Innovative Drug Delivery with TiO₂ Nanotubes:

Targeted Approaches and Applications

 

S. A. Bhagat¹*, S. L. Patwekar², M. S. Gajale³, R. B. Rajmane⁴

¹Research Scholar, Department of Pharmaceutics, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra Pin: 431606.

²Associate  Professor, Department of Pharmaceutics, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra Pin:431606.

³Research Scholar, Vidyabharti College of Pharmacy, SGBAU, Amravati Maharashtra Pin: 444602.

⁴Assistant Professor, Department of Pharmaceutics,

ASPM’s K. T. Patil College of Pharmacy, Dharashiv, Maharashtra Pin: 431501.

 

ABSTRACT:

Nanotechnology is pivotal in developing diverse nanomaterials with applications across various fields, including medicine, electronics, and environmental science. After the carbon nanotubes (CNTs) discovery bythe scientist“Iijima” in 1991, there has been a surge of interest in low-dimensional nanomaterials, particularly metal oxide nanotubes (MO-NT), owing to their unique propertiesand diverse applications. Among all, titanium dioxide (TiO2) nanotubes (TNT) have garnered noteworthyconsideration in recent years due to their remarkable features,including nanosized, large porosity and surface area (SA), crystalline structure, and high stability. It has versatile utility in the electrochemical, environmental, and biomedical fields. Thus, this article briefly deliberateson the progress of nanotube research following the discovery of TNTs, highlighting the growing importance of MO-NTs. The review also explores synthesis methods, including template-assisted, sol-gel, hydrothermal, and electrochemical anodization (EAD), elucidating their benefits and applications. Furthermore, the present work delves into the mechanisms for targeted therapeutic action either by surface functionalization using specific ligands or by external triggers using pH, light, magnetic field, temperature, etc. These biomedical applications are supported by evidence from cell line studies and animal models. Finally, the article addresses existing challenges and regulatory considerations and offers insights into future perspectives for the continued advancement and application of TNT in targeted drug delivery (TDD) and beyond.

 

 

 

1. INTRODUCTION: 

Nanotechnology has created new possibilities for designing and developing nanomaterials with unique properties and specific functions. Transition metal oxide nanomaterials such as TiO₂¹, tungsten trioxide (WO₃)², zinc oxide (ZnO)³, ferric oxide (Fe₂O₃)⁴, and copper/cuprous oxides (CuO/Cu₂O)⁵ have been thoroughly examined. Amongst all transition MO, TiO₂ is extensively researched due to its diverse functional properties, including its synthesis in the form of nanowires, nanoparticles (NPs), nanosheets, nanorods,nanotubes, and microspheres⁶ (Fig. 1). Recent studies indicated that MO-NTs surpass other forms of nanomaterials, including CNT⁷.

 

Figure 1: Different types of TiO₂nanomaterials⁶.

 

Titania nanotubes possess a high surface area, stability, improved electron transfer, and exceptional photo- and electro-catalytic properties, which set them apart. These unique features position them as promising candidates for extensive applications, including photo-catalytic, photo-electrochemical, water splitting, solar cells, and biomedicine^8–11. In 1999, the 1^streportdemonstrated the viability of generating highly ordered arrays of TNTs, and then the field expanded quickly. Researchers focus on enhancing synthesis methods for greater efficiency, uncovering novel uses, and integrating TNTs with other nanomaterials. The potential of TNTs for TDD adds aninnovative dimension to the field⁶. The process of drug delivery using TNT typically involves loading the desired drug molecules onto the surface or within the tubes of the nanomaterial. The release of drugsmight be triggered by various stimuli, likewise changes in pH, temperature (temp.), or exposure to light^12,13. Their customizable nature, as well as their ability to deliver therapeutics with precision, hold great potential for advancing therapeutic strategies and improving patient outcomes in various medical conditions, including bone disorders¹⁴, dental, cancer¹⁵, infectious and inflammatory conditions^16,17.

