Introduction: 1. Introduction
Micelles are colloidal aggregates formed by amphiphilic molecules, which contain both hydrophilic (water-absorbing) and hydrophobic (water-repelling) components. Usually, these molecules arrange themselves in a spherical shape in aqueous solutions, with the hydrophilic heads that face outward and the hydrophobic tails inward. This unique structure is critical for micelle formation, as it minimizes the energetic cost of exposing hydrophobic parts to water (1).
The critical moment in formation of micelles is when the concentration of amphiphilic molecules exceeds a certain limit, known as the critical micelle concentration (CMC). Below this concentration, the molecules exist as individual molecules, while above it, they self-assemble into micelles (2). This organization results in a hydrophilic outer layer, which mostly interacts with the aqueous environment, and a hydrophobic core that can encapsulate non-polar materials (3).
Micelles have some unique properties that make them valuable in many applications. Their ability to solubilize hydrophobic drugs in an aqueous environment enhances drug bioavailability and stability (4). This characteristic is relevant in fields such as gene therapy, where they can facilitate the delivery of nucleic acids, and in imaging techniques and enhance the contrast of diagnostic agents (5, 6) but most importantly in drug delivery systems, where micelles can deliver therapeutic agents directly to target regions, improving efficacy while minimizing side effects of the therapeutic method (7).
Methods: Micelles are very useful tools in medicine, but they pose many challenges and limitations that
reduce their widespread clinical application in nanomedicine. One of the prevalent challenges is
the scalability and reproducibility of micelle production. Changing methods from laboratory level
into industrial-scale manufacturing has considerable difficulties. Producing micelles with the same
size, composition, and drug-loading capacity is critical for making sure that therapeutic outcomes
are uniform. Variations during production can lead to unpredictable pharmacokinetics and
pharmacodynamics and underminethe reliability of micelle-based treatments. Plus, many
techniques that are effective at a small scale face some barriers when scaled up, which often results
in reduced stability and efficacy of the micelle in clinical settings , which makes the way for their
applications as standard tools in nanomedicine (108).
Another significant obstacle is expanding the regulatory perspective for micelle-based therapies.
Regulatory agencies require extensive data to approve such nanocarriers for clinical use, such as
comprehensive information on their safety, efficacy, and quality. The process is more complicated
by the lack of standardized evaluation criteria specific to nanomedicine. Unlike traditional smallmolecule drugs, micelle formulations must be done with precise characterization to address their
unique physicochemical and biological properties. The long-term safety of micelle-based systems
is still a concern, as there is limited data on their chronic effects in biological systems. Potential
issues include bioaccumulation, unforeseen toxicities, and interactions with complex biological
environments (109).
BBB
Figure 4. Nanocarries crossing BBB
The intrinsic properties of micelles also present several limitations that reduce their effectiveness.
The nanoscale size of micelles, while suitable for tumor penetration, can also lead to challenges
such as rapid renal clearance or unintended uptake by the reticuloendothelial system. These
phenomena can reduce the availability of therapeutic agents at the target site and so compromises
treatment efficacy. Premature drug release is another important issue because it can result in
subtherapeutic concentrations of the drug reaching the target that destroys the overall therapeutic
benefit (110).
Delivery efficiency is also a significant challenge for micelle-based systems. Making sure that
micelles will be stable during circulation and release their payload specifically at the target site is
still a difficulty. Micelles can prematurely disintegrate or lose their encapsulated drug due to
dilution in the bloodstream or interactions with serum proteins, which further reduces their
effectiveness. Identifying these challenges requires an inclusive approach that includes the
development of advanced materials for micelle construction, optimization of drug-loading
strategies, and integration of targeting mechanisms to improve site-specific delivery (111).
To overcome these barriers, interdisciplinary collaboration is essential. Advances in materials
science, engineering, and pharmacology are required to establish strong and scalable production
processes. At the same time, regulatory frameworks must evolve to provide clear guidelines for
the evaluation of nanomedicine-based therapeutics. Comprehensive studies to examine the
pharmacokinetics, biodistribution, and long-term safety of micelle-based treatments are crucial to
reduce concerns about their chronic use. By addressing these challenges systematically, the full
potential of micelles in clinical settings can be realized, paving the way for their adoption as
standard tools in nanomedicine.
