Cite this asKumar D, Sharma PK (2018) Nanoparticulate system for cancer therapy: An updated review. Int J Nanomater Nanotechnol Nanomed 4(2): 022-034. DOI: 10.17352/2455-3492.000027
Nowadays, pharmaceutical nanotechnology has been developed as the most emerging branch in the field of pharmacy. “Nanotechnology refers to the nanosize formulation. These nanoformulations may be used in treatment of various life-threading diseases like cancer. Due to the advantages of their nano size and shape, nanoformulations have been shown to be favorable drug delivery systems and may be useful for encapsulating and conjugating of drugs, enabling most precise tumor targeting and controlled release. Nanoparticle drug delivery system have several advantages such as enhanced intracellular infiltration, hydrophobic solubility, and drug circulation time and also reduce nonspecific uptake and toxic effect for cancer therapy. A large number of Nanoparticle technologies have been developed for cancer treatment to improve the therapeutic efficacy and safety for anticancer drugs. In this paper, we review the most significant advancement in pharmaceutical nanotechnologies with methods of preparation and their use in drug delivery for cancer therapy.
According to national nanotechnology initiative, Nanoparticles are structures of sizes ranging from 1 to 100 nm in at least one dimension. Nanoparticles properties like physicochemical and biological are more easily taken up by cell than larger molecules, so Nanoparticles may be more suitable as drug delivery system .
Now days Nanoparticulate system gained more importance than conventional dosage form in cancer therapy because conventional dosage form have more challenge to deliver the drug in adequate quantity to the tumor site. While Nanoparticulate system may be possibility to deliver chemotherapeutic drug at target site easily .
Chemotherapeutic drugs are toxic to cancer cell but their high toxicity and low specificity also destroyed the healthy cells. A possible strategy to overcome these problems or improve therapeutic efficacy and decrease their toxic effect is called Nanoparticles technology . The main object of these nanotechnologies is to transport proper amount of drug to desirable site and decreases toxic effect of drugs on other tissues .
In this review, we discussed Nanoparticles technologies and also focused on parameter for material selection for Nanoparticle and their advantages. These technologies include Liposomes, Polymer drug conjugates, Polymeric Nanoparticles, Micelle, Dendrimer, Polymersome, Protein Nanoparticles, Biological Nanoparticles, Inorganic Nanoparticles and Hybrid Nanoparticles.
Advantages of nanoparticles technologies in cancer therapy
Various studies show that Nanoparticles have ability to target to cancer cells without damaging healthy cells. So now a day Nanoparticles technologies are considered as superior drug delivery system in cancer therapy than other conventional dosage form. Target and enter into selective tissue at molecular level.
Increase cellular uptake and drug localization.
Accurate and selective drug delivery to cancerous cell without interaction with healthy cells
Providing large surface area
Providing high absorption rate
Less amount of dose required.
Decrease drug resistance.
To improve the uptake of poorly soluble drugs
Nanoparticles can better deliver drugs to tiny areas within the body.
Nanoparticles overcome the resistance offered by the physiological barriers in the body [5-7].
Factors affecting the selection of material for nanoparticles preparation are
Need of Nanoparticles size.
Drug properties such as stability and aqueous solubility
Desired drug release profile
Required surface charge of Nanoparticles
Biocompatibility and biodegradability
Toxicity and antigenicity of product .
Cancer is one of the most common problems and serious health issue in this world. Human body contains millions of tiny cells; these tiny cells are living units of the body. Cancer is a complex disorder that results from multiple genetic changes and cellular abnormalities . Genetic changes that cause cancer can be, Inherited from our parents, Person’s lifetime and Environmental exposures such as chemicals in tobacco, smoke, radiation, ultraviolet rays from the sun .
