1,4School of materials science and nanotechnology, Jadavpur University, Kol-32, India.
2Peerless Hospital and B.K Roy Research Centre, Kolkata, India.
3Baruipur College, University of Calcutta, South 24 Parganas,743610, India.
This review provides a comprehensive overview of the application of nanomaterials in drug delivery, specifically highlighting the efficacy and benefits of herbal drugs, with a particular focus on Curcuma Longa (turmeric).We have discussed various types of nanocarrier systems, including curcumin-encapsulated formulations and their release mechanisms.In addition, the review addresses potential challenges and future directions in the development of nanotechnology for the delivery of herbal drugs to a comprehensive understanding of how nanomaterials can improve the administration and effectiveness of herbal medicines such as Curcuma Long.
The key objective of researchers in the field of drug delivery is to create therapeutic agents that can be precisely targeted to specific areas of the body, such as tissues, organs, or cells, while minimizing their side effects and maximizing the therapeutic benefits. Systemic drugs can offer significant advantage but can lead to unwanted side effects. Chemotherapy drugs can be exemplified as the challenge of balancing effectiveness with potential toxicity. The goal is to improve therapeutic outcomes by improving the properties, efficacy, safety, and convenience of the drug while minimizing side effects by targeting the drugs more precisely in affected areas, thus increasing patient adherence and overall quality of life.[1] Nano materials possess distinct physicochemical properties, such as a large surface-to-volume ratio, the ability to undergo surface modifications, and precise control over their size and shape[2][3] , that enhance their effectiveness as carriers for therapeutic substances[2] compared to macro materials.[3][4] A diverse array of medicinal plants is used to create extracts for raw drugs, each offering a range of therapeutic properties. [5] These plants contain active compounds that are used in the treatment of various human diseases.[6] In the modern world, herbal drugs, also known as herbalism or botanical medicine [7] or phytomedicines or herbal medicines [4], are a therapeutic approach that uses plants or plant extracts and are preferred over chemical drugs due to their lower risk of side effects. [6][4] Turmeric (Curcuma longa L.), a member of the Zingiberaceae family, [5] is universally recognized for its medicinal properties and has been used in traditional medicine since ages. As a herbal drug, curcumin, the bioactive compound of turmeric, is responsible for many of its health benefits, including anti-cancer, anti-inflammatory, anti-microbial, and anti-oxidant effects. [8][9]Recent advancements in nanotechnology have paved the way for improving the delivery and efficacy of curcumin through the use of diverse nanoparticle systems. In this review, we have tried to explore the recent developments in curcumin-loaded nanoparticle drug delivery systems, their impact on curcumin pharmacokinetics and therapeutic efficacy. By examining various nanoparticle-based delivery systems, through this review we aim to give a comprehensive overview of how nanodrug delivery systems can potentially reform the clinical application of curcumin.
Nanomaterials used for drug delivery:
Nanomaterials referes to that class of materials that have a length scale, in any dimension between 1 and 100 nanometers.
3-D nanomaterials are materials where all three dimensions exceed 100 nm i.e no dimension below this threshold. These materials exhibit 0-dimensional quantum confinement that means they restrict particle movement in three degrees of freedom, ex: bulk nano materials.
Zeolites: Zeolites are an encouraging carrier [10] in biomedicine for the delivery of various drugs such as anti-inflammatory, anticancer, and antimicrobial. [11]Zeolites have been tested successfully for delivering various antimicrobial drugs, such as antibiotics, chemotherapeutics, metallic ions, and nitric oxide (NO). [12]Zeolites and their composites are also proved to be compatible to carry anticancer drugs, such as 5-fluorouracil, dxorubicin, and mitoxantrone. [11][13][14]
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Fig:1 Different Types of Nanomaterials
Mesoporous silica nanoparticles are more commanding carriers for drug loading as compared to other nano carriers due to their scalable morphology, meso structure, uniform porosity[15], supreme biocompatibility[16], and ease of function- alization [17].In addition, these mesoporous nano materials have a large surface area and a large pore volume that give them the privilege to hold drugs within them.[18] MSNs involve biomedical applications like diagnostics, photodynamic therapy, tomography, bio imaging, antimicrobial activity, and gene therapy[18], also in drug delivery for the treatment of periodontitis, cancer, dental cavities.[14]
They can be classified based on the pore sizes like micro porous (< 2nm), meso porous (2-50 nm), and lastly macro porous (> 50nm) [19].They are synthesized by either pyrolysis or physical or chemical activation of organic precursors at elevated temperatures. It is observed that the mixed porous carbon (amalgamation of three types) gives the largest surface area among all types of carbon materials. [20][19]Mesoporous carbon nanomaterials are broadly used in drug delivery as carriers.[19][21]
Nano diamonds are carbon nano structures with diameters smaller than 10 nm [21]. Due to their good yield, [22] potential for surface functionalization, high biocompatibility, nano diamonds are inherent materials in medical applications. Nano diamonds serve as efficient chemotherapeutic drug carriers. [23] Doxorubicin hydrochloride (DOX), an apoptosis-inducing drug largely used in chemotherapy, [22] is interiorized in functionalized ND and inserted into murine macrophages along with human colorectal carcinoma cells efficiently. The adsorption of DOX onto the NDs surface, and its release is achieved by controlling Clion concentration and the NDs deliver the drug inside living cells efficaciously.[19][24]
Gold NPs are less toxic as compared to other particles,[25] with large surface area, good biocompatibility, and optical properties. [26]Gold nanoparticles are really attractive as a carrier for delivering drugs or other therapeutic agents. [27] Gold nanoparticles functionalized with targeted specific biomolecules, for example, proteins, DNA, amino acids, carboxylic acids, etc, can actively destroy cancer cells or bacteria. [26]
ZnO nano particles can easily be prepared from its several low-cost precursors. [29]Among other metal oxide nano particles, ZnO NP is a semiconductor nano material with a wide range of applications in the fields, for example, electronics and optoelectronic devices, photo catalysis, cosmetic products also in biomedicine due to their biocompatibility. [29] ZnO NPs exhibit various biomedical applications, including tissue engineering, drug delivery systems,[30] and bio imaging, and can also be used as antibacterial, antioxidant, and ant diabetic agents [29][31].
Magnetic nano particles (NPs) have acquired interest in biomedical applications.[32] Maghemite (Fe2O3) is one of the most suitable magnetic materials[33] because of its low cytotoxicity[6][34].Iron(III) ions are found in the human body, so oozing of metal does not cause noteworthy side-effects [33][35].
Copper oxide nanoparticles possess exceptional antimicrobial properties[36] and have been advantageous in wound healing and antimicrobial drug delivery.[37] Copper oxide nanoparticles prepared by electrochemical reduction method[36] has been used to investigate the antibacterial activities using human pathogens like Escherichia coli and Staphylococcus [36] [37][13].
