INTRODUCTION:

Nanotechnology is the science that usually deals with the size range from a few nanometers (nm) to several hundred nm, depending on their intended use. (1) Nanotechnology represents a broad field with an exponential growth, holding of the immense potential in cancer treatment. The intense on-going worldwide research is mainly focusing on targeting cancer cells using nano-sized particles. Conceptually, a highly sensitive nano-biomolecule consists in a responsive nanoparticle that has attached a delivery carrier with affinity for unique surface receptor proteins located inside the cellular wall. Nanoparticles are small collidal particles which are made of non-biodegradable and biodegradable polymers. nanoparticle are particles between 1-100 nanometre (nm) in size with a surrounding interfacial layer. the diameter is generally around 200nm. one can distinguish two types of nanoparticles.

Nanospheres, which are metrix system; and nanocapsules, which are reservior system composed of polymer membrane surrounding an oily or aqueous core (2). Nanoscale devices smaller than 50nm can easily enter most cells, and those smaller than 20nm can move out of blood vessels as they circulate through the body. Nanodevices are suitable to serve as customized, targeted drug delivery vehicles to carry large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells. (3) Nanoparticles (NPs) loaded with chemotherapeutic agents such as the dendrimers, polymer nps and lipid nps have the ability to overcome drug resistance. Multidrug resistance (MDR) is one of the biggest challenges in cancer chemotherapy. Development of cancer drug resistance is attributed to a number of factors including inefficient drug delivery to tumor cells, partly due to inefficient targeting and the rapid removal of the drug from tumor cells by the efflux pump, P-glycoprotein (P-gp).(4) A number of obstacles may be overcome with various novel applications of Nano drug delivery. For example, many drugs are not very soluble, making it difficult to administer therapeutic doses. These compounds can be “solubilized” by formulating them into crystalline Nano suspensions that are stabilized by surfactants, or by combining them with organic or lipid nanoparticles that keep them in circulation for longer periods. If an efficacious compound has a short half-life in the circulation, its stability can be increased tremendously by encasing it within nanosized liposomes as a drug carrier. In the case of central nervous system cancers, many drugs have difficulty in crossing the blood– brain barrier to attack the tumor. Drug-loaded nanoparticles are able to penetrate this barrier, and have been shown to greatly increase therapeutic concentrations of anticancer drugs in brain tumors⁽³⁾

NECESSITY OF NANOPARTICLE –BASED DRUG FORMULATION:

There are various reasons why using nanoparticles for therapeutic and diagnostic agent, as well as advancement of drug delivery, is important and much needed. One of them is that, traditional drugs available now for oral or injectable administration are not always manufactured as the optimal formulation for each product. Product containing proteins or nucleic acid requires a more innovative type of carrier system to enhance their efficacy and protect them from unwanted degradation. It is notable that the efficiency of most drug delivery systems is directly related to particles size. Due to their small size and large surface area, drug nanoparticles show increase solubility and thus enhanced bioavailability, additional ability bto cross the blood brain barrier (BBB), enter the pulmonary system and be adsorbed through the tight junctions of endothelial cells of the skin. Specifically, nanoparticles made from natural and synthetic polymers (biodegradable and non-biodegradable) have received more attention because they can be customised for targeted delivery of drugs, improve bioavailability, and provide a controlled release of medication from a single dose; through adaptation the system can prevent endogenous enzymes from degrading the drug. (5)

ADVANTAGES OF NANOPARTICLES:

Some of the advantages of using nanoparticles as a drug delivery system are as follows;

1. Ease of manipulation of the particle size and surface characteristics of nanoparticles so as to achieve both passive and active drug targeting after parenteral administration.

2. The nanoparticle surface can be modified to alter biodistribution of drugs with subsequent clearance of the drug so as to achieve maximum therapeutic efficacy with minimal side effects of the drug.

3. Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents. (6)

4. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or use of magnetic guidance.

5. Liposomes and polymer based nanoparticulates are generally biodegradable, do not accumulate in the body and so are possibly risk free.

6. Small sized nanoparticles can penetrate smaller capillaries, which could allow efficient drug accumulation at the target sites.

