New Advances in Biomedical Application of Polymeric Micelles
Abstract
:1. Introduction
2. Polymeric Micelles as Versatile Drug Delivery Carriers
3. Morphology, Partitioning, and Pharmacological Performance in Polymeric Micelles
4. pH-Sensitive Polymeric Micelles for Tumor-Targeted Delivery of Proteins
5. Pluronic®-Based Polymeric Micelles
5.1. Pluronics® for Cancer Treatment
5.2. Pluronics® for Cancer Theranostics
6. Polymeric Micelles: A Promising Pathway for Dermal Drug Delivery
7. Micelleplexes: The Key to Achieving Success in Therapy
8. Polymeric Micelles Limitations and Their Respective Solutions
9. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Polymers | Properties | References | |
---|---|---|---|
Hydrophobic Polymers | poly(D,L-lactide)–PLA | PLA-based PMs are clinically-approved (Genexol®, Nanoxel®). | [11,12,13,14,15,17,18] |
poly(lactic-co-glycolic acid)–PLGA | PLGA is used as a biodegradable surgical suture in the clinic (Vicryl®). Biodegradable. | ||
poly(β-benzyl-l-aspartate) | The presence of the benzyl group grants increased hydrophobicity. Biodegradable. | ||
poly(γ-benzyl-α, l-glutamate) | The presence of the benzyl group grants increased hydrophobicity. Ultra-high loading capacity for various poorly soluble drugs (ex. paclitaxel, etoposide) as well as a versatile library of polymer structures. | ||
poly(2-n-butyl-2-oxazoline) | The presence of the benzyl group grants increased hydrophobicity. Ultra-high loading capacity for several poorly soluble drugs, such as curcumin. | ||
Hydrophilic Polymers | polyethylene glycol (PEG) | Has been used in clinically-approved nanoformulations including PMs (Genexol® PM). | |
poly(2-methyl-2-oxazoline)–PMeOx | PMeOx is more hydrophilic than PEG. | ||
poly(sarocosine) | Evaluated as PEG replacement. Biodegradable. | ||
dextran | Has been used as a component in block and graft copolymers. Has highly variable molecular weight and dextran has been used as an excipient in clinically-approved injectable products (Feraheme®). Biodegradable. | ||
Amphiphilic block copolymers | poly(propylene oxide)–PPO poly(ethylene oxide)–PEO PEOn-PPOm-PEOn | PEOn-PPOm-PEOn triblock copolymers are usually used in pharmaceutical formulations as non-active pharmaceutical ingredients. Pluronic®-based PMs entrapping Doxorubicin, SP1049C, had entered clinical trials and have been granted orphan drug designation by the FDA. Commercially available as poloxamers (Pluronic®). Biocompatible. |
Nanosystem | Size | Advantage | Limitations | References |
---|---|---|---|---|
Solid lipid nanoparticles (SLN) | 50–1000 nm | Biocompatible; Biodegradable; High drug loading; Good stability; Enhanced bioavailability; Excellent nanocarriers for controlled release and for targeted drug delivery to the reticuloendothelial system. | Costly and complex methods of preparation; Expulsion of the drug from the SLNs over time; Only suitable for loading hydrophobic drugs. | [16,30,36,37,38] |
Liposomes | 25–2500 nm | Loading simultaneously with two drugs (hydrophobic and hydrophilic); Easy functionalization of the surface; Biocompatible; Low toxicity; Biodegradable. | Costly and complex methods of preparation. | |
Nanoemulsions | <100 nm | Loading simultaneously with two drugs (hydrophobic and hydrophilic); Facilitate the bioenhancement of hydrophobic drugs; | Not form spontaneously; Considerable energy is required to generate nanoemulsions; Limited stability; Lack of controlled release functions; Tendency to flocculate and coalescent. | |
Micelles | 5–100 nm | Easy loading of hydrophobic drug; Enhanced permeability; Low toxicity; Extended blood half-life | Low loading efficacy; Instability. | |
Polymeric nanoparticles | <1000 nm | High drug loading capacity; Drug release regulated by selecting; Appropriate preparation methods; High stability; High membrane permeability; Biodegradable; Easy functionalization of the surface. | Costly and complex methods of preparation; Prone to aggregation and opsonization in the bloodstream; Need of functionalization. | |