Titanium oxide, a widely used semiconductor photo catalyst, exhibits antimicrobial properties by producing free radical oxides and peroxides when exposed to light [38]. Its antimicrobial effectiveness varies with the complexity of the cell wall, i.e., the type of bacteria, showing the strongest activity against E. coli, followed by Pseudomonas aeruginosa, Staphylococcus aureus,Enterococcus faecium, Candida albicans[39].Metal doping boosts TiO2’s light absorption, hence enhancing its photo catalytic action and antibacterial activity [40]. For example, silver-coated TiO2 with optimal silver loading shows superior anti-bacterial effects than TiO2 alone. [41][42]
Aluminum oxide nanoparticles exhibit a suppressive effect on microbial growth, primarily disrupting cell membranes at higher concentrations (above 1000 µg/mL). This effect is due to the interactions between the surface charges of the particles and the microbial cells. Similarly, when doped with silver, Al2O3 enhances antimicrobial activity. Studies have shown that TiO2-Ag and Al2O3–Ag composite NPs synthesized via a wet chemical approach with oleic acid surface modification to attach Ag for antibacterial tests (disc diffusion methods) against E.coli and S.epidermidis has revealed their enhanced antimicrobial effectiveness. [43][42]
Dendrimers are one of the examples of organic nanoparticles [44]. A dendrimer has three parts. 1) A central core or void that is useful for encapsulating drugs or metals. 2) Layers consisting of repeating units are affixed to the core (each layer is called”Generation”). 3) Functional groups on the external surface are useful for bioconjugation. Functional groups can be anionic, neutral, or cationic terminals. [45] MTX (methotrexate) Encapsulated dendrimer has shown potential in the treatment of gliomas [45][46] (growth of cells in the brain or spinal cord). Dendrimers used for the encapsulation of drugs PAMAM and PPI dendrimers, the encapsulation of anti-bacterial drugs like sulfamethoxazole (SMZ) has also been successfully employed.[47][46]
Liposomes are spherical, amphiphilic (a molecule having both hydrophobic (nonpolar) and hydrophilic (polar) regions) materials with an aqueous core surrounded by one or more circular lipid bilayers, [48], around 50–200 nm in size [49]. They are classified on the basis of the number of layers and diameter like a. multilamellar vesicles (MLVs, diameter> 200 nm), b. unilamellar vesicles (large unilamellar vesicles (diameter 100–400 nm), c. Small unilamellar vesicles (diameter < 100nm)). Liposomes are also widely used as carriers in cancer therapy. [42]Doxil, or Caelyx, a PEGylated liposomal formulation enclosing the anticancer drug doxorubicin, is used for breast and ovarian cancer. [48][50]Besides, cancer therapy Liposomes are drafted for the treatment of thrombosis carrying thrombolytic drug Urokinase .[49]
Micelles are amphiphilic colloidal structures with with hydrophobic cores and hydrophilic shells [49]. The application of PCL-PEG (poly(caprolactone)-b-poly(ethylene glycol), where PEG is hydrophilic combined with PCL, which is hy- drophobic) based micelles in cancer therapeutics has shown positive results as drug carriers for different types of cancer, such as breast cancer, colorectal cancer, lung cancer, colon cancer, prostate cancer, and so on. PCL-PEG-based nanopar- ticles as nanocarriers for chemotherapeutic drugs such as paclitaxel, camptothecin, and doxorubicin [51]. In addition, cationic polymeric micelles have been prepared to encapsulate lumbrokinase (LK) (LK is a fibrinolytic enzyme arisen from earthworm, which shows antithrombotic action) for the treatment of thrombosis. [49][51][52]
The most commonly and broadly used polymeric NPs are poly-d, l-lactide-coglycolide, polylactic acid, poly-caprolactone, poly-alkyl-cyanoacrylates, chitosan and gelatin.[53]For example Abraxane (albumin-bound paclitaxel nanoparticles) is used for treating breast cancer, utilizing albumin nanoparticles to deliver paclitaxel effectively.[54][55]
Two-dimensional nanomaterials (2D NMs) have one dimension less than 100 nm, resulting 1D quantum confinement with two degrees of freedom. They typically exhibit a plate-like or sheet-like structure, which can be single-layered or multi-layered.ex: clay.
Clay minerals, stacking layers of silicate sheets hold immense promise in bioformatics due to their distinctive properties of adsorption, intercalation [56],biocompatibility ,ion exchange capacity[57]and dissolution.[56][58] Ecologically friendly clays, perform an optimistic role in antidiarrheal treatment, gastrointestinal protection, also as hemostatic agents, antibacterial antiviral agents. Kaolinite or Kaol (Hydrous Aluminum Silicates) is the most yielded clay mineral and is commonly used in skin inflammation, antibacterial, hemostasis, and wound healing applications.[56][59]
One-dimensional nano materials (1D NMs) have two dimensions below 100 nm, leading to 2D quantum confinement with one degree of freedom. These materials generally have a needle-shaped, rod-shaped, tube-shaped or wire-shaped shape, imparting unique electrical and mechanical properties.Example: nano wire, nano tube.
Carbon nanotubes (CNTs) and carbon nanohorns (CNHs)[60] are promising nanoallotrops of carbon for drug delivery, particu- larly for cancer therapies. Single-walled functionalized CNTs (SWCNTs)[61] and multi-walled CNTs (MWCNTs) can improve cell penetration and effectively deliver anticancer drugs such as cisplatin, doxorubicin, and carboplatin [62][63][64]and show superior results compared to other carriers while reducing toxicity. Other than anti-cancer drugs, CNTs are promising in de- livering drugs for inflammation (dapsone, ketoprofen), fungal infections (Amphotericin B), and Alzheimer’s (acetylcholine).On the other hand CNHs also exhibit low toxicity and high purity, showing release of anticancer drugs[60] such as cisplatin and anti-inflammatory drugs prednilisone (PSL) and dexamethasone(DEX).[22][65][66]
Zero-dimensional nanomaterials (0D NMs)exhibit 3D quantum confinement, restricting particle motion entirely, with zero degrees of freedom.They possess unique optical and electronic properties, like size-dependent fluorescence, making them highly valuable in bioimaging, quantum computing, solar cells and so on.ex:quantum dots.
Another carbon allotrope which displays promise for a variety of medical application is fullerene [67].Toxicity of fullerene is less that makes them promising carrier agents for biomedical applications such as anti-HIV activity, DNA cleavage, free radical scavenging and antimicrobial activity. They can even be used in the fight against osteoporosis. An example is the use of poly fluoro bisphosphonate fullerene derivatives as bimodal drugs for osteoporosis (Bisphosphonate compounds are bone-active) [22][68].
Semiconductor quantum dots (QDs) like CdSe QDs, CdTe QDs, ZnO QDs, Si QDs have high photostability,large sur- face area, and excellent colloidal properties,[69]making them useful in biomedical imaging, sensing, catalysis, and even drug delivery.[69][63] One of the most important applications of Quantum dots (QDs) is in cancer diagnosis,[63] For example, Doxorubicin (DOX),anti-chemotherapy drug loaded on to ZnO QDs(3nm)functionalized with poly(ethylene glycol) (PEG) and hyaluronic acid have been successfully studied in targeting cancer cells, another drug ,quercetin loaded on to CdSe@ZnS QDs shows enhanced antibacterial effects against Escherichia coli and Bacillus subtilis[70].Graphene quan- tum dots (GQDs),due to their non-toxicity, sustainability, ultra-small size, excellent photostability,high water solubility are used in several biomedical applications[61].The integration of graphene quantum dots (GQDs) with Cisplatin significantly improves its efficacy.[69] [71][72]Additionally, hyaluronic acid QDs conjugated with melphalan enabl pH-responsive breast cancer treatment[69][73] and CdTe QDs encapsulated with folic acid conjugated chitosan is designed for controlled delivery of mercaptopurine.[69][74]
Usually composite means material consist of two or more materials with different physical and chemical properties and they remain distinct within the final material. Now nano composite means where one of the phases in one /two/three di- mensions is in nano range i.e less than 100nm or the phases repeat themselves after nanoscale intervals. Natural nano composites are bone, shell etc.They can be classified into different types:
∗ Plate like nano filler-Polymer nano composites.