Results: Difficulties of Crossing the BBB and Micelles’ Potential
Brain tumors include a wide range of neoplasms with different pathological and clinical
characteristics. Their classification is based on the cell of origin and molecular profiles, which
influence tumor behavior and treatment response (1). Gliomas, the most common primary brain
tumors in adults, include subtypes like glioblastoma (GBM), noted for its aggressive nature, rapid
growth, and poor prognosis due to intra-tumoral heterogeneity (87). Meningiomas, arising from
the meninges, are the second most common brain tumors, with most being benign (WHO grade I),
but some can be atypical (grade II) or malignant (grade III), leading to higher recurrence rates (88).
Other types include primitive neuroectodermal tumors (PNETs), such as medulloblastoma, and
brain metastases from other cancers (89). Treatment strategies are tailored to the tumor's type, size,
location, and the patient's health. Surgical resection is the primary approach, often complemented
by radiotherapy and chemotherapy, particularly for high-grade tumors (90). Temozolomide, in
combination with radiotherapy, has improved survival rates in GBM patients (91). However,
challenges remain, notably the blood-brain barrier (BBB) and tumor heterogeneity, which
complicate effective treatment and contribute to recurrence.
The blood-brain barrier (BBB) is a highly selective barrier that protects the brain from harmful
substances while allowing essential nutrients to pass through. This barrier poses a significant
challenge for drug delivery, especially for treating neurological disorders and brain cancers. The
BBB's tight junctions and specific transport mechanisms restrict the entry of most drugs, making
it difficult to achieve therapeutic concentrations in the brain (92, 93).
The emergence of nanotechnology in the treatment of brain tumors signifies a crucial change in
overcoming the significant challenges presented by the brain's protective barriers and the intricate
tumor microenvironment (94).
The design of nanoparticles (NPs) is crucial for enhancing their ability to penetrate the blood-brain
barrier (BBB) and improve therapeutic effectiveness. Key factors influencing this design include
size, charge, and surface modifications. Size is a critical parameter, with NPs in the range of 20–
100 nm being optimal for BBB penetration. Research shows that this size range benefits from the
enhanced permeability and retention (EPR) effect, allowing for accumulation in tumor tissues
characterized by leaky blood vessels. NPs smaller than 20 nm are rapidly cleared from circulation,
while those larger than 100 nm face challenges in crossing the BBB. Therefore, targeting NPs
within this size range is essential for effective delivery to brain tumors (95). The surface charge of
NPs also plays a significant role in their interactions with the BBB. Neutral or slightly negative
charges are preferred because they reduce non-specific interactions with the endothelial cells of
the BBB. This minimizes opsonization and immune clearance, thereby enhancing NP penetration
through the barrier by decreasing electrostatic repulsion, -specific interactions with the endothelial cells of
the BBB. This minimizes opsonization and immune clearance, thereby enhancing NP penetration
through the barrier by decreasing electrostatic repulsion with cell membranes (96). Moreover, the
functionalization of NPs with specific ligands that target receptors on the BBB or tumor cells can
greatly improve their capacity to cross the BBB and reach tumor sites. Ligands such as transferrin
or specific peptides can facilitate receptor-mediated transcytosis. Additionally, PEGylation, which
involves adding polyethylene glycol chains to the NP surface, extends circulation time and reduces
recognition by the immune system. This modification enhances the specificity and efficacy of NPbased therapies, making it a vital aspect of NP design for brain tumor treatment (97, 98).
Micelles, which are nanoscale carriers formed by the self-assembly of amphiphilic molecules,
offer a promising solution to this challenge. Their small size and ability to encapsulate hydrophobic
drugs make them suitable for crossing the BBB. Micelles can be engineered to exploit various
transport mechanisms, such as receptor-mediated transcytosis, to enhance drug delivery to the
brain (92, 93).