7. Various routes of administration are available including oral, nasal, parenteral, intra-ocular etc. (7)

LIMITATIONS:

In spite of these advantages nanoparticles do have limitations like,

1. Altered physical properties which lead to particle – particle aggregation, making physical handling of nanoparticles difficult in liquid and dry forms due to smaller size and larger surface area.

2. Smaller the particles size greater the surface area and this property makes nanoparticles very reactive in the cellular environment.

3. Small particles size results in limited drug loading and burst release. These practical problems have to be sorted out before nanoparticles can be used clinically or made commercially available.

4. Can be quickly scavenged by RES system of body resulting in low biological half-life. 5. Organic solvent remaining (residual) during the preparation of nanoparticle may cause toxicity. (8)

TYPES OF NANOPARTICLES:

INORGANIC NANOPARTICLES:

Inorganic nanoparticles are particles that are not made up of carbon. Metal and metal oxide based nanoparticles are generally categorised as inorganic nanoparticles. the field of Modern material science Inorganic nanoparticle has been developed the role based upon their unique physical properties and particularly in biotechnology⁽⁹⁾

POLYMERIC NANOPARTICLES:

Polymeric nanoparticles are colloidal structures composed of synthetic or semi synthetic polymers. The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix. Depending upon the method of preparation, nanoparticles, nanospheres or nanocapsule can be obtained. Nanocapsules are systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed. Polymers such as polysaccharide Chitosan-Polylactic acid, Polylactic acid coglycolic acid, Poly-caprolactone, Chitosan nanoparticles have been used. (7)

SOLID LIPID NANOPARTICLES:

Solid lipid nanoparticles (SLN) are colloidal carriers developed at the beginning of the 1990s. Generally, they are made of solid hydrophobic core having a monolayer of phospholipids coating. The solid core contains the drug dissolved or dispersed in the solid high melting fat matrix. The hydrophobic chains of phospholipids are embedded in the fat matrix. They have potential to carry lipophilic or hydrophilic drugs or diagnostics.⁽¹⁰⁾

DENDRIMERS:

Dendrimers are extensively studied nanocarriers, they are uniformly distributed complex. Dendrimers are able to carry hydrophobic as well as hydrophilic drugs due to the presence in them of hydrophobic core and hydrophilic surface. The size, shape and pharmacokinetics of dendrimers depend on the generation number, chemical composition of core and branches as well as surface function group. Dendrimers have been used for various applications such as solubility enhancement, photodynamic therapy, drug delivery, bio imaging, cancer treatment and 3D nanoscalecore–shell structures⁽⁹⁾

QUANTUM DOTS (QDS):

Quantum dots are small devices that contain a tiny droplet of free electrons. QDs are colloidal semiconductor nanocrystals from 2 to 10 nm in diameter. QDs can be synthesized from various types of semiconductor materials via colloidal synthesis or electrochemistry. The most commonly used QDs are cadmium selenide (CdSe), cadmium telluride (CdTe), indium phosphide (InP), and indium arsenide (InAs).⁽¹¹⁾

CARBON NANOTUBES:

Carbon nanotubes are carbon cylinders composed of benzene rings that have been applied in biology as sensors for detecting DNA and protein, diagnostic devices for the discrimination of different proteins from serum samples, and carriers to deliver vaccine or protein. Antifungal agents (amphotericin B) or anticancer drugs(methotrexate) have been covalently linked to carbon nanotubes with a fluorescent agent (FITC). The multiple covalent functionalizations on the sidewall or tips of carbon nanotubes allows them to carry several molecules at once, and this strategy provides a fundamuental advantage in the treatment of cancer.⁽¹²⁾

PREPARATION OF NANOPARTICLES:

The appropriate method for the preparation of nanoparticles depends on the characteristics of polymer and the drug that is to be used in Nano preparations therefore in order to achieve the properties of interest the mode of preparation plays a vital role. Different techniques employed in preparation and synthesis of nanoparticles is discussed below:

SOLVENT EVAPORATION:

Solvent evaporation was the first method that was developed for the preparation of nanoparticles, in this technique the polymer solutions were prepared in volatile solvents and emulsion were formulated by employing dichloromethane and chloroform^.(13) Emulsification-solvent evaporation involves two steps. The first step requires emulsification of the polymer solution into an aqueous phase. During the second step polymer solvent is evaporated, inducing polymer precipitation as nanospheres. The nano particles are collected by ultracentrifugation and washed with distilled water to remove stabilizer residue or any free drug and lyophilized for storage^.(11)

