Stimuli Responsive Nanocarriers for Targeted Drug Delivery: A Review

Figure no 1: Schematic illustration of stimuli-responsive smart nanocarriers showing drug release

CLASSIFICATION OF STIMULI RESPONSIVE NANOCARRIERS:

Internal stimuli-responsive:

Internal stimuli-responsive systems are the systems that take advantage of microenvironmental changes of the diseased tissues like change in pH, temperature, or concentration of specific enzymes or difference in redox potential. In response to such endogenous stimuli, such systems are designed to deliver the drug in a selective and predetermined manner accordingly improving drug’s biological effect and reducing side effects elsewhere in the body.

1. pH:⁸

The most commonly used stimuli for delivery is pH, targeted at either whole organs or the internal structures within individual cells; it has also been used to release the therapeutics under altered pathological conditions, like cancer, inflammation, or ischemia with marked pH changes. pH-responsive polymers, which are capable of accepting or donating protons in pathological pH, allow moderate structural changes to occur, and are employed for these systems.

2. Temperature:⁹

Temperature may be used as an both type of stimuli i.e., as an external stimulus or as an internal stimulus. In case of tumor tissue, it is slightly warmer than normal tissue. Heating the tumor site increases the local blood supply and permeability of the tumorous tissues. Temperature-responsive nanocarriers like liposomes, polymeric micelles and vesicles are used in combination with other stimuli. Among these nanocarriers, temperature responsive nanomaterials commonly uses polymer hydrogels as a vectors. The properties of the polymers enable them to have a critical solution temperature range, which the polymer becoming insoluble when the temperature increases beyond the lower critical solution temperature. Poly(N-isopropyl acrylamide) (PNIPAAm) is the most popular thermosensitive polymer used for the delivery of therapeutics. Another common type of temperature-responsive carrier is thermosensitive liposomes. The strategic parameter of thermosensitive liposomes is the transition temperature (Tm) of phospholipids from the gel phase to fluid phase.

3. Enzyme:^10,11

Enzymes plays a important role in most metabolic processes. The levels and activities of enzymes are different in diverse tissues and organs, which means that enzymes have tissue-specificity or organ-specificity. Nanocarriers can be designed as enzyme-responsive systems when the enzyme activity is associated with a particular tissue or when there is increase in the  level of an enzyme at the target site. Enzyme-responsive nanocarriers are more suitable for programmed delivery when compared with other stimuli delivery strategies due to changes in certain enzymes caused by the disease.Several enzyme responsive nanocarriers have been developed for achieving controlled release of medication like mesoporous silica nanoparticles, dendrimers, magnetic nanoparticles, polymeric micelles and liposomes  etc. The enzyme-sensitive nanocarriers could be utilized in the following aspects: (1) Activating prodrugs, probes and ligands by cutting the enzyme-sensitive bonds; (2) Degradation of nanocarriers through enzyme triggered cleavage of polymer backbones; (3) Direct cleaving the conjugation between nanocarriers and drugs; (4) Enzyme triggered physical disruption of nanocarriers; (5) Enzyme-triggered controlled release of cargos.

4. Redox:¹¹

The nanocarriers releases the therapeutics through a redox reaction where the nanocarriers are made up of redox sensitive bonds and linker such as di-sulfide bond. Nanocarriers that are made up of with di-sulfide-based bond  that is known to cleave by glutathione (GSH), where therapeutics are delivered by  the response of redox reaction.⁷ Redox-responsive polymer materials are of two types: glutathione (GSH) and reactive oxygen species (ROS). GSH types are sensitive to high GSH levels, resulting in precise delivery and rapid drug release into site specific region.

ROS is a by-product of aerobic metabolism induced by carcinogenic transformation; therefore, ROS level is higher in cancer cells when compared to normal cells. The functional groups that are susceptible to ROS are thioacetone, thioether, selenide, diselenide, ferrocene groups and boronic acid esters. Under ROS conditions, hydrophobic thioether- containing polymers are oxidised to hydrophilic sulfoxide or sulphone groups. Thus, the ROS-responsive nanocarriers are developed by polymers containing thioether groups.