∗ Tube like nano filler polymer nano composites
∗ Nano particle -polymer composites
Polymer/clay nano composites are a promising nano carrier for drug delivery.The addition of clays like bentonite, mont- morillonite to polymers can improve the loading capacity and release profiles of nanocomposites. The clay layers help in the targeted delivery of drugs to specific tissues or cells by controlling the release mechanism, making these systems highly effective in cancer therapies. [75][76]
Normal /Conventional drug delivery and its limitations:
Conventional drug delivery refers to established methods of administering medications to achieve a desired effect in the body. These methods typically include, Oral delivery, Injectable delivery [77], Topical delivery [78], Inhalation delivery [77], Sub- lingual delivery, and rectal delivery [79]. The main target of conventional drug delivery is to ensure effective absorption, maintain proper drug levels in the body and reduce side effects. However, these methods face several challenges that lead us to move towards alternative delivery methods. [77][80]
Here are some challenges associated with conventional drug delivery method:
t1/2 = (0.7 ∗ Vd)
Cl
Where Vd is volume of distribution and Cl is clearance. [78]Drugs with short half-life need to be taken more often to keep their effects lasting longer. For example, Insulin requires multiple daily injections because its therapeutic effect is short-lived. [83]
Nanomaterial based drug delivery and its importance:
Nanometarials have a handful of characteristics that make them very optimistic as a carrier in drug delivery and offer many advantages over the conventional drug delivery system for example:
Mechanism of nano-carrier based drug delivery systems:
Co-loading method refers to the strategy where the drug is loaded or encapsulated during the formation or synthesis of nanoparticles. Various systems have been developed including pure drugs, drug-polymer conjugate, drug-silsesquioxane con- jugate, MOF with drug incorporated, solid-lipids, proteins and polymers. Covalent binding together with hydrophobic, elec- trostatic and π-πinteractions are important for these type of systems.It is observed that by using co-loading strategy, 18.5 to 100.0% drug loadings have been achieved, with nanoparticle sizes ranging from 29 to 400 nm.[92][93]
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Fig :2 Different Loading Mechanism
Paclitaxel(PTX)-loaded bovine serum albumin(BSA) nanoparticle is produced with drug loading capacity of 27.2% and encapsulation efficiency of 95.3% by a desolation method(a co-loading technique).[92][94] Caffeine, loaded to zeolitic imidazolate frameworks(ZIF-8)by using the co-loading strategy called one step mixing method with high drug loading capacities of 28% shows controlled release for 27 days.[95][96] Similarly metal ions and an anti-cancer drug methotrexate are taken together to form MOF particles via coordinate interac- tions between drug molecules and metal ions, followed by coating a double-layer lipid and such solid-lipid MOF nano-particles have very high drug loading capacity of 69-79.1%.[96]
Post-loading strategy means, at first nano-carriers are fabricated then they are loaded with drugs, enabling high drug-loading capacities. Common nano-carriers for this approach include porous materials like silica, carbon nano-particles, metal-organic frameworks (MOFs) and hydrogels. These porous structures offer high surface areas, adjustable pore sizes, and functionalization versatility, enhancing drug loading efficiency. Along with porous materials, on-porous carriers like polypeptides and proteins have also been used for post-loading. Drugs are incorporated into the carriers through different noncovalent interactions, like hydrophobic forces, electrostatic attraction, hydrogen bonding and π–π stacking. Lastly it is seen that this strategy can improve drug loading efficiencies ranging from 11.8%to 68.1%. [92] Mesoporous silica nano-particles (MSNs) are capable of loading drugs like camptothecin, curcumin, and doxorubicin via post- loading methods with efficiencies ranging from 20% to 61.2%. Drug loading can be enhanced by factors like weak acidic conditions, surface modifications. For example post-loading of doxorubicin onto MSNs is more effective at pH 6.0 than at pH 7.4. [97][98] In contrast, mesoporous carbon nanoparticles (MCNs) offer higher surface areas but they are hydrophobic, making drug administration challenging. Surface modifications with carboxyl and hydroxyl groups and hydrophilic polymers like PEG, improve their properties. For example , DOX-loaded MCNs has shown only 4.1% drug loading efficiency due to lower surface area ( 500 m²/g) however, a template-based carbonization can significantly enhance the surface area to 1400 m²/g also improves drug-loading capacity around 51.9% of DOX.[94][99] Drug loading in MOF nano systems is influenced by pore volume, the size ratio of drugs to MOF pores and interaction strengths like hydrophobic effects, π–π stacking and coordinate bonds.So, proper design is necessary to match drug sizes with MOF pores to minimize wasted space. Researchers have synthesized various MOF nanoparticles (e.g., MIL-53, MIL-88A, MIL-89) using iron(III) and organic linkers with a successful loading of range of drugs including azidothymidine triphosphate, doxorubicin (DOX) and ibuprofen with up to 69.2%drug loading efficiency[101][100]. Nanogels are hydrogel nanoparticles that are the combination of the properties of hydrogels and nanomaterials with high water content, tunable properties, good mechanical strength, and biocompatibility Researchers have synthesized a nanogel using the anionic polymer poly (methacrylic acid) (PMAA) to load the cationic drug doxorubicin (DOX) via electrostatic interactions and achieved a drug loading capacity of 42.3% and encapsulation efficiency of 95.7%. [101] Other materials such as calcium silicate hydrate, hydroxyapatite, magnesium silicate and polypeptides have also been de- veloped as drug delivery platforms through post-loading strategies, achieving drug loadings between 26.1% and 69.6%. [92] [102][103]
• Pre-Loading Method:
Pre-loading method is a strategy for creating drug loaded nanoparticles where a drug core is made at first, then it is surrounded by a protective shell. This shell can be adjusted in thickness to increase the amount of drug it will hold. Mostly used nano- particle systems in this method for the shells are polymers, due to their good compatibility with the body decomposability and they are easy to make. Other materials like silica and lipids have also been explored by researchers. Drug loading capacity in these nanoparticles can vary from 12%to 78.5%, with sizes ranging from 40 to 984 nm. [92][104] Some hydrophobic drugs, like curcumin can naturally form stable nanoparticles without any extra surfactants. In this case the pre-loading method can be used to cover these nanoparticles with polymers to enhance their stability for a longer period. For example, researchers have developed a method to make curcumin nanoparticles coated with a polymer and achieved 78.5%drug loading capacity where they have made curcumin nano-particles by dissolving it in tetrahydrofuran with water, then covered them with a polymer using ultrasound. This coating has slowed down the drug release compared to uncoated nanoparticles and it is seen that these polymer-coated nanoparticles exhibit better therapeutic efficacy than free curcumin. [92]
In unstable drug nano-particles due to the strong interactions between the molecules, drug dimers are created where two drug molecules are linked together. For example, Researchers have created camptothecin (CPT)(a plant alkaloid used as an anticancer drug)loaded PLA-PEG nanosystem with a dimeric drug core and polymer shell and achieved over 50% drug loading capacity and nearly 100% encapsulation efficiency. This approach has reduced strong interactions that cause aggregation, by allowing the creation of stable nanoparticles with controlled release properties. [92][105] Drug-core silica-shell nanoparticles with 65%drug loading and 99% encapsulation efficiency are developed using a biomolecule templating method. Bifunctional amphiphilic peptides stabilize hydrophobic drug nanoparticles and enhance bio silicification to form a silica shell. By adjusting the silica shell thickness and nanoparticle size, drug loading efficiency can be tuned. These nanoparticles release drugs slowly at pH 7.4 but accumulate at pH 4.5. [92][106] Furthermore, researchers have created drug-core polymer-shell nanoparticles with a high drug loading efficiency of 58.5%using a bulk sequential nan precipitation method by using different polymers like PLGA, PLGA-PEG, PLA-PEG, and shellac along with various drugs such as paclitaxel, docetaxel, curcumin, ketamine, ibuprofen, amphotericin B, scutellarin, and bulleyaconitine.This method permits effective encapsulation of the drugs in the polymer shell . [92][107]
Drug Release Kinetics and corresponding kinetic models:
Study of pharmacokinetics of drugs or drug release kinetics is important because it helps us to understand in a time course absorption, distribution, metabolism, and excretion of the drug applied to the body.This knowledge is crutial to determine appropriate dosing regimens, predict drug behavior and duration of action and also to evaluate potential drug interactions in optimizing therapy, ensuring safety and efficacy in clinical practice.Drug kinetic models refer to the mathematical frameworks used in this kinetic study of drugs. These models help to describe and predict how drugs are absorbed, distributed, metabolized, and eliminated from the body over time.[78][108][109]
Model dependent approach:
In zero-order drug release kinetics drug is released from a delivery system at a steady rate regardless of its concentration
over time. This can be represented mathematically as:
Qt = Q0 + k0t
Here, Qt is the amount of drug released in time t,Q0 is the initial amount of drug and K0 is the zero order release constant having units of concentration/time. When we plot cumulative drug release against time, the resulting graph will be a straight line and slope provides the value of K0.[110]
Application:
This release model is ideal for maintaining stable drug levels in the bloodstream,with less fluctuations .This behaviour is typically seen in osmotic pump systems, transdermal patches, matrix tablets with low-solubility drugs and coated drug formulations.[78][110][111]
In first-order release kinetic model the release rate of drug from systems is dependent on the concentration of the drug.This can be expressed by the equation:
dC/dt = −kt
where,k is the first-order rate constant having units of time -1.