 

Thus, this review primarily focuses on the significant advantages of TNT in biomedical applications. It also explores the drug release mechanisms to attain targeted therapeutic action using cell lines and animal models. The paper begins by tracing the historical development of TNT and exploring its unique characteristics andsignificant benefits. Finally, the review addresses existing challenges and regulatory concernswhile offering insights into future research directions and possible applications in TDD.

 

MATERIAL AND METHODS:

Related information was searched from Google Scholar, Medline, Cochrane Library, Web of Science, PubMed, and other official portals using the combination of the following keywords: “TiO₂,” “Titania nanotubes,” “Targeted drug delivery,” “Surface functionalization,” “Stimuli-responsive,” “In-vitro analysis,” “Animal model,” and “Biomedical applications.”

·       The inclusion criteria for review were: a)Articles related to history, properties, and synthesis of TNT. b)Mechanisms of TNT, cell line and animal studies, challenges, and regulatory considerations.

·       The exclusion criteria were: Details on carbon nanotubes or other metal oxide nanotubes.

 

1.1 Metal oxide nanotubes and its types:

Metal oxide nanotubes are a type of nanomaterial characterized by their tubular, hollow structure and composed of metal oxides. The term "nanotubes" (NTs) refers to their distinctive shape, whose length is significantly greater than the diameter, creating a cylindrical or tubular form. These NTs are typically measured in nanometers (nm) to a few microns in length, with diameters few to tens of nanometers. They come under the class one-dimensional (1D) nanomaterials, and the nanotubes array comes under 3D nanomaterials if classified dimensionally¹⁸.The MO-NTscan be used as sensors, photo-catalysts⁷, dye-sensitized solar cells (DSSC).They stand out as a distinct option from CNTs in the biomedical field. Various types of MO-NTs, such as ZnO-NT, TiO₂–NT, MgO-NT, Fe₂O₃-NT, etc., are available as promising candidates for biomedicine and other applications¹⁹. The unique features and purposes of MO-NTs are mentioned in detail in Table 1.

 

Table 1: Types of MO-NTs along with unique features.

Type	Properties	Synthesis method	Applications
ZnO-NT	Biocompatible, fast electron-transfer rate,nontoxic, and ease of application.	Electrodeposition20, hydrothermal, atomic layer deposition processes and electrospinning in mixed approach21, sol-gel method.	Electrochemical biosensors22, antibacterial23,antimicrobial21, gas sensor, semiconductor.
Fe2O3-NT	Higher coercivity24,generates heat under magnetic field, increase tensile strength.	Selective chemical etching and Kirkendall process, one-pot double galvanic approach25, electrochemical anodization, hydrothermal, template-directed growth method.	Photocatalysis, bio-magnetic sensors, drug delivery26,antimicrobial, increase drug loading and release capabilities27.
TNT	Crystal structure, self-organization, low dimensional, easy surface modification28.	Anodization, hydrothermal, replica, template method.	Photocatalyst, dye-sensitized solar cells, and biomedical devices29, bone implants, dental implants, cancer therapy, antibacterial, anti-inflammatory.
Al2O3-NT	Highly crystalline structure.	Laser ablation process30,atomic layer deposition, nanoimprint-guided anodization.	Superhydrophobic surface, catalysis, energy storage, etc.
CuO-NT	Narrow bandgap, stable, visible light absorption.	Direct current electrodeposition, surfactant-assisted soft template approach, nano-scratch technique.	Semiconductor, electronic, optical and energy conversion devices, catalyst31,drug delivery, antimicrobial coatings, and other biomedical applications.
MgO-NT	Resistance to corrosion, mechanical strength, and durability.	Thermal evaporation.	Enhance anticancer activity of drugs, electronic sensors32,  environmental applications, photocatalyst.