External stimuli:

Stimuli-responsive system responds to external stimuli  like  magnetic,light, ultrasound, electric field.

1. Light:¹²

Light is also a attractive variety of parameters, such as wavelength, duration, beam intensity and beam diameter, can be developed to achieve the desired release profile and penetration into tissues. Electromagnetic light wavelengths below 650  nm cannot deeply penetrate through tissue (>1 cm) due to the scattering and absorption by endogenous chromophores; Although UV light  has the triggering power for many chemical reactions, it is useful in treating the superficial level on the skin and mucosa as a triggering agent. To strategize the deeper light penetration, near-infrared (NIR) light within the wavelength range of 650–1000 nm, which leads to the less damage to living Cells.The  chromophore is the key element in the light-responsive NPs. Mechanisms like photo-crosslinking, photo-un-crosslinking, photochemical hydrophobicity switch, and photo-induced cleavage of chemical bonds are developed to induce light-triggered release of nanocarriers. Some important photo-sensitive chemical groups that undergo a photo-isomerization transition are azobenzene and spiropyran  and that undergoes a photo-crosslinking reaction coumarin .

2. Magnetic:^13,14

Magnetic nanoparticles (MNPs) is one of the broad spectrum of nanoscale materials thar are used for biomedical application, because of the intrinsic magnetic properties, which enable tracking through radiology and magnetic resonance (MR) imaging. In response to different types of magnetic field, permanent magnetic (PMF) or alternating magnetic field (AMF), MNPs, which can be applied to magnetic triggered drug delivery, hyperthermia and imaging-guided therapy.

MNPs commonly consist of iron, cobalt, nickel and their corresponding oxides. Among these, iron oxide nanoparticles (IONPs) are widely applied in biomedicine including magnetite, hematite, maghemite etc. The magnetite and maghemite nanoparticles   are referred to as superparamagnetic iron oxide nanoparticles because they exhibit high magnetic magnetization and(SPIONs), characterized by their excellent biocompatibility, fine biodegradability, and stability. These SPIONs have found to have application in biomedical field like magnetic resonance imaging (MRI), drugs delivery, hyperthermia and biosensing.

3. Ultrasound:^15,16

The Spatiotemporal release of a drug from a nanocarriers systems is effectively achieved by  Ultrasound (US) mediated imaging and drug delivery.  Ultrasonic energy facilitates the release of medication from nanocarriers by acoustic energy(ultrasound).  Ultrasonic energy induces (i) cavitation, (ii) mechanical stress  (iii) localized heat in order to disrupt the nanoparticles and releases the medication. The  Permeability of the cell is enhanced by mechanical forces of oscillation and destruction of microscopic and nanoscopic bubbles by exposing to ultrasound. It is advantageous because of its non-invasiveness, the absence of ionizing radiations, and the facile regulation of tissue penetration depth by tuning frequency, duty cycles and exposure time. Additionally, it could reach deeper sites into the body than light-trigger (except for NIR-responsive).

4. Electric field:^17,18

Electroresponsive drug delivery is another stimuli of  choice for sustained, pulsed or “on demand” drug release. A weak electric field (1V) is applied for controlled delivery. Electroresponsive ones consist of polyelectrolytes, with  ionizable groups, which give the opportunity for responsiveness to electrical stimuli. This behavior may result for the release of drug by various kinetic mechanisms. Another effective way for electroresponsive drug delivery is through electroporation. The Formation of pores in cell membranes due to the high transmembrane voltage leads enhanced permeability to drugs. This method has been studied for the delivery of a wide variety of APIs, including proteins, genes, drugs and diagnostic agents.

Various electro-responsive materials like biopolymers (cellulose and starch), inorganic particles (titania, zeolite, mesoporous materials, silica) and conducting polymers which shows electroresponsive behaviour.