This can also be written as:
logCt = logC0 − kt/2.303
Here C0 is the initial concentration of drug and Ct is the concentration at time t. When we plot the logarithm of the cumulative percentage of drug remaining against time, the resulting graph will be a straight line and the slope is equal to (-k/2.303).[110][112]
Application:
This model is useful to characterize the dissolution of drugs in formulations, particularly for water-soluble drugs within porous matrices.[78][110][112]
According to Higuchi model drug release is represented by the equation:
Q = A[D(2C – Cs)Cs t ]1/2
In the equation Q signifies the amount of drug released over time t per unit area A, C denotes the initial concentration of the drug, Cs is the drug’s solubility in the surrounding media and D represents the diffusivity or diffusion coefficient of the drug molecules within the matrix. The simplified Higuchi model explains drug release from insoluble matrices as a process that is dependent on the square root of time called Fickian diffusion. This relationship is expressed by the equation:
Q = kHt1/2
where, KH is Higuchi dissolution constant.When we will plot cumulative percentage of drug release against square root of time, the slope of the graph will give the value of this Higuchi dissolution constant KH.[110][113][114]
Application:
This relationship is applicable for studying the release of both water-soluble and poorly soluble drugs that are incorporated
into semi-solid and solid matrices.[100][78]
According to Korsmeyer-Peppas model the equation to describe drug release from polymeric systems is expressed as :
Mt/M∞ = Ktn
where, Mt/M∞ is the fraction of drug released at time t, K is the release rate constant and n is t he release exponent that indicates the drug transport mechanism through the polymer. Different n values help to classify the release behavior as Fickian, non-Fickian, Case II, or super Case II. To determine the exponent n, only the portion of the release curve where Mt/M∞< 0.6 should be analyzed.In vitro drug release data is plotted as log cumulative percentage drug release versus log time to study the release kinetics.[110][115]
Application:
This model is useful for describing drug release from a polymeric system when the release mechanism is unknown or when more than one type of drug release phenomenon is involved.[116][117]
Hopfenberg model describes drug release from surface-dissolving polymers.It is assumed that the surface area remains constant during the degradation process. The cumulative fraction of drug, released over time t is represented as:
Mt/M∞ = 1 − [1 – k0 t / CLa ]n
where k0 is the zero order rate constant describing the polymer degradation (surface erosion) process,[118] CL is the initial amount of drug loaded in the system, a represents the half-thickness (i.e the radius for spheres and cylinders),n is an exponent that varies with geometry n = 1(for flat geometry), 2 (for cylindrical geometry))and 3(for spherical geometry).[110][119]
Application:
This model is useful to understand the release mechanism of drugs from optimized oil spheres having good solubility and a moderate release rate by analyzing the release mechanisms by using data from composite profiles, which often show site-specific biphasic release kinetics.[111][120]
This model has been developed by Baker and Lonsdale from the Higuchi model to describe drug release from spherical matrices is given by the equation :
f = 3 Mt/M∞ (1 − (1 − Mt/M∞ )2/3 )
Where, k is release constant which corresponds to the slope.
To analyze the release kinetics, data achived from in vitro drug release studies are plotted as d(Mt/M∞) dt against the square root of time.[78][110]
Application:
This model is effectively used to linearize the release data from various formulations such as microcapsules or microspheres, providing a better understanding of release behavior of drugs.[120]
Model independent approach:
– Using Difference and Similarity Factor:
A model-independent approach involves using a difference factor(f1) and a similarity factor (f2)to compare dissolution profiles. [78] The difference factor (f1) quantifies the percent difference between two curves at each time point and also a measure of the relative error between them. It can be calculated by using the formula:
f1 = t=1n(
Rt– Tt)/ t=1nR
t
Where, Rt is the dissolution value of the reference batch at time t. Tt is the dissolution value of the test batch at time t.n is the number of time points.[111][121] The similarity factor(f2 )describes how similar two dissolution profiles are. It is based on the logarithmic reciprocal square root transformation of the sum of squared differences between the two curves. It is calculated by using the formula:
f2 = 50log (( 1+1n
t=1n
(Rt – Tt)2 )/(1+1nt=1n
Rt2 ))-1
higher f2 value indicates greater similarity between the profiles.[111] This model independent approaches are suitable for dissolution profile comparison when three or four or more dissolutiontime points are available.[78][110]
Types of drugs:
Herbal drugs over Chemical drugs:
Now the first question arises why we will choose herbal drugs over chemical drugs, here are some reasons:
Turmaric, a promising herbal drug and its therapeutic importance:
Curcuma longa, widely known as turmeric is a perennial herb in the Zingiberaceae family native to Southeast Asia. It has a long history of use in traditional medicine due to its diverse therapeutic benefits. This herbal plant is valued both as a culinary spice and a medicinal agent since ages. [125][126][127]
Curcuma longa contains a diverse array of phytochemicals.Major phytochemicals include,
Curcuminoids are a group of phenolic compounds and the most prominent active constituents of Curcuma longa.Prime curcuminoids are curcumin,demethoxycurcumin, and bisdemethoxycurcumin. Where curcumin is the most abundant and biologically active compound, known for its anti-inflammatory, antioxidant, antimicrobial, and anticancer properties. [125] [128] Curcumin is a polyphenol that gives turmeric its yellow color. [129][130]
Besides curcuminoids volatile oils including tumerone, atlantone, and zingiberone [125] [128] contribute significantly to the bioactivity of Curcuma longa. They not only provide the distinct aroma and taste of turmeric but also possess antimicrobial, anti-inflammatory, and antioxidant properties. [125]
Another group of compounds present in Curcuma longa are complex carbohydrates polysaccharides known as the”ukonan” fractions. They have demonstrated promising immune-stimulatory effects. [125]
Curcuma longa also contains a variety of secondary metabolites for example sterols, fatty acids, and sugars which elevate its medicinal benefits. Notably, this herb is rich in various flavonoids and alkaloids which play significant roles in its antioxidant
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Phytochemicals Present in Turmeric
And anti-inflammatory actions. [125][128][131]
Curcuma longa has proven effective against a variety of bacterial strains, encompassing both Gram-positive and Gram- negative types. [126][125][130] Extensive research has explored its antimicrobial potential in both in vitro and in vivo.[125][126] These investigations provide considerable evidence in favour of its strong antimicrobial efficacy across a diverse range of microorganisms[125].Infections causing from multidrug-resistant bacteria like methicillin-resistant Staphyloccus aureus (MRSA)[132] are a rising global health concern. In this regard ,Curcumin with certain commertial antibiotics such as oxacillin, ampicillin, ciprofloxacin, and norfloxacin, has shown promising antibacterial effects against MRSA.[133][130][134]A study reveals that the ethanolic extract of Curcuma xanthorhiza (commonly known as Java turmeric) demonstrated significant effectiveness in combating Mycobacterium tuberculosis.[134][135] The methanol and hexane extracts of Curcuma longa has exhibited antibacterial activity against 13 different bacterial strains, namely Bacillus cereus, Aeromonas hydrophila, Bacillus subtilis, Streptococcus agalactiae, Staphylococcus agalactiae, Staphylococcus epidermidis, Staphylococcus aureus etc[136].[137] Turmeric oil has been shown to effectively resist various bacteria, including Bacillus coagulans, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli. Adding 0.3%curcumin extract to cheese has been found to decrease the levels of harmful bacteria such as Pseudomonas aeruginosa and Salmonella enterica serotype typhimurium .It also helps to decrease the presence of Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus, even after the cheese has been stored for 14 days.[136][138]