 

Apart from that, Ogihara et al. producedseveralMO-NTs,including ZrO₂, Al₂O₃, and SiO_2, with an effective shape-controllable technique with the help of carbon nanofibers as templates. Afterwards, he used the same method to produce mixed MO-NTs of SiO₂-Al2O₃ and SiO₂-TiO₂ nanotubes. The V₂O₅-NTs were created utilizing an iced lipid NT as a template using the sol-gel transcription technique³³. Tangand co-workers reported a one-pot method for SiO₂- NT synthesis³⁴.

 

1.2 Titania nanotubes:

Titanium dioxide (Fig. 2), also referredto as titania, is a metal oxide that naturally occurs in various crystalline forms, including anatase, rutile, and brookite³⁵. Optically, it boasts high opacity, an exceptionally high refractive index (RI: >2.4), and strong UV absorbance. Due to its potent oxidative potential, it serves as an excellent catalyst as an inorganic material. Additionally, it is non-toxic, chemically stable, and cost-effective³⁶. These minerals serve as precursors for synthesizing nanoscale TiO₂, producing spherical particles (ranging from 100-200 nm) and elongated materials. The elongated materials, such as NTs (Fig. 2) or nanowires (NWs), possess high SA, and the increase in possible reactive sites due to their tubular structure³⁷. Regarding this, TNTs have noteworthy qualities that have been thoroughly studied, including inertness, a high RI, chemical and thermal stability, non-toxicity, durability, affordability, and corrosion resistance³⁸.As previously mentioned, their potential has drawn considerable attention in an array of applications, including gas sensing, photocatalysts, energy storage, environmental uses, DSSC, and biomedical applications like anticancer, antimicrobial, and joint regulations³⁹.

 

 

 

Figure 2: Structure of TiO₂and TNT⁴⁰ (Own creation).

1.2.1 Journey of TNT:

The TiO₂has numerous polymorphs. The three naturally occurring, well-known phases of titania are anatase (discovered in 1801), rutile (1803), and brookite (1825)⁴¹.Akira Fujishima discovered the photocatalytic characteristics of nanosized TiO₂ in 1967 and published his findings in 1972. This process was known as the “Honda-Fujishima effect”^42,43.Titania exhibits strong stability and biocompatibility. There has been a lot of interest during the last 20 years, in this class of nanotubular materials. The first report, published in 1999, demonstrated that creating highly organized arrays of TNTs was possible using a simple yet effective EAD of titanium (Ti) metal sheet. The finding sparked a flurry of research on the development, alteration, features, and uses of these 1D nanostructures⁴⁴.In the same year,Zwilling et al. were pioneers in creatingthe 1^stself-organized TNT by EAD in chromic acid electrolytes containing fluorine ions; afterwards, the field sparked quickly⁴⁵.

·       In 2001, Gong and coworkers revealed the formation of TiO₂ nanotubular layers in aqueous hydrofluoric acid (HF) electrolytes with the tube size dependent on the applied anodization voltage^9,46.

·       2002-2005: Researchers explored various anodization factors such as electrolyte voltage, composition, and duration to refine the procedure of creating TNT. These refinements allowed for better control over the structure, length, and diameter of the NTs.

·       2005-2010: Following the development of reliable synthesis methods, researchers began investigating various applications for TNT, including solar cells, photocatalysis, water purification, and drug delivery.

·       2010-2015: Research into functionalization and hybrid structures gained momentum. Scientists developed methods to modify TNT surfaces with organic and inorganic compounds, allowing for applications in targeted drug delivery.

·       2015 to present: Research on TNT continues to grow, with an emphasis on improving synthesis efficiency, exploring new applications, and integrating nanotubes with other nanomaterials. Since last 10 years, more than 33,800 articles from 2002-2017 featuring the keyword “titania nanotubes” have been published, and research is continuing⁴⁵(Fig.3).

Figure 3: Origin and journey of TNTs (Own creation).

 

Table 2: Unique features of TNT.

