the core or the shell of self-assembled PMs;
Layer by layer coating of PMs;
Host-guest complex micelles;
Micelle-like nanoparticles;
Integrate drug attached polymers into lipids.		 [191,192,193,194,195]
High CMC Increasing chain length of the hydrophobic block;
Decoration of micelle cores with various fatty acid;
Addition of benzyl groups.		 [179]
Rapid clearance PEGylation approach;
Cross-linked with various stimuli-sensitive linkers.		 [75,112]
Low selectivity PEGylation approach;
High-affinity targeting ligands.		 [75]
Low membrane disrupting capability Hydrophobic moieties and cationic groups;
Polymers with buffering capacity at endosomal pH;
High-affinity targeting ligands.		 [89,95,196]
Low efficiency in drug delivery Cross-linked with various stimuli-sensitive linkers;
High-affinity targeting ligands;
Intracellular redox-responsive drug release.		 [112,197,198]