Curcumin not only has antibacterial properties but also displays antifungal activity. [134] Curcuma longa has shown anti- fungal activity against various fungal species. [125]Candida albicans, an opportunistic fungus that can lead to infections in immunocompromised individuals. However, curcumin has been found to be effective against Candida albicans in such challenging cases.[134]Curcumin has demonstrated antifungal efficacy not only against Candida albicans but also against 200 clinical isolates of various Candida species, including Candida tropicalis,Candida kefyr, Candida krusei, Candida guilliermondii, Candida glabrata,and Candida parapsilosis successfully, with minimum inhibitory concentration (MIC) values ranging from 32 to 128 µ g/ml[134][139].The anti-candidal activity of curcumin, both alone and in combination with ascorbic acid, is studied against Candida strains. The combination resulted a significantly lower MIC compared to curcumin alone against Candida albicansand Cryptococcus neoformans, with MIC values of 128 and 256µg/ml, respectively[134][140].Besides,the alcoholic extract of curcumin is tested against various Fusarium species such as Fusarium graminearum,Fusarian chlamydosporum, Fusarian tricinctum,Fusarian culmorum, Fusarian oxysporum and was found to be most effective against Fusarium graminearum.[134]These findings suggest that curcumin holds promise as a potential therapeutic agent for fungal infections, either alone or in combination with other commercially available antifungal agents.[141]
Research indicates that Curcuma longa exhibits antiparasitic properties, especially against protozoan parasites such as Plasmodium and Leishmania species.Cryptosporidium parvum, a zoonotic parasite,[142] a major health threat and a prevalent contaminant in food and drinking water.[143] Additionally, curcumin has demonstrated antiprotozoal activity in both in vitro and in vivo studies, targeting parasites such as Trypanosoma and Giardialamblia( the most common protozoan parasite responsible for causing diarrhea in millions of people all over the world[134]).Anti-protozoal activity suggests it can serve as a complementary or alternative treatment for various protozoal diseases. However, further studies and clinical trials are needed to confirm its efficacy. [134] [125] [134] [143]
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Curcumin In Different Disease Treatment
Curcuma longa and its derivatives, particularly Curcumin has shown significant anti-HIV activity by inhibiting HIV-1 integrase, a crucial enzyme for viral replication. It also blocks HIV gene expression induced by UV light, indicating its potential as a novel therapeutic agent for HIV treatment. Beyond HIV,studies indicate its antiviral effects against a variety of viruses, including Vesicular stomatitis virus (VSV), Flock house virus (FHV), Respiratory syncytial virus (RSV),[134] Herpes simplex virus (HSV), Influenza type A virus, Ebola virus,[144] and Hepatitis C virus (HCV). Furthermore, curcumin has demonstrated antiviral activity against mosquito-borne viruses such as Zika virus and Chikungunya virus,[145] with effects that are both dose-dependent and time-dependent.[134] These findings suggest that curcumin interferes with viral replication processes, offering promising benefits in reducing viral activity and enhancing antiviral strategies.[125][134]
Turmeric shows high anti-inflammatory properties as it encompasses many natural cyclooxygenase inhibitors. Turmeric extracts, turmeric oil and curcuminoids had been found effective against arthritis [124].Turmeric’s anti-inflammatory activity is attributed to its ability to reduce histamine levels and boost cortisone production. It supports gall bladder and liver functions and is beneficial for conditions like rheumatoid arthritis, osteoarthritis, and injuries. Research indicates that its ethanolic extract, along with derivatives like feruloyl-(4-hydroxycinnamoyl)-methane and sodium curcuminate, exhibits strong anti-inflammatory activity in carrageenan-induced rat models. [136][146]
Curcumin shows strong anticancer potential across various malignancies, including colorectal, breast, and prostate can- cers. [136] It can reduce inflammation, oxidative stress, inhibit tumor growth and metastasis and also enhance con- ventional treatments.[147] Although preclinical results are promising, more research is needed to confirm its clinical effectiveness.[148][149] [150]
∗ Curcumin in breast cancer:
Breast cancer is a common and serious disease that occurs in the breast tissue, primarily in the ducts or lob- ules.Doxorubicin is widely used in chemotherapy for various cancers, including breast cancer. It works by intercalating with DNA, inhibiting topoisomerase II, and generating reactive oxygen species (ROS), leading to cell death. However it can harm the heart and lose effectiveness over time. Using it together with curcumin has been found to improve its ability to target cancer cells and lower their chances of survival. In an open-label Phase I dose-escalation trial, curcumin has been tested with docetaxel for advanced and metastatic breast cancer patients. The study yields promising results, indicating that curcumin can be an effective adjuvant to docetaxel in breast cancer treatment. [148]
∗ Curcumin in oral cancer:
Oral cancer, a type of head and neck cancer and curcumin shows promise in treating it. It enhances the effects of other treatments, inhibits cancer cell growth, and improves radiotherapy sensitivity. Clinical trials have shown curcumin can improve precancerous lesions (a collection of cells that look like cancer cells but may not be able to spread to other organs) and reduce symptoms like pain and itching. [148]
∗ Curcumin and cervical cancer:
Cervical cancer originates in the cervix, the lower part of the uterus due to an abnormal cell growth in the cervix lining, often caused by HPV (Human Papillomavirus) infection. In a phase I clinical trial, taking a daily oral dose of curcumin ranging from 0.5 to 12 grams given over 3 months led to noticeable improvement in precancerous lesions(a collection of cells that look like cancer cells but may not be able to spread to other organs)[151] in one out of four patients with cervical intraepithelial neoplasia. [148]
∗ Curcumin on Digestive System Cancers:
Gastric cancer or stomach cancer is caused because of infection by Helicobacter pylori bacteria. Usual treatments like 5-FU and FOLFOX sometimes fail because some cancer cells become resistant. A phase-I clinical trial on six patients with stomach intestinal metaplasia are given 0.5–12 grams of curcumin daily for three months and one of these six has showed improvement in precancerous lesions. These finding indicates that combining curcumin with FOLFOX can improve outcomes and reduce cancer recurrence. [148][152] In a study of 15 patients with advanced colorectal cancer, treatment with curcuma extract (0.44 and 2.2 g/day) for up to 4 months, containing 36–180 mg of curcumin, showed no toxicity. This treatment has decreased in cancer biomarkers from 310 to 175 after 2 months.[152]
Curcumin in lung cancer:
Lung cancer, one of the leading causes of cancer death involves uncontrolled growth of abnormal cells in the lungs and primarily includes small cell lung carcinoma and non-small-cell lung carcinoma (NSCLC). Treatment options, such as surgery, radiotherapy, and chemotherapy with drugs like doxorubicin and carboplatin, often face challenges like drug resistance and poor uptake. Research has shown that methoxy poly (ethylene glycol)-poly (?-caprolactone) [153] (MPEG-PCL) micelles with doxorubicin and curcumin, can enhance treatment efficacy.Curcumin has been found to improve chemotherapy outcomes by reducing metastasis (the spread of cancer cells from the original tumor to other parts of the body) inhibiting cancer cell growth, and sensitizing cisplatin-resistant cells. Thus it is showing promise as an effective adjuvant in lung cancer treatment. [148]