Features of TNT
Structural	Elemental	Optical	Electrical	Mechanical
·    Organized structure, tiny geometrical size, large surface-to-volume ratio. ·    10-500nm of tube diameters. ·    Layer thicknesses between a few 100nm to 1000μm. ·    Well-defined internal and external surfaces, robustness, uniform inner diameters, and non-porous smooth surfaces47. ·    Hydrophobic surface. ·    Different crystalline phases: Anatase, rutile, or a combination of both, depending on synthesis conditions.	·    High chemical stability ·    High durability. ·    Consists of titanium and oxygen, with the Ti:O ratio 1:2. ·    Resistance to corrosion38.	·    High RI. ·    The optical band gap (3.0 to 3.2 eV)allows to absorb UV light48. ·    High photocatalytic activity. ·    Influence light scattering and transmission. ·    The ability of light and electrolyte species to penetrate the TNT deeper layers.	·   Photoconductivity. ·   Photovoltaic- electron transport properties. ·   Semiconducting properties. ·   High dielectric constant.	·   High tensile strength. ·   Hardness. ·   Good mechanical stability. ·   Lower elastic modulus49.

 

1.2.2 Structural, elemental, optical, and other characteristics of TNT:

Some unique features of TNT, including structural, elemental, optical and others, are depicted in Table 2.

 

1.2.3 Key benefits of TiO₂ nanotubes:

·       Affordable.

·       Protective against corrosion.

·       Low toxicity.

·       Good biocompatibility³⁴.

·       Ease of preparation.

·       Highly stable.

·       Excellent drug delivery properties¹².

·       Available in different forms, based on application.

·       Sites are easily modified and are valuable for detecting, capturing, and altering ions and molecules.

·       Improve the photocatalytic and photoelectricity conversion effects due to several potential reactive points.

·       Beneficial in biochemical sensing, optoelectronics, nanoelectronics, and biomedical domains⁵⁰.

 

1.2.4 Synthesis strategies of TNT:

Much research has been done on the synthesis of TNT since few years. These nanotubes can be produced using various techniques. Template-assisted was the first method and developed in 1996, then sol-gel (1998), the hydrothermal (1999), and currently EAD performed in 2001^6,51,52.

 

i. Template-assisted method (TAM):

This stands out as an accessible and affordable method for creating TNT. This approach allows for a wide dimension range and ensures great uniformity through easy adjustments to the size and framework of the templates. Moreover, it offers compatibility with a diverse array of substrates, such as glass and silicon⁵³. Porous materials, typically anodic Al₂O₃, served as the template, with TiO₂ layers deposited at the bottom. Hoyer et al. pioneered TNT using TAM by employing an Al₂O₃ template alongside a positive polymer mold, which could be dissolved using acetone⁵³. Li and colleagues utilized a porous CNT sponge as a template to create the linked TNT as a macroscopic bulk product. This macrostructure is a potential solution for wastewater treatment as it can easily separate and recycle the catalysts⁵⁴. Michailowskiet al. used anodic Al₂O₃ as a template to synthesize a TNT by impregnation-decomposition of titanium (IV) isopropoxide to TiO₂ at 500°C⁵⁵. Furthermore, Yuan et al.exploredthe preparation of TNT by Ti(OC₄H₉)₄ hydrolysis using thesame template between H₂O and the Ti(OC₄H₉)₄ solution⁵⁶. Paralleloutcomes are reported by authors using immerging anodic Al₂O₃ in an aqueous (NH₄)₂TiF₆ solution⁵⁷. Liang et al.displayedthat TNT was synthesized by deposing the TiCl₄ on anodic Al₂O₃ by means of atomic layer deposition⁵⁸. Liu et al. have formed broadband-distributed Bragg reflectors for visible-light-driven photocatalysis using functionalized nanoporous anodic alumina TiO₂photonic crystals^59,60.