Multi-stimuli responsive systems:¹⁹

Multi-stimuli responsive drug delivery systems has a ability to create complex trigger detection systems allows them to detect single triggers or activate multiple triggers sequentially. The combination of both the activation mechanisms in dual-responsive systems enhances specificity by creating pH/temperature and redox/enzyme sensitivity that results is better accumulation of single responsive nanoparticles. Stimuli-responsive elements in nanocarriers that permit precise spatiotemporal control of drug delivery profiles with minimal premature leakages at specific pH levels and temperatures. This system is designed with multiple, layered safety mechanisms that must be unlocked one after another. This system enhances delivery of  nanoparticles by reponding to specific bloodstream conditions and environment triggers before responding to intracellular activation of enzymes. To achieve superior therapeutic results, synergistic responsive mechanisms are utilized by cooperative stimulation process than independent responses would achieve alone.

Figure no 2:  Different types of stimuli responsive

Table 1: Types of stimuli with their mechanism of action²⁰.

Mechanisms Of Drug Release:²¹

The release of drugs from stimuli-responsive carriers depends on the interaction of carrier and the trigger (stimulus). These mechanisms determine drug therapeutic action in its target site more precisely and effectively.

4.1 Swelling and Deswelling

• Swelling: Swelling is caused when specific stimulus is exposed and the polymer matrix absorbs water, which increases the size of pores or mesh network within the carrier. This allows encapsulated drug molecules to diffuse out easily into the surrounding environment.
• Deswelling: Inversely, Polymer gets shrinked or collapsed by some stimuli which results in squeezing out the drug molecules.  For example, PNIPAAm is a example for temperature responsive polmers, collapse above their Lower Critical Solution Temperature (LCST), pushing the drug out.
• Impact: This mechanism provides a controlled, gradual release rate that can be adjusted by altering the  composition of polymer or density of crosslink.

4.2 Bond Cleavage and Degradation

• Chemical Bond Cleavage: Chemical bonds between the drug and carrier or within the carrier matrix breaks down by the stimuli such as acidic pH, enzymes or redox agents. For example, pH-responsive systems like  acid-labile hydrazone bonds breaks in acidic environment leads to drug release.
• Polymer Degradation: The release of drug is caused by the stimuli via degrading the carrier polymer by itself. For instances, Enzyme-responsive polymers are cleaved by upregulated enzymes at the site of disease, and in case of redox-responsive polymers degrade in the reducing intracellular environment.
• Outcome: This results in triggered burst or sustained release depending on the rate of bond breakage and degradation.

4.3 Structural Reconfiguration

• Stimuli can bring about physical changes in the carrier structure like disassembly of micelle, rupturing of vesicle or polymer conformational changes. For instances, Nanoparticle coatings can get destabilized by break down of enzyme leading to disassembly of carrier and drug release.
• This changes are advantageous in on-demand therapy  which often results in the rapid release of drug.

4.4 Phase Transition

• Polymers like PNIPAAm Polymers shows reversible phase transitions near to body temperature.
• The polymer gets swollen and is a hydrophilic in nature below the LCST and collapses and becomes hydrophobic above LCST.
• The polymer expels the drug as it collapses by utilizing triggerer to release the drug by heating mildly.

Materials used to Design Stimuli-Responsive Nanocarriers:

Lipid-Based Nanocarriers:

1. Liposomes:^22,23

Liposomes are also a colloidal or microparticulate carriers. Liposome are a nanoparticulates with size ranging about 100nm. Liposomes are the sphere shaped vesicular structures made up of one or more phospholipid layers. Both hydrophilic and lipophilic drugs are loaded into liposomes. 

Advantages:

1. Targeted Drug Delivery
2. Improved Bioavailability
3. Sustained Release
4. Reduced Toxicity

2.  Niosomes:^24,25

Niosomes are nanoscale drug delivery systems with  good biocompatibility, biodegradability and reduced toxicity. Niosomes are similar to liposomes but differs by bilayer membrane of niosomes which is comprised of non-ionic surfactants instead of phospholipids(Liposomes).

Advantages:

1. Stable and osmotically active
2. Controlled and targeted delivery
3. Increased dermal penetration and oral bioavalilablity
4. Improved therapeutic performance
5. Cost of production is economical

3. Solid lipid nanocarriers(SLNs):^26,27

SLNs are the colloidal carriers of nanoscopic size 50–1000 nm, composed of  solid lipids that can overcome the limitations of polymer nanoparticles and liposomes. This colloidal system consists of Spherical solid lipid particles with solid water- repellent core containing collection of single covering of protein attached lipids.