∗ Curcumin on leukemia and lymphoma:
Leukemia is a cancer that starts in the bone marrow, causing a surge of abnormal white blood cells, known as blasts. Methotrexate (MTX) treats leukemia but faces resistance, often due to poor drug uptake. Curcumin boosts MTX uptake and effectiveness, helps in overcoming resistance, and inhibits cancer cell growth [154] .It also works with other drugs like doxorubicin and disrupts cancer cell processes in various models. [148]
∗ Curcumin in bone cancer:
Bone cancer is rare and affects generally the long bones of the arms and legs. According to the index of the American Cancer Society about 3,970 new cases are diagnosed (2,270 in males and 1,700 in females) and about 2,050 deaths (1,100 in males and 950 in females) in 2024 so far. [155]Curcumin shows promise in treating bone cancer by targeting various pathways. It helps to induce apoptosis in bone cancer cells by reducing NF-κB, IL-6, and IL-11, and suppresses MMP13 in chondrosarcoma cells (malignant bone tumor cells that are derived from cartilage). Curcumin also inhibits ERK and Bcl-2 (both are proteins involved in cell survival and death) and reduces osteoclast function (break down old or damaged bone tissue, making room for new bone growth and repair). When used with radiotherapy, curcumin enhances tumor cell death and reduces radiation resistance in a mice model. [148]
Curcumin, can be helpful in treating heart diseases because it reduces inflammation and fights against oxidation.[137] It can also improve blood vessel function, manage cholesterol ,lower blood pressure and blood clotting. Curcumin also helps to protect heart cells during heart attacks and can prevent heart damage from certain drugs and diabetes. It works by blocking proteins that cause heart problems. However, more studies are needed to confirm these benefits and curcumin should be used alongside, not instead of regular heart treatments because it’s not easily absorbed by the body. [144][142]
Pulmonary fibrosis is a serious lung condition where lung tissues become thick and scarred (fibrosis) causing breathing problem. [156]Curcumin reduces inflammatory cells, cytokines, ROS, and growth factors contributing to fibrosis. Studies on animal models have shown its potential in this case.[143][157]Asthma, a condition causing inflammation and narrowing of airways leading to breathing issue.Curcumin shows ability to block inflammatory chemicals (IL-4, IL-5),hence reduce histamine effects(that triggers allergy symptoms)and influence NF-κB and Nrf2 proteins, involved in the inflammatory process.[157][158][159]
– Effects On Neurological Disorders:
The World Health Organization (WHO) defines neurological disorders as conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, nerves, and muscles. Curcumin, has shown notable promise in treating a range of neurological and psychological conditions.[160][161] In anxiety and depression, curcumin blocks monoamine oxidase (MAO-A and MAO-B) enzymes, leading to improve of serotonin, dopamine, and norepinephrine levels. It also boosts BDNF(Brain-derived neurotrophic factor) expression via the ERK (Extracellular signal-regulated kinases)pathway, hence improves hippocampal neurogenesis and reduces inflam- mation significantly by lowering pro-inflammatory mediators and cytokines through NF-κB signaling. Alzheimer’s disease, curcumin binds with amyloid-beta (Aβ) peptides preventing its aggregation and stabilizing fibrils thereby reduces neuronal damage.[161] For Parkinson’s disease, it protects dopaminergic neurons, restores dopamine levels, reduces oxidative stress, and inhibits inflammatory pathways like NF-κB and AP-1.[163]Due to its ability to cross the blood-brain barrier and its anti-inflammatory and antioxidant properties,curcumin shows promise for stroke treatment.[159][160][163] It also shows potential in Autism Spectrum Disorder (ASD)cure by significantly lowering TNF-α and MMP-9 levels, hence improving behavioral symptoms. Though more promising research is required to establish its efficacy. [163] Collectively, these findings highlight curcumin’s versatility in addressing various neurodegenerative and psychiatric con- ditions, although further clinical research is needed to confirm its efficacy and safety in humans.
– Wound Healing Property:
Curcumin can accelerate wound healing by promoting, granulation tissue formation, collagen deposition and tissue remodeling. Studies have shown that it enhances epithelial regeneration, fibroblast proliferation, and vascular density when applied to wounds. [164]
Mechanism of Curcumin for the purpose of different disease treatment:
Wound healing is a process that involves various cells, components of the ECM, cytokines, and growth factors. It occurs in these steps: (a) hemostasis and inflammation, where blood clotting and inflammation occur; (b) proliferation that includes formation of granulation tissue ; and (c) remodeling, where new epithelium forms and scarring occurs.[164][165][159] Curcumin, has shown promise in promoting wound healing due to its anti-inflammatory, antioxidant, and antimicrobial properties. Here’s how curcumin contributes to the wound healing process:
Hemostosis is body’s natural process to stop bleeding from a wounded site or a blood vessel. Curcumin helps to regulate platelet aggregation and blood clotting. Due to its anti-inflammatory action it can prevent excessive clot formation and support a balanced hemostatic response. By stabilizing the clotting process, curcumin can successfully create a stable environment by reducing cytokines like TNF-α and IL-1, which are involved in the inflammatory response. It also exhibits the activation of NF-κB, a transcription factor linked to inflammation and oxidative stress. This reduces swelling, redness, and pain, while also preventing prolonged inflammation, which can delay healing. Curcumin also enhances macrophage activity, helping in clearing cellular debris and preventing infection.[159][166] Studies have revealed that curcumin-loaded oleic acid-based polymeric (COP)bandages reduce kinase activity in the PI3K/AKT/NF-κB pathway along with lowering the inflammation in wound sites.Also,an another study found that curcumin promotes normal inflammatory responses by increasing nitric oxide, which may again improve healing. [164][165]
Fibroblast infiltration is essential for granulation tissue formation and collagen deposition during wound healing. Impaired fibroblast proliferation and migration can delay healing. Studies show that curcumin enhances fibroblast penetration and promotes myofibroblast presence at wound sites within four days. However, curcumin’s effect is dose-dependent; high concentrations (25µM) induce fibroblast apoptosis via free radical production, while lower concentrations (5–10 µM) are non-toxic and preserve fibroblast morphology. [164] Studies have shown that curcumin-loaded systems for example, curcumin in chitosan-alginate or collagen matrices enhance granulation tissue formation and increase hydroxyproline content, indicating myofibroblast activity, which is key for wound healing.[165][166]
The extracellular matrix (ECM), primarily composed of collagen (70–80%), is crucial for wound reorganization and remodeling. Collagen production is important for providing strength and structure for the healing tissue. Treatment with COP bandages has been shown to increase collagen content, promote better alignment and accelerate maturation of collagen fibers.[168] Studies have revealed that curcumin-treated wounds exhibit higher tensile strength, faster collagen synthesis (peaking around day 8) and improved wound contraction as fibroblasts transition to myofibroblasts by day 7.[166][167]
Epidermis, the outer layer of skin that protects against physical, chemical and microbial damage, relies on re-epithelialization for barrier restoration. It is tested that curcumin significantly accelerates this process, reducing the healing time from 23 to 11 days in rat models also enhances re-epithelialization in diabetic wounds, leading to faster wound closure.[165][166]