 

ii. Sol-gel process:

This process has produced high homogeneous and pure TiO2 materials in large quantities. A titanium is hydrolyzed and condensed to create a sol that becomes a gel. After that, the solvent evaporates, yielding a xerogel. The high degree of crystalline structure is obtained by further processing the xerogel using heat treatment and milling. Tsvetkovet al. generated pristine and (Niobium) Nb-doped TiO₂ NPs and NTs. An Nb-doped TNT network is a possible substitute for indoor photovoltaic applications and has significant possibilities for use as photoelectrode in high-performance DSC⁶¹. Pang et al. attained successful synthesis of TNT through a mixture of the sol-gel and the hydrothermal method. They utilized this method to degrade Rhodamine B in an aqueous solution effectively⁶². Kovalenko, D.L. et al. used the same combination of methodsfor the synthesis of ZnO nanorods to use in solar energy⁶³. Similarly, Liu et al. elaborated TNT arrays using the sol-gel method, utilizing the nanorods of ZnO as a template. Combining the sol-gel process with additional methods has made it possible to produce highly organized and functioning TNT in an efficient manner⁶⁴.

 

iii. Hydrothermal method:

This method gives pure TNT with a great crystallinity. It is cost-effective, gives high yield, and is applicable on a large scale.It involved utilizing a Teflon-sealed autoclave to combine TiO₂ powder with a highly concentrated NaOH solution at less than 150°C and under high-pressure⁵⁰. The synthesized TNT depend upon many attributes, such as precursor, hydrothermal temperature⁶⁵, and post-treatment. The hydrothermal dissolution-recrystallization process is used to produceAnatase-TNTs without calcination and shows excellent photocatalytic CO₂ reduction compared to titanate nanotubes⁶⁵. Zavala MÁet al. Synthesized stable TNT by this method, then the hydrothermal treatmenteffect, annealing temp.,acid washing, and morphology of TNT were assessed⁶⁶.

 

iv. Electrochemical anodization:

Currently, an EAD has become a popular approach for developing TNT layers. Because the layer forms directly on the Ti metal, this method offers many advantages, such as high mechanical adhesion and excellent electrical conductivity⁶⁷. It produces highly ordered nanoporous TiO₂ films most effectively. Although several factors affect EAD, for example, applied potential⁶⁸, anodization bath temperature⁶⁹,electrolyte composition⁷⁰, anodizing time⁷¹, water content in the electrolyte⁷²,as well as fluoride ion concentration.Kulkarni and colleaguesrevealed the consequence of EAD parameters on the structure and the mechanism of converting formed nanopores to nanotubes⁴⁹.Isik et al. synthesized TNT by EAD using a neutral 0.5% and 1% (wt) NH₄F in glycerol solution dependent on anodization time and voltage at 20°C⁷³.Sivaprakash et al. synthesized TNT using the same method and analyzed the influence of different electrolytes⁷⁴.

 

1.2.5           Mechanisms of TNT for achieving targeted drug delivery:

a.     Surface functionalization:

Titania nanotubes can be functionalized with specific ligands, such as antibodies, peptides, aptamers, or chemical groups, to target specific cells, cellular components, or receptors, allowing for precise drug delivery (Fig. 4). Themagnitudes and surface modification plays a significant role in monitoring drug release from TNT⁷⁵. Some examples are quoted in Table 3, elaboratingon targeted applications using surface modifications.

 

Figure 4: Surface functionalization using specific ligands (Own creation).

 

Table 3: Targeted applications of TNT using surface modification.

S. No.	Ligand	Applications
1.	Bone morphogenetic protein- 2 (BMP2)	Cell proliferation and differentiation76.
2.	PAMAM-TNT with curcumin, methotrexate, and silibinin	Showed a notable enhancement in drug loading and release characteristics along with cytotoxicity77.
3.	Dopamine polymer coating	EndorsingIbuprofen (IBU) loading and sustainable DR,which is crucial for bone implant therapies78.
4.	Bioinspired polydopamine	Excellent candidates as specific drug delivery systems79.
5.	Gly-Arg-Gly-Asp-Ser conjugates	Encourage the cell growth and expansionof the osteoblast-like cell80.
6.	Quercetin	Alternative for treating post-operative infection, anti-inflammatory, and fast healing with well osseointegration81.