SALTING OUT:

The salting outis modification of emulsification solvent diffusion technique in which water miscible solvent is separated from aqueous solution through salting out process where, initially polymer and drug are dissolved in a solvent such as acetone, then it emulsifies into an aqueous gel consisting a salting-out agent in it as electrolytes such as magnesium chloride, calcium chloride, and magnesium acetate, or non- electrolytes such as sucrose. Importance of technique depends upon the type of salting out agent used, as it play an important property of encapsulating efficiency of the drugs because the solvent and the salting out agent are then eliminated by cross-flow filtration⁽¹⁴⁾

DOUBLE EMULSION AND EVAPORATION METHOD:

The emulsion and evaporation method suffer from the limitation of poor entrapment of hydrophilic drugs. There fore to encapsulate hydrophilic drug the double emulsion technique is employed, which involves the addition of aqueous drug solutions to organic polymer solution under vigorous stirring to form w/o emulsions. This w/o emulsion is added into second aqueous phase with continuous stirring to form the w/o/w emulsion. The emulsion then subjected to solvent removal by evaporation and nano particles can be isolated by centrifugation at high speed.⁽¹¹⁾Double emulsions are complex systems, also called “emulsions of emulsions”, in which the droplets of the dispersed phase contain one or more types of smaller dispersed droplets themselves. Double emulsions have the potential for encapsulation of both hydrophobic as well as hydrophilic drugs.⁽¹⁵⁾

EMULSIONS- DIFFUSION METHOD:

The mechanism of formation of polymer nanoparticles prepared by the emulsification-diffusion method was evaluated under different preparation conditions and by turbidimetry measurements. The encapsulating polymer is dissolved in a partially water-miscible solvent (such as propylene carbonate, benzyl alcohol), and saturated with water to ensure the initial thermodynamic equilibrium of both liquids. Subsequently, the polymer-water saturated solvent phase is emulsified in an aqueous solution containing stabilizer, leading to solvent diffusion to the external phase and the formation of nanospheres or nanocapsules, according to the oil-to-polymer ratio. Finally, the solvent is eliminated by evaporation or filtration, according to its boiling point. (16)

SOLVENT DISPLACEMENT / PRECIPITATION METHOD: SOLVENT:

displacement involves the precipitation of a preformed polymer from an organic solution and the diffusion of the organic solvent in the aqueous medium in the presence or absence of surfactant. Polymers, drug, and or lipophilic surfactant are dissolved in a semipolar water miscible solvent such as acetone or ethanol. The solution is then poured or injected into an aqueous solution containing stabilizer under magnetic stirring. Nanoparticles are formed instantaneously by the rapid solvent diffusion.⁽¹¹⁾

NANOPARTICLES TARGETING STRATEGIES:

There are two major tumor targeting strategies, passive and active targeting.

PASSIVE TARGATING:

In passive targeting, macromolecules including nanoparticles accumulate preferentially in the neoplastic tissues as a result of the enhanced permeability and retention (EPR) phenomenon. The EPR is based on the nanometer size range of the nanoparticles and two fundamental characteristics of the neoplastic tissues, namely, the leaky vasculature and impaired lymphatic drainage.passive targeting is based on the retention effect of particle of certain hydrodynamic size in cancerous tissue so the cancers tissue of tumor location.it will be having a leaky blood vessels and also have enhance retantion effect due to that Nanoparticles wiill go and bind only to the tumerlocation.leaky blood vessels of tumor cells will allow the Nanoparticles to accumulate in the tumer location and it will release the drug and kill the tumer cells. (17)

ACTIVE TARGETING:

In case of active targeting, nanoparticles containing the chemotherapeutic agents are designed in such a way as they directly interact with the defected cells. Active targeting is based on molecular recognition. Hence, the surface of the nanoparticles is modified to target the cancerous cells. Usually, targeting agents are attached with the surface of nanoparticles for molecular recognition. Designed nanoparticles target the cancerous cells either by ligand-receptor interaction or antibody-antigen recognition. Nanotechnology based targeted delivery system has three main components: (i) an apoptosis-inducing agent (anticancer drug), (ii) a targeting moiety-penetration enhancer, and (iii) a carrier. A variety of substances are used to construct a nanoparticle. Commonly used materials include ceramic, polymers, lipids, and metals (7)