Killing cancer cells with minimizing toxicity to normal tissues is definitely a major challenge as normal tissue damage can cause issues like heart failure, respiratory disorders and gastrointestinal problems. Chemotherapeutic therapies can effectively increase the treatment but at the same time gives rise to normal tissue damage. [159][168] Curcumin can regulate immune responses, tumor suppressor genes, and redox pathways [170] by enhancing cancer treatment without harming to normal tissues. [150][170][171]
Apoptosis (process of cell death) is crucial stage for preventing tumor development by abolishing pre-cancer and cancer cells[171].Apoptosis is triggered by releasing signals like Fas ligand(FasL) , TNF-α, which activate death receptors and caspase proteins on cancer cells leading them to death.[173] Tumor suppressor genes like p53 and PTEN are crucial for initiating apoptosis. However, cancer cells with mutated or absent p53 and PTEN can evade apoptosis by overexpressing survival genes like PI3K, NF-κB, and Bcl-2, [173] while reducing pro-apoptotic genes. [174]
Radiation and chemotherapy incite apoptosis by induction of DNA damage and generating free radicals, overwhelming the cell’s repair mechanisms.[174] Curcumin enhances a safer and effective cancer therapy by generating tumor suppressor and apoptotic genes.[171][175]
NF-κ-B(Nuclear factor kappa B) is a transcription factor that promotes cell survival by boosting the generation of protective genes like Bcl-2 and COX-2.[176] In normal cells, NF-κ-B is usually present but in cancer cells, over activation of it causes due to mutations that helps cancer cell resist treatments.NF-κ-B activation depends on the inhibitor named Iκ-B,controlled by Iκ-B kinase (IKK).[177]By the time these Iκ-B degrades in presence of oncogenes or cytokines, NF-κ-B moves to the nucleus with an elevation of anti-apoptotic genes like COX-2 and Bcl-2.[170][178] In a study it is found that combining curcumin with radiation therapy enhances apoptosis, overcoming treatment resistance in cancers like colon, colorectal, and laryngeal squamous cell carcinoma as curcumin inhibits IKK-NF-κB [179]pathway hence deregulates the levels of protective genes like Bcl-XL, Bcl-W, and cyclin D1.[114][170][180]
Curcumin can inhibit micro-RNAs like miR-21,a key oncogenic compound that promotes tumor resistance by inhibiting tumer suppresser gene PTEN ((phosphatase and tensin homolog )and activating the PI3K/AKT pathway, which again gives rise the anti-apoptotic factors like Bcl-2, HIF-1, and mTOR. Curcumin can reverse this by suppressing miR-21, restoring PTEN, and reducing tumor resistance.[181]
This effect has been seen in various cancers, such as gastric, colon, lung, leukemia, as well as in gemcitabine-resistant pancreatic cancer cells.[170]
The immune system cells such as NK cells and CD8+ T cells or cytotoxic T cells can kill cancer cells by releasing reactive oxygen species (ROS), lytic enzymes and apoptosis-inducing signals like FasL and TNF-α.However, tumors can also develop resistance by releasing cytokines like, TGF-β, IL-10 and recruiting immunosuppressive cells like Tregs, TAMs, and CAFs those can suppress immune activity and encourage tumor survival. [182] Now, Curcumin boosts the immune response by activating NK cells and CTLs, also inhibits immunosuppressive cells like Regulatory T cells or Tregs and TAMs. Thus it enhances tumor immunity that leads to apoptosis in cancer cells.[170]
Curcumin prompts cancer cell death by disrupting the cell’s redox balance and also swifts the generation of reactive oxygen species (ROS).[169]In this process curcumin protects normal cells from oxidative damage. These ROS activates MAPK pathway, triggering proteins like JNK, ERK, and p38 that leads to the up regulation of death receptors like Fas, DR5, and TRAIL.[183] So,curcumin-induced ROS production and MAPK activation adequately reduce cancer cell proliferation in various cancers including glioblastoma, liver, and gastric cancers.[170]
Nano encapsulated herbal drug-curcumin in medical application: Curcumin has been broadly known for its antimicrobial, anti-inflammatory, antioxidant, and antitumor actions. As it has very poor properties including less absorption, penetration and targeting efficacy. Encapsulation of curcumin in different nanomaterials has come out to be a solution for these limitations [184] Different curcumin-loaded nanocarriers have been prepared and employed for various diseases treatment.[144][185] Some pharmaceutical applications with nanoencapsulated curcumin are summed up here.
Curcumin loaded Dendrimers:
Curcumin loaded in surface functionalized polyamidoamine (PAMAM) dendrimers are efficient to boost the effective delivery of therapeutic dosages of curcumin to cells.[186] On rat-F98(F98 ,glial-like cell used as rat brain tumor models in neuro- oncology.) mouse-GL261 and human-U87 GBM[188] (Glioblastomas)(Glioblastoma (GBM) is the most hostile and aggressive brain tumor. Four types of GBM cell lines (LN229, SNB19, U87, U251) are cultured in a micro fabricated 3-D model to study their in vitro behaviors in neuroscience and immuno-oncology research [187].) Cell lines, [188] the efficacy of curcumin loaded dendrimer is evaluated advantageously. [189][190]
Curcumin loaded liposomes:
In a study on glioblastoma (GBM) [187], curcumin is used to target glioma cells, while quinacrine induces cell death in glioma progenitor cells. To enhance this drug delivery, p-aminophenyl-D-mannopyranoside is used to help liposomes in crossing the blood-brain barrier (BBB) and reaching the glioma cells.[191] In lab tests, these specially designed liposomes have increased drug effectiveness by boosting apoptosis and cell uptake. In a mouse model, ligand-conjugated liposomes have improved survival rates and slowed tumor growth. Overall, curcumin and quinacrine delivered via these liposomes exhibit strong potential for treating GBM. [189][192][193]
Curcumin with clay-polymer nanocomposite:
Curcumin shows great promise in cancer treatment and its effectiveness in drug delivery[194] can be elevated by incorporating clay minerals like montmorillonite (MMT) into PLGA nanoparticles.[195]Studies using simulations has indicated that MMT interacts strongly with both the polymer and curcumin via van der Waals forces thus it improves the drug’s release. This suggests that MMT-PLGA composites can be effective in delivering curcumin for cancer therapy. [196][197] Additionally, hydrophilic biopolymers like chitosan (CH) [197] are gaining attention for their biocompatibility and biodegrad- ability. Chitosan, in acidic conditions, becomes positively charged, allowing it to interact with negatively charged cancer cell membranes. A recent study has showed that MMT-CH nanocomposites are effective in controlling curcumin release, [198] the release is faster in acidic environments due to chitosan’s swelling behavior, which increases the release of curcumin as the polymer swells and its amino groups become protonated in low pH conditions. This pH-dependent release could be particularly useful for targeting cancer cells in acidic tumor environments. [199][200]
Curcumin loaded silica:
Curcumin-loaded mesoporous silica nanoparticles (MSNs) has emerged as a promising drug delivery systems with multiple ap- plications. Mesoporous silica nanoparticles (MSNs) loaded with curcumin and gentamicin for dual anticancer and antibacterial effects.[201]A trio-hybrid nanocomposite,featuring mesoporous silica ,copper and silver nanoparticles has displayed enhanced photo killing of E.coli when combined with curcumin by reducing bacterial viability after irradiation significantly.[202][203] Furthermore, chitosan-curcumin-loaded MSN film has shown stronger antibacterial activity against Staphylococcus aureus than E. coli. Hybrid nanofiber mats integrating curcumin-loaded MSNs with polyvinylpyrrolidone (PVP)has increased efficacy against methicillin-resistant S. aureus.[204] Copper-loaded MSNs with immobilized silver nanoparticles can photodynamically inactivate E.coli by generating reactive oxygen species (ROS).[206] [207]Also a temperature controlled duel imaging drug car- rier to prevent Zika virus infection when loaded on curcumin has been designed and for increasing biocompatibility and solubility of curcumin, it is loaded onto MSNs, doped with PEGMA-temperature-responsive polymers and phosphorescent metal ions—i.e.,Gd3+ and Eu3+.The effectiveness of the curcumin-loaded nanoparticles compared to free curcumin for antiviral activity,has demonstrated their potential in inhibiting the Zika virus.[207][208]