 

Table 4: Stimuli-responsive drug release systems.

Mechanism	Proven study results
pH-responsive drug release This mechanism enables drug release only in specific pH ranges, reducing off-target effects and improving therapeutic efficacy.	·       Liu et al. showed that the Fe-TNT coordination system may be used as a carrier to extend the alendronate drug release time to over 15 days in a pH-responsive manner82. ·       Lee et al. developed a pH-responsive cinnamaldehyde (CIN)-TNT coating. They successfully attached CIN to the TNT surface, which exhibited improved release characteristics in low-pH environments83. ·       In anotherwork,a simple drip coating technique was employed to create TNT arrays/mesoporous silica complexcoated with tannic acid (TA)-Fe (III) conjugate. The stability of the coating varied based on the coordination conditions of the TA-Fe(III) complex under diverse pH levels, allowing for intelligent modulation of drug release84.
Light-activated release triggered by UV or visible light allows controlled drug release upon light activation.	·       Moon etal.performed research by immobilizing gold nanorods (GNRs) on TNT surfaces through a grafting method and examined the DR triggered by near-IR laser irradiation. The outcomesshowed that IR laser irradiation controls the photothermal activity of GNR85. ·       Moon et al. in 2018 prepared gold nanorod–sputtered TNT; the results indicated that the photocatalytic effect was only within the UV-to-near-IR region86. ·       In another investigation, the three bacteria' planktonic cell counts and biofilm development were estimated to assess the antimicrobial qualities of modified and unmodified acrylic resins exposed to ultraviolet (UV) and non-UV radiation. The study's findings showed that, compared to the control group, the modified UV-activated acrylic specimens had much fewer planktonic cells and fewer biofilms(p = 0.00)52.
Magnetic targeting Combining TNT with magnetic nanoparticles(MNP) enables external magnetic field-based targeting, directing the nanotubes to specific body regions.	·       Authors demonstrated that magnetic TNTs do not harm HeLa cells at ≤200 µg/mL. Adherence and endocytosis of MNP were improved in the occurrence of a magnetic gradient field87. ·       The author developed drug-releasing implants with loaded TNTs. Regarding the DR, it has been verified that the cumulative release of the 3-drug carriers reaches approximately 100% within 1–1.5 hours when subjected to magnetic field88.
Thermal-responsive drug release Release drugs in response to specific temperature changes.	·       Cai et al.prepared a thermal-responsive DDS of TNTs using vitamin B2 and explored the controlled DR kinetics under the influence of temperature89. ·       In another work, TNT was used to load Simvastatin and then covered with a Glycerine (Gly)--containing thermosensitive hydrogel. This hydrogel exhibited immunoregulation and in vivo antibacterial activity90.

 

b.    External stimuli-responsive drug release from TNTs:

This mechanism refers to a controlled drug delivery system in which the release of the drug encapsulated within or on the surface of TNTs is triggered by specific external stimuli. These stimuli can include light, pH changes, temperature variations, magnetic fields, or other environmental factors (Table 4, Fig. 5). The keyaim of such a system is to attain precise control over the timing and location of drug release, thereby improving therapeutic efficacy while reducing potential adverse effects.

 

 

Figure 5: Stimuli-responsive drug release (Own creation).

 

Table 5: Role of TNT in TDD.