CHARACTERIZATION OF NANOPARTICLES:

Nanoparticles are generally characterized by their size, morphology and surface charge, using such advanced microscopic techniques as scanning electron microscopy (SEM), transmissionelectron microscopy (TEM) and atomic force microscopy (AFM). The average particle diameter, their size distribution and charge affect the physical stability and the in vivo distribution of the nanoparticles. Electron microscopy techniques are very useful in ascertaining the overall shape of polymeric nanoparticles, which may determine their toxicity.

TRANSMISSION ELECTRON MICROSCOPE:

TEM operates on different principle than SEM, yet it often brings same type of data. The sample preparation for TEM is complex and time consuming because of its requirement to be ultra thin for the electron transmittance. The nanoparticles dispersion is deposited onto support grids or films.⁽¹¹⁾TEM forms a major analysis method in a range of scientific fields, in both physical and biological sciences. TEMs fin application in cancer research, virology, materials science as well as pollution, nanotechnology, and semiconductor research.⁽⁹⁾

SCANNING ELECTRON MICROSCOPY:

A conventional scanning electron microscope operated in transmission mode (TSEM) was used for imaging silica, gold and latex nanoparticles. Particles were applied to conventional transmission electron microscope (TEM) grids with different supporting films. A semiconductor detector capable of accomplishing both bright-field and dark-field imaging was used to record transmitted electrons. Particle diameter was determined from the images by comparing measured data with the results of corresponding Monte Carlo simulations which took into account particle and instrument propertie.⁽¹⁸⁾

DYNAMIC LIGHT SCATTERING (DLS):

DLS is widely used to determine the size of Brownian nanoparticles in colloidal suspensions in the nano and submicron ranges. Dynamic light scattering (DLS), also known as photon correlation spectroscopy (PCS), is a very powerful tool for studying the diffusion behaviour of macromolecules in solution. The diffusion coefficient, and hence the hydrodynamic radii calculated from it, depends on the size and shape of macromolecules.⁽¹⁹⁾

APPLICATION OF NANOPARTICLE IN CANCER TREATMENT:

Today Cancer still remains a major cause of mortality and death worldwide, in humans. (20) Nanomedicines have been investigated for the targeted delivery of drugs to treat a large variety of diseases. (21) Nanoscale devices smaller than 50nm can easily enter most cells, and those smaller than 20nm can move out of blood vessels as they circulate through the body. Nanodevices are suitable to serve as customized, targeted drug delivery vehicles to carry large doses of chemotherapeutic or therapeutic genes into malignant cells while sparing healthy cells. The greatest immediate impact of nanotechnologies in cancer therapy is in drug delivery. Nanoparticles attached to chemotherapeutic drugs allow them to traverse the blood-brain barrier for brain tumor treatment. (3) Historically, combination chemotherapy has been the primary choice of treatment. However, chemotherapeutics have pharmaceutical limitations, among which include problems with stability and aqueous solubility. Likewise, dose limiting toxicity is significant with nonspecific toxicity to healthy cells, hair loss, loss of appetite, peripheral neuropathy and diarrhea being typical side effects. The emergence of Multidrug resistance (MDR) also presents a significant challenge for the successful treatment of cancer whereby cancer cells become cross resistant to many of the chemotherapeutic agents used. Nanotechnology presents a new frontier for cancer treatment. It holds potential in minimizing systemic toxicity through the development of functionalized particles for targeted treatment. They also provide an alternative strategy to circumvent multidrug resistance as they have a capacity to by-pass the drug efflux mechanism associated with this phenotype. Aside from the advantages they offer in treatment, nanoparticles are also emerging to be valuable diagnostic entities. (22) Targeting molecules, such as antibodies, small molecular weight ligands, or aptamers, attached to the surface of nanocarriers contribute to drug delivery to the tumors, thus allowing specific binding to tumoral cells by the nanocarriers. However, the need of additional structures which are necessary for the stealth effect so as to exhibit selective tumor distribution along with the binding of targeting molecules for the targeting effect become the nanocarrier design in a highly challenging task. (23)