Curcumin loaded polymeric miscelles:
Curcumin-loaded MPEG-PCL micelles(nanoparticles made up of two polymers: methoxy polyethylene glycol (MPEG) and polycaprolactone (PCL).[209]This micelles form a core-shell structure, where the hydrophobic PCL core encapsulates drugs and the hydrophilic MPEG shell makes the micelles water-soluble) are made using nano-precipitation method.[210] Compared to other nano-curcumin formulations, these micelles have several benefits, like small size, high drug loading efficiency and good re-solubility.[211] Cur/MPEG-PCL micelles effectively slow down the growth of C-26 colon carcinoma by angiogenesis and killing cancer cells.[212] Encapsulating curcumin in these micelles improve the effectiveness in the body, making it promising for colon cancer treatment.[213]
Curcumin loaded with carbon nanotubes:
The anticancer potential of the SWCNT-curcumin combination is tested on HFF-2 cancer cells and it has shown a significantly lower cancer cell survival rate with combination therapy i.e SWCNT-Cur/radiation therapy. The curcumin loading rate on SWCNTs is calculated to be 14.87 %, a moderate but effective drug-loading capacity with its pH-sensitive release of 78%in acidic tumor-like environments and 24%in normal conditions within 10 hours.[214] [215] The combination of SWCNT-curcumin with radiation therapy shows significant cancer cell reduction, [216]showing a promising approach for more effective breast cancer treatment.Additionaly ,Blood toxicity tests show that all tested concentrations of SWCNT-curcumin have less than 10 % toxicity, indicating good biocompatibility[217]and making it suitable for further biological applications.[215]
Curcumin loaded magnetic nanoparticles:
Magnetic nanoparticles have grabbed attention and showed promising applications in drug delivery due to their ease of preparation, minimal toxicity , versatility in surface functionalization and simplicity of separation.[218] [219]Magnetic nanoparticles loaded curcumin exhibit controlled and sustained release of the drug[220] and ensures its coherent anticancer activity.[219][221][222] The anticancer herbal drug curcumin is encapsulated in a polymeric magnetic nanoparticle which is prepared from polymers β-cyclodextrin that is cross linked with epichlorhydrin, dextran byoleoylchloride (hydrophobic modification is done to embrace hydrophobic drugs in the dextran matrix enhancing the solubility of such drugs) and magnetite as magnetic material. [223]
Curcumin loaded quantum dots:
Carbon dots (CDs) synthesized from folic acid using hydrothermal method are effectively loaded with curcumin, that ex- hibits pH-sensitive release.[224]Curcumin-loaded folic acid carbon dots (Cur-FACDs) are tested successfully for their anticancer effects against aggressive cervical cancer cell lines (Hela cells) and liver cancer cells (HepG2).[225] This folic acid carbon dot/Curcumin nanocomposite has also shown antibacterial activity, combating gram-negative bacteria (Pseudomonas aeruginosa) and gram-positive bacteria (Staphylococcus aureus). [226][227]
Curcumin loaded polymeric nanomaterials:
Curcumin-loaded polymeric nanomaterials has shown potential in Alzheimer’s disease (AD)treatment.[228] Curcumin’s ability to reduce inflammation and prevent amyloid-beta buildup supports its effectiveness in treating AD.[229]These nanocarriers enhance curcumin’s bioavailability, effectiveness, solubility and stability while enabling targeted brain delivery by overcoming barriers like the blood-brain barrier. Despite challenges like biological barriers and stability issues, future research on advanced formulations and clinical applications may overcome these obstacles. [230][231]
Toxicity of curcumin:
Curcumin, often considered as the ‘Wonder Drug of Life’ due to its numerous medicinal benefits and is widely used in pharma- ceutical applications. Numerous studies have highlighted its efficacy in preventing and treating various diseases.[134]
Although curcumin is generally considered safe, some in vitro studies suggest its potential negative effects. In one experiment, short-term use of curcumin (up to 8 g / day) is found to not cause significant toxicity, but long-term use (0.9 to 3.6 g / day for 1 to 4 months) can lead to adverse effects such as nausea, diarrhea, and elevated serum markers. Short-term high doses (500–12,000 mg over 72 hours) have been associated with diarrhea, headache, rash, and yellow stool [134] .From the above discussion, it is evident that further research is needed to assess the toxicity of curcumin at various doses and durations, both short and long term.
Nanomedicine challenges:
Nano-drug delivery systems are useful because they offer targeted delivery and enhance efficacy. However, careful evaluation of safety and toxicity is needed. Some nanoparticles can cause inflammation in organs like the liver, lungs, and brain due to stress on the cells. Although they can cross the blood-brain barrier, which is helpful for treating brain diseases, they can cause neurotoxicity if not properly targeted. [78] Research has demonstrated that low-solubility nanoparticles are more hazardous and toxic on a mass by mass basis than larger particles. Other potential risks include explosions and catalytic effects. It is important to note that only specific nanomaterials are considered risky, particularly those with high reactivity and mobility. [232][233] However, more research is needed to improve precision and prevent damage to healthy tissues. Regulatory guidelines, particularly from the FDA are essential for nanomedicine development, as safety and toxicity concerns still pose challenges. [78]
CONCLUSION:
Nanomaterials offer a transformative approach in the field of drug delivery, significantly improving the bioavailability, stability and targeted release of therapeutic agents, as exemplified with Curcuma longa (curcumin). By overcoming conventional drug delivery limitations, nanocarriers offer precise, controlled, and efficient drug delivery, minimizing side effects and enhancing therapeutic outcomes. Nanocarriers, such as liposomes, nanoparticles, dendrimers, micelles, nanotubes, quantum dots and so on, significantly enhance the therapeutic outcomes as they not only protect the drug from degradation during its circulation in the body but also allow for its controlled release, reducing toxicity and minimizing side effects which is commonly associated with conventional drug delivery methods. In case of Curcumia Longa, studies have shown that its encapsulation in nano-systems will be helpful to overcome its poor solubility and rapid metabolism. So, Nanoencapsulated herbal drug Curcumin holds immense promise for a variety of diseases including deadly cancer, inflammation , cardiovascular and neurodegenerative disorders. Overall, nanomaterilas exhibit great promise in advancing herbal drug therapies, with Curcuma longa serving as a prime example, offering better treatment effectiveness and patient outcomes. In addition, safety and toxicity concerns are also present when we talk about large-scale production of nanomaterials for drug delivery, and that remains a significant challenge. Scaling up production in parallel with maintaining the quality and reproducibility of nanomaterial-based formulations is crucial for their successful commercialization. Cost-effective manufacturing techniques have to be developed to make these advanced drug delivery systems to use in healthcare.
REFERENCES
Ansua Roy*, Satadal Das, Saswati Saha, Mahua Ghosh Chaudhuri, Applications Of Nano Materials in Drug Delivery and Release Mechanism: A Review Exemplified With A Herbal Drug, Curcuma Longa, Its Potential In Different Disease Cure, Encapsulation With Different Nano Materials, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 5, 503-544 https://doi.org/10.5281/zenodo.15335362
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