Polymeric micelles | 10–100 nm | Easy and high loading hydrophobic drug; Drug release regulated by polymers structure; Small size; Prevention of rapid clearance by reticuloendothelial system; Low CMC Easy and cheap preparation; Biocompatible; Extended circulation time; Lower toxicity of a drug; High stability in vitro and in vivo | Complex characterization; Lack of stability in blood; Limited number of polymers for use; Lack of suitable methods for scale-up; Dependency of critical micelle concentration. | |
Dendrimers | 1–10 nm | High drug loading capacity; Small size; Versatility of surface functionalization. | High cytotoxicity; Haemolytic properties; Non-biodegradable; Not a good candidate carrier for hydrophilic drugs; Elimination and metabolism depending on the generation and materials; High cost for their synthesis. | |
Inorganic Nanoparticle | 1–100 nm | Stimuli-responsive behavior; Good microbial resistance and good storage properties; Versatility of surface functionalization. | Poor data regarding long-term exposure; Toxicity and instability. | |
Nanocrystal | <500 nm | Well-understood and established manufacturing techniques; Excellent reproducibility; Applicable to drugs with different solubility profiles; Suitable for oral administration; | Requires high energy input that drives up costs; Needs further modification to ensure stability; Lack of controlled release functions. | [39] |
Active Compounds | Polymers Used in the Composition of Micellar Carrier | Conclusions | Ref. |
---|---|---|---|
Anti-Ageing | |||
Oleanolic Acid | Poloxamer 407 | Enhancement in the efficacy of wrinkle alleviation treatment | [141] |
Hyaluronan | Oleyl-hyaluronan Hexyl-hyaluronan | Drug reached deeper layers in porcine skin | [143] |
CoQ10 | Oleyl-hyaluronan | Enhancement in skin hydration | [143] |
Acne Vulgaris | |||
All-trans Retinoic Acid (Tretinoin) | Poly(ethylene glycol)-conjugated Phosphatidylethanolamine | Higher stability profile with slower drug oxidation | [144] |
All-trans Retinoic Acid (Tretinoin) | Diblock methoxy-poly(ethylene glycol)-poly(hexyl-substituted lactic acid) | Higher efficiency than marketed formulations | [144] |
Adapalene | D-α-tocopheryl polyethylene glycol 1000 succinate | Targeted drug delivery capacity Higher efficiency at lower dose than the marketed formulations | [145] |
Benzoyl Peroxide | Pluronic® F127 | Targeted drug delivery capacity | [146] |
Psoriasis | |||
Tacrolimus | Diblock Methoxy-poly(ethylene glycol)-poly(hexyl-substituted lactic acid) | Enhancement in skin drug deposition | [147] |
Resveratrol | Pluronic® P123 Pluronic® F127 | Decrease in the cytokine levels | [148] |
Silibinin | - | Reduction of psoriasis index area | [149] |
Fungal Infections | |||
Clotrimazole Econazole nitrate Fluconazole | Methoxy-poly(ethylene glycol)-poly(hexyl-substituted lactic acid) | Enhancement in skin drug deposition | [150] |
Terconazole | Pluronic® P123 Pluronic® F127 Cremophor EL | Higher permeation Higher skin deposition | [142] |
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] |
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Figueiras, A.; Domingues, C.; Jarak, I.; Santos, A.I.; Parra, A.; Pais, A.; Alvarez-Lorenzo, C.; Concheiro, A.; Kabanov, A.; Cabral, H.; et al. New Advances in Biomedical Application of Polymeric Micelles. Pharmaceutics 2022, 14, 1700. https://doi.org/10.3390/pharmaceutics14081700
Figueiras A, Domingues C, Jarak I, Santos AI, Parra A, Pais A, Alvarez-Lorenzo C, Concheiro A, Kabanov A, Cabral H, et al. New Advances in Biomedical Application of Polymeric Micelles. Pharmaceutics. 2022; 14(8):1700. https://doi.org/10.3390/pharmaceutics14081700
Chicago/Turabian StyleFigueiras, Ana, Cátia Domingues, Ivana Jarak, Ana Isabel Santos, Ana Parra, Alberto Pais, Carmen Alvarez-Lorenzo, Angel Concheiro, Alexander Kabanov, Horacio Cabral, and et al. 2022. "New Advances in Biomedical Application of Polymeric Micelles" Pharmaceutics 14, no. 8: 1700. https://doi.org/10.3390/pharmaceutics14081700
APA StyleFigueiras, A., Domingues, C., Jarak, I., Santos, A. I., Parra, A., Pais, A., Alvarez-Lorenzo, C., Concheiro, A., Kabanov, A., Cabral, H., & Veiga, F. (2022). New Advances in Biomedical Application of Polymeric Micelles. Pharmaceutics, 14(8), 1700. https://doi.org/10.3390/pharmaceutics14081700