NANOPARTICLE-BASED COMBINATION THERAPY TOWARD OVERCOMING DRUG RESISTANCE IN CANCER:

The use of multiple therapeutic agents in combination has become the primary strategy to treat drug resistant cancers. However, administration of combinatorial regimens is limited by the varying pharmacokinetics of different drugs, which results in inconsistent drug uptake and suboptimal drug combination at the tumor sites. Conventional combination strategies in aim to maximize therapeutic efficacy based on maximum tolerated dose does not account for the therapeutic synergism that is sensitive to both dosing and scheduling of multiple drugs. In the development of multidrug-loaded nanoparticles against drug resistant cancers⁽²⁴⁾

NOVEL DOXORUBICIN-MITOMYCIN C CO ENCAPSULATED NANOPARTICLE FORMULATION EXHIBITS ANTICANCER SYNERGY IN MULTI RESISTANT HUMAN BREAST CELL:

Anthracycline-containing treatment regimens are currently the most widely employed regimens for the management of breast cancer. These drug combinations are often designed based on non-cross resistance and minimal overlapping toxicity rather than drug synergism. Moreover, aggressive doses are normally used in chemotherapy to achieve a greater therapeutic benefit at the cost of more acute and long-term toxic effects. To increase chemotherapeutic efficacy while decreasing toxic effects, rational design of drug synergy-based regimens is needed. Our previous work showed a synergistic effect of doxorubicin (DOX) and mitomycin c (MMC) on murine breast cancer cells in vitro and improved efficacy and reduced systemic toxicity of DOX-loaded solid polymer-lipid hybrid nanoparticles (PLN) in animal models of breast cancer. Herein we have demonstrated true anticancer synergy of concurrently applied DOX and MMC, and have rationally designed PLN to effectively deliver this combination to multidrug resistant (MDR) MDA435/LCC6 human breast cancer cells. DOX-MMC Co-loaded PLN were effective. DOX-MMC co-loaded PLN were effective in killing MDR cells at 20-30-fold lower doses than the free drugs. This synergistic cell killing was correlated with enhanced induction of DNA double strand breaks that preceded apoptosis. Importantly, co- encapsulation of dual agents into a nanoparticle formulation was much more effective than concurrent application of single agent-containing PLN, demonstrating the requirement of simultaneous uptake of both drugs by the same cells to enhance the drug synergy. The rationally designed combination chemotherapeutic PLN can overcome multidrug resistance at a significantly lower dose than free drugs, exhibiting the potential to enhance chemotherapy and reduce the therapeutic limitations imposed by systemic toxicity⁽²⁵⁾

liposomal doxorubicin (Doxil™/Caelyx™) was the first anti-cancer nanomedicine approved by the FDA in 1995. Doxil™/Caelyx™ achieves a differential distribution of doxorubicin versus the free drug and is now approved for several indications based on improved safety with equivalent or superior efficacy versus standard therapies. In patients, Doxil™ has achieved a nearly 300-fold increase in area under the curve, relative to free doxorubicin, although this includes free (bioavailable) and liposome-encapsulated (non-bioavailable) doxorubicin. (26)

CONCLUSION:

Nanocarriers as drug delivery systems are designed to improve the pharmacological and therapeutic properties of conventional drugs. The present pharmaceutics is often characterized by poor bio-availability which far too often results in higher patient costs and inefficient treatment but also, more importantly, increased risks of toxicity. Nanotechnology focuses on the very small and it is uniquely suited to creating systems that can better deliver drugs to tiny areas within the body. Nano enabled drug delivery also makes it possible for drugs to permeate through cell walls, which is of critical importance to the expected growth of genetic medicine over the next few years. Due to the lack of drug availability adverse side effects and drug resistance, the conventional therapy failed to achieve proper treatment of cancer. Nano- technology has great potential to radically improve current approaches to the diagnosis and treatment of patients with various types of cancer.

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Received on 30.03.2020 Modified on 21.04.2020

Res. J. Pharmacognosy and Phytochem. 2020; 12(3):168-173.

DOI: 10.5958/0975-4385.2020.00028.X