Advantages:

1. Reduced toxicity
2. Larger surface area
3. Prolonged drug release
4. Superior cellular uptake when compared to traditional colloidal carriers
5. Capability to improve solubility and bioavailability of drugs

4. Nanostructured lipid carriers(NLCs):²⁸

SLNs and NLCs has great encapsulating efficiency and are capable of encapsulating hydrophilic and lipophilic drugs when compared to liposomes. SLNs has a limitations like low entrapment efficiency and high risk of drug expulsion on storage due to polymorphic transitions. Therefore, to overcome the limitations of SLNs, NLCs are used because of the combination of nanostructured solid and lipids within the core SLNs comprised by solid lipids, whereas NLCs are modified by adding liquid lipids. Hence, NLCs are the spherical structures with oil droplets within a solid lipid droplets.

Advantages:

1. High efficiency
2. Improves drug solubility and bioavailability
3. Enables targeted delivery

5. Cubosomes:^29,30

Cubosomes are the lipid-based nanoparticle which reflects their cubic molecular crystallography of submicron size particles (10-500nm). It is the bicontinuous cubic liquid crystalline phase. There are 3 stages in cubosomes like  Im3m (Schwarz surface), Pn3m (Diamond surface), Ia3d (gyro surface) which explains about the shapes and also induces transportation of drug to the target site. 

Advantages:

1. Targeted and controlled drug release
2. Inert, stable, non-toxic, biodegradable
3. Good adhesive property
4. High surface area

6. Lyotropic Liquid Crystalline Nanoparticles:³¹

Lyotropic liquid crystalline nanoparticles are the nanocarriers with significant technological advantages in their internal morphology of 3D or 2D structured network of lipid bilayer in cubic or hexagonal mesophase.

Advantages:

1. High drug entrapment efficiency
2. Ability of modifying drug release kinetics
3. Functional versatility,
4. Greater membrane stability than liposomes

Polymeric nanocarriers:

1. Polymeric nanoparticles:³²

Polymeric nanoparticles have potential to improve the therapeutic efficacy by providing protection and facilitating drug delivery at target site. These nanoparticles have unique polymeric composition  when compared with other delivery systems.

Advantages:

1. Controllable size, shape, and surface charge

2. Polymeric micelles:³³

The polymeric micelles are the novel techniques to enhance the solubility and the problems associated in the administration of drugs. Polymeric micelles are nothing but supramolecular structure where aggregation of colloids formed in self-constructed amphipathic polymer solution. The the of Polymer size ranges between 10nm to 100nm.

Advantages:

1. Smaller particle size
2. Simple manufacturing and sterilization procedures
3. Greater solubilization capabilities

3. Dendrimers:^34,35

The term dendrimer originated from the combination of two Greek words “dendron” means tree and “meros” means parts i.e.,branched structure. Dendrimers are the hyper-branched macromolecules with  many end-group functionalities and a compact molecular structure. The multiple branches are emerged from the central core molecule which give a  structural framework.

Advantages:

1. Excellent monodispersity
2. Has a very precise molecular weight, size, and architecture.

4. Polymeric nanogels:³⁶

The IUPAC defines a nanogel (NG) as a particle of gel of any shape with an equivalent diameter of approximately 1–100 nm. NGs are the soft nanomaterials composed of swellable polymeric networks, which results in greater capacity for fluid retention. The unique features of NGs depends on the ability to sweel in different solvent, deformability, dynamic, permeable and network-like structure. made of swellable polymeric networks, which display a high capacity for retaining fluids such as water.

Advantages:

1. Swelling/shrinking behavior
2. Structural versatility
3. Increased colloidal stability
4. Good biocompatibility

5. Polymeric nanowires:³⁷

Polymeric nanowires are the emerging nanotechnology based drug delivery systems which improves the cellular uptake and endosomal escape of nucleic acids. These nanowires  has the capability to bind with various biomolecules like proteins and nucleic acids that deliver the molecules to target site.