Cell/ model	Drug candidate/ molecule	Applications	Findings
In vitro studies
Schwann cells-RSC96	Minocycline	Osseo-perception of implant denture	Proliferation and associated gene/protein expression of Schwann cells91.
SKOV-3 cells	Doxorubicin	Anti-tumor	Results demonstrated efficient drug carriers for drug-loading in tumour therapy92.
MC3T3-E1 cells	GL13K peptide	Anti-bacterial	GL13K-TNTs' antibacterial capabilities and biocompatibility suggest that they are a good choice for infection prevention at implant sites93.
Sycamore plant cell, CHO K1	5-fluorouracil	Anti-cancer	Good bio-imaging ability, biocompatibility, a promising candidate for anticancer DDS94.
CAL-27 cells	Honokiol (HNK)	Tongue cancer	Greater anti-proliferative, apoptosis-enhancing, and migration-inhibiting effects95.
RAW 264.7 cells	ZnO-NPs	Antibacterial, inflammation inhibition	Decreased the inflammatory response and increased the antibacterial efficacy of Ti-based implants, which is a possible method to improve their bioactivity96.
In vivo studies
Wistar rats (4-month-old male)	Icariin and polydopamine	Bone healing	Improved osseointegration process as showing better efficiency in inducing new bone formation97.
Distal femur condyles of rats	-	Osteogenesis	Verified the critical part of Yap in nano topography-stimulating osteogenesis and proved its downstream effector molecule, Piezo1, a mechanosensitive cation channel98.
A total of 24 rabbits (2.5-3.0 kg)	Poly- hexamethylene guanidine (PHMG)	Antibacterial	In a co-culture of S. aureus and infected rabbit model, the PHMG-TNT group demonstrated superior efficacy in preventing bacterial infections compared to cp-Ti and TNT group99.
B16F10 murine melanoma &2-stage chemical carcinogenesis model	Quercetin	Skin cancer	Reduced tumour growth, had negligible results on skin colour,prolonged the death rate in tumour-bearing mice, very low epidermal hyperplasia, converted γδ T cells to normal skin level100.
Sprague−Dawley rats	B-TNT/PDA/IL-4	Modify implant surfaces	Lessen the inflammatory response, hinder osteoclast differentiation, and finally endorse osseointegration of implants101.

Where, B-TNT: black TiO₂ nanotube, IL-4: interleukin-4, PDA:polydopamine.

 

Other mechanisms to achieve TDD are encapsulation, leverage of the enhanced permeability and retention (EPR), and conjugation with biomolecules.

 

1.2.6           Exploring the role of TNT in TDD: Insights in cell lines and animal studies

Cell line and animalstudies provide the latent of TNT in biomedical applications, highlighting its versatility, effectiveness, and safety in laboratory and real-world settings (Table 5).

 

1.     Challenges and prospects of TNTs:

While TNTs hold promise in various applications, they still possess toxicity and adverse impact.Nanosizedand greater SA TNT raise concerns about their potential toxicity to living organisms. Studies have shown that nanomaterials can penetrate biological barriers and interact with cells, potentially leading to negative effects such as inflammation, oxidative stress, and genotoxicity^102,103. The biological behaviours of the examined cells are regulated by the critical threshold NT diameter of 20 nm. However, it may also be inextricably impacted by specific surface properties. Likewise, length, surface energy, roughness, and wettability of NT.Further research is required in these areas. Furthermore, it would be helpful to contrast TNT's effects on other cell lines¹⁰⁴.Inadequate affinity, wide band gap energy, recovery difficulties, and facile recombination are some of the obstacles facing TNT's uses for dye degradation, which would reduce the efficiency of the photocatalysis¹⁰⁵. The mechanism of TNT creation is known, but since it directly influences the morphology, dimensions, and subsequent properties, a thorough understanding of the electrolyte species and their kinetics of interaction with the titanium surface is crucial¹⁰⁶.Pulmonary inquiries experience the carcinogenicity consequences of TiO2 particles through inhalation and intratracheal tests. As long as dermal exposure discoveredcontradictoryconsequences to pulmonary studies, TiO₂-NPs are non-carcinogenetic¹⁰⁷. The long-term health effects of exposure to TNT are still not fully understood. Studies on chronic exposure and potential carcinogenicity are necessary to comprehensively assess their safety for human health.