Table 1. A brief review of case studies in the usage of nanomicelles for crossing blood-brain barrier .
barrier Disease/Condition Description Key Findings
Alzheimer’s Disease
(AD)
Development of lactoferrincoated multifunctional
copolymer micelles for drug
delivery across the BBB.
High stability, biocompatibility, and
effective BBB penetration in mice,
indicating potential for CNS disorder
treatment (99).
Brain Cancer Star-polymer unimolecular
micelle nanoparticles
designed to deliver
doxorubicin across the
BBB.
Prolonged circulation, efficient BBB
penetration, and reduced cardiotoxicity
in mice, highlighting potential for
brain-specific cancer therapy (100).
Gene Therapy Polymeric micelles are used
for delivering nucleic acids
in neurological disorders.
Protect nucleic acids from degradation
and enhance cellular uptake, showing
promise in preclinical models for
various brain diseases (101).
Glioma (Micelle-Based) Micelle-based nanocarrier
designed to cross the BBB
for glioma treatment,
loaded with doxorubicin
(DOX).
Effective BBB penetration,
accumulation in the brain, and
significant anti-tumor effects in animal
models (102).
Glioma (ApoE-Coated) Novel brain-targeted
nanomicelles coated with
ApoE for glioma treatment,
loaded with paclitaxel
(PTX) and decorated with
Aβ-CN peptide.
Improved cellular uptake, better
inhibition of glioma cell proliferation,
increased apoptosis, and prolonged
survival of glioma-bearing mice in
animal models (103).
Glioma (TransferrinModified)
Hybrid micelle system
modified with transferrin
for delivering paclitaxel
(PTX) to glioma.
Enhanced targeting capabilities,
improved delivery to glioma cells,
better anti-tumor efficacy, and reduced
systemic toxicity in both in vitro and
in vivo studies (104).
6.2. Future Prospects
The future of micelle-based drug delivery systems in treating brain-related diseases is highly
promising. Advances in nanotechnology and a deeper understanding of blood-brain barrier (BBB)
transport mechanisms are expected to significantly enhance the design and efficacy of micelles for
brain-targeted therapies (105, 106). Researchers are developing stimuli-responsive micelles that
release their therapeutic payloads in response to specific triggers within the brain environment,
such as pH changes or enzymatic activity. Additionally, combining micelles with other delivery
methods, like transnasal pathways, could further improve drug delivery to the brain by bypassing
the BBB (105).
Emerging strategies also include the use of micelles for delivering a combination of drugs and
genetic material, which could provide more comprehensive treatment options for complex
neurological disorders. For example, micelles loaded with both chemotherapy drugs and gene
therapy agents are being explored for their potential to treat brain tumors more effectively (107).
Overall, micelles hold significant potential for revolutionizing the treatment of brain-related
diseases, offering hope for more effective therapies for conditions like Alzheimer's disease, brain
cancer, and other neurological disorder
Conclusion: 8. Future Directions and Conclusion
Micelles are poised to revolutionize nanomedicine through enhanced drug delivery and imaging applications (112, 113). Future research will likely focus on improving targeting capabilities by incorporating specific ligands that bind to cancer cell receptors, thereby minimizing off-target effects (111, 114). Additionally, the integration of micelles with other treatment modalities, such as radiotherapy and immunotherapy, could provide synergistic effects (115, 116). Advances in the design of nanoparticles, particularly regarding size and surface modifications, will enhance their ability to cross biological barriers like the blood-brain barrier, which is crucial for effective brain tumor treatment (117, 118).
In conclusion, micelles offer a versatile platform for advancing cancer therapies and diagnostics. Their ability to encapsulate hydrophobic drugs and improve bioavailability makes them invaluable in modern medicine (72, 119). As research continues to address challenges related to stability, biocompatibility, and targeted delivery, micelles are expected to play an increasingly significant role in the diagnosis and treatment of various diseases, ultimately leading to improved patient outcomes.
Keywords: Nanomicelles, Non-ionizing radiation, Cancer treatment, medical imaging