Advantages:

1. It is safe and non-toxic.
2. Has a capability to adhere to cell surfaces.

6. Hydrogels:³⁸

Hydrophilic polymeric networks that have the ability to absorb large amount of water and leads to swelling and shrinking that facilitates the controlled drug release are known as hydrogels. Enzymatic, hydrolytic or environmental stimuli influence hydrogels to release the drug at site of target.

Advantages:

1. Provides sustained release
2. A high local concentration
3. Retained over a long period of time

Inorganic nanoparticles:

1. Gold nanoparticles:³⁹

Gold Nanoparticles are one of the key systems in the targeted drug delivery system. Gold nanoparticles have unique features like precise target, simpler manufacturing process, surface functionalization, distinctive optical and photo thermal capabilities.  These unique features makes gold nanoparticles to stand out from other nanoparticles.  The size of Gold nanoparticles ranges from 1nm to 8 µm by exhibiting different shapes like spherical, sub-octahedral, octahedral, decahedral, icosahedral multiple twined, multiple twined, irregular shape, tetrahedral, nanotriangles, nanoprisms, hexagonal platelets and nanorods.

Advantages:

1. High bioavailability and safety
2. Surface functionalization, tunability
3. Ease of production
4. Strong optical properties

2. Magnetic Nanoparticles:⁴⁰

Magnetic nanomaterials have been used in the fields like catalysis, electromagnetic wave adsorption, and especially biomedicine. Conventional magnetic nanomaterials which contains magnetic elements like iron, cobalt, nickel, and manganese, and their size, shape, structures and chemical components are adjusted by optimizing the physical and chemical properties. This optimization leads to improving the utility in biomedicine. These nanoparticles are frequently used nanoparticles because of their low toxicity and good biocompatibility. The contribution of this type of nanoparticles are in magnetic resonance imaging (MRI), biosensing,and drug delivery.

Advantages:

1. Non-toxicity
2. Biocompatiblilty
3. High-level aggregation in the desired tissue.

3. Mesoporous silica nanoparticles (MSMs):⁴¹

MSNs are SiO2 nanoparticles have the size between 2 and 50 nm  and with a total diameter of a maximum of 1 µm. The material known as mesoporous silica was discovered by Mobil Oil Corporation in 1992. Their first drug delivery application was demonstrated in 2001 when MCM-41 silica was used to release ibuprofen. Since then, MSNs have become a popular drug delivery system due to their advantageous properties and have been generally recognized as safe by the FDA.

Their pore size is located between microporous and macroporous systems which are  used in various shapes like sphere, cube, ellipsoid, rod and with different pore sizes and structures.

Advantages:

1. High stability
2. Has a rigid framework

4. Quantum dots:⁴²

Quantum dots (QDs) are semiconductor crystals with size of 2–10 nm enabling them to emit a wide range of bright, photobleaching-resistant light with distinguished chemical and physical properties. The  QDs’ size and composition is adjusted by tuning the size of  fluorescence. Spherical, cylindrical, pyramidal, conical, tetrahedral, and lens-shaped quantum dots are among the different shapes that are most commonly used. Quantum dots are mainly madeup of a single substance, often metallic chalcogenides such as cadmium telluride (CdTe) or lead sulfide (PbS).

Advantages:

1. Increase their cellular uptake
2. Reduced toxicity
3. Increase stability in biological settings

5. Carbon based nanoparticles:⁴³

Carbon-based nanoparticles have attracted more attention due to their wide distribution, low processing cost and easy method of preparation. Carbon based nanoparticles are classified into based on their physicochemical properties are carbon quantum dots (CQDs), fullerenes, carbon nanotubes, graphene and its derivatives, nanodiamond, and graphene oxide.

Advantages:

1. Have excellent thermal, electrical, and photosensitive properties
2. High mechanical strength
3. Good biocompatibility,
4. High water solubility, low toxicity
5. Easy surface functionalization.

Figure no 3: Types of Smart nanocarriers