 

2.     Regulatory considerations for titania nanotubes:

Due to remarkable features and uses,TNTs are being increasingly explored. However, their regulatory status is still evolving, particularly regarding potential risks associated with their nanostructure.Depending on the intended application and potential exposure routes (inhalation, ingestion, etc.), TNT may undergo risk assessments to evaluate potential hazards.Regulatory agencies, such as the United States Environmental Protection Agency (EPA) and the European Chemicals Agency (ECHA), may classify them based on their physical and chemical properties, toxicity, and potential environmental impact. Proper classification helps to determine appropriate labelling requirements to communicate hazards associated with the nanotubes¹⁰⁸.Occupational health and safety regulations, such as those enforced by the Occupational Safety and Health Administration (OSHA) in the United States and similar agencies worldwide, apply to workplaces where TNT are manufactured, handled, or used. These regulations set exposure limits, require the use of personal protective equipment, and mandate employee training to minimize occupational hazards¹⁰⁹.Regulatory agencies may also establish limits on the discharge of nanomaterials into air, water, and soil, as well as environmental monitoring and reporting requirements.Also, product safety regulations are enforced by government agencies¹¹⁰.

 

3.    CONCLUSION:

In conclusion, the review mainly highlights the unique properties of TNT, making them well-suited for encapsulating and delivering therapeutic agents to specific target sites within the body. Through surface modifications and functionalization, they can be tailored to achieve controlled drug release profiles, enhanced targeting capabilities, and reduced systemic toxicity. Moreover, TNT can also be harnessed for triggered drug release upon exposure to external stimuli, such as light, pH, magnetic field, and thermal response. These applications are explained by using cell line studies or animal models. Despite the considerable progress in this field, challenges remain, including the need to evaluate the long-term toxicity, more focus on clinical studies, and the need to explore other applications besides cancer and bone regulation. Overall, the continued research and development of TNT-based DDS hold great potential for advancing personalized medicine, improving therapeutic efficacy, and minimizing adverse effects of various diseases and medical conditions.

 

4. ACKNOWLEDGEMENTS:

The authors are thankful to School of Pharmacy,Swami Ramanand Teerth Marathwada University, Nanded for providing the necessary facilities for review work.

 

5. CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

6. LIST OF ABBREVIATIONS:

Al₂O₃      Aluminium trioxide

BMP2    Bone morphogenetic protein- 2

CIN        Cinnamaldehyde

CNTs      Carbon nanotubes

CuO/Cu₂O Copper/cuprous oxides

DR          Drug release

DSC        Differential scanning calorimetry

EAD       Electrochemical anodization

ECA       European Chemicals Agency

EPA        Environmental Protection Agency

EPR        Enhanced permeability and retention

Fe₂O₃     Ferric oxide

HF          Hydrofluoric acid

IBU        Ibuprofen

MgO       Magnesium oxide

MNP       Magnetic nanoparticles

MO-NTsMetal oxide nanotubes

NaOH    Sodium hydroxide

NM         Nanometers

NT          Nanotubes

NW         Nanowires

OSHA    Occupational Safety and Health Administration

RI          Refractive index

TA          Tannic acid

TAM      Template-assisted method

TDD       Targeted drug delivery

Temp.    Temperature

TiO₂            Titania  

TNT       Titanium dioxide nanotubes

UV          Ultraviolet

V₂O₅       Vanadium oxide

WO₃           Tungsten trioxide

ZnO        Zinc oxide

 

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Received on 12.07.2024      Revised on 14.01.2025 Accepted on 16.04.2025      Published on 01.07.2025 Available online from July 05, 2025 Research J. Pharmacy and Technology. 2025;18(7):3385-3395. DOI: 10.52711/0974-360X.2025.00489 © RJPT All right reserved
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