Liposome Nanoparticles: Liposomes were the first Nanoparticles technology applied in medicine in 1961 . Aim of liposomal drug delivery system to increase efficacy, decrease toxicity and easy administration . Liposomal Nanoparticles are most used Nanoparticles for cancer therapy, these are easily and self-assembled from amphiphilic lipid and excipients. The lipid part form a bilayer based on hydrophobic interaction with hydrophilic head groups. Hydrophobic drug molecules can be encapsulated in lipid bilayer and hydrophilic drug molecules can be encapsulated in aqueous phase . Drug release from liposomes depends on composition, pH, and osmotic gradient and surrounding environment . Lipids are used in these formulations are approved by FDA, that are DSPE (1, 2-distearoyl-sn-glycero-3-phosphoethanolamine), HSPE (hydrogenated phosphatidylcholine from soybean lecithin), EggPG (egg yolk phosphatidylglycerol), DSPC (1, 2-distearoyl-glycero-3-phosphocholine). Liposome Nanoparticles have demonstrated multiple special benefits as drug delivery system, such as used to carry very potent drug to their low encapsulated load, instability in blood stream and poor solubility of many drugs. Many times researchers reported various challenges during the production of liposome are difficult reproducing formulation process, uniform particle size, efficient drug loading, and time consuming process.
Types of liposomes: On the basis of phospholipid bilayer and the size of liposomes, these are following types [15-16].
Multilamellar Vesicles (MLV) - these types of liposomes are contains multiple number of phospholipid bilayer member separated by aqueous phase. The size of multilamellar vesicle liposomes may up to 5 μm.
Small Unilamellar Vesicles (SUV) - these types of liposomes are contains single phospholipid bilayer member surrounding the aqueous phase. The of Small unilamellar vesicles liposome may be in the range of 20-100 nm.
Large Unilamellar Vesicle (LUV) - these types of liposomes are also contain single phospholipid bilayer member surrounding the aqueous phase. The of Small unilamellar vesicles liposome may be in the range of 100-250 nm.
Polymer drug conjugates nanoparticles
The concept of polymer conjugates for anticancer agent was proposed in 1975 . Polymer drug conjugation achieved enhanced permeability and retention effect by tumor specific targeting .
Polymeric drug conjugation system is the most important and older polymeric drug delivery system. Polymer–drug conjugates are most advancement in the field of Nanoparticles technology and currently in clinical trials phase III. These Nanoparticles can deliver high dose of chemotherapeutic drugs because in which drug conjugates with polymer through side chain. The size of polymer conjugates is below 20 nm mostly. The way of conjugating the drug to the Nanoparticles and its strategy is most important in cancer therapy. A drug molecule may be encapsulated in Nanoparticles or covalently attached to surface of Nanoparticles. Covalent attaching strategy had more advantages than other ways . On the basis of various studies found that, application of Nanoparticles to tumor may be improved by the conjugated of polymer and drug moiety. These conjugations may allow more specific recognition and preferential interaction of drug to targeted tumor site .
The purpose of polymeric Nanoparticles was to develop Nanoparticles for prolonged drug delivery system . Polymeric Nanoparticles are flexible in design because of polymer properties such as biodegradable and non-biodegradable, synthetic and natural synthetic sources . Commonly used polymers are poly (lactic acid) (PLA), dextran, and chitosan . Polymer Nanoparticles can be used to improve the efficacy, toxicity, bioavailability, solubility and pharmacokinetics of a drug. These particles may reduce toxicity in tumors and improved therapeutic response . Polymeric Nanoparticles may offer encapsulation and delivery of bio-molecules for genetic medicine, immunotherapy and gene editing. Polymeric Nanoparticles offer the various advantages in cancer therapy but during the development of these particles some challenges affect the safety and efficacy of the polymer formulations . These challenges are process scalability, process reproducibility, particle size control and efficient drug loading. Drug can be encapsulated on polymeric Nanoparticles during polymerization step . Drugs may be released from polymeric Nanoparticles by desorption, diffusion, or Nanoparticle erosion in target tissue .
Micelles are self assemble Nanoparticles with hydrophobic core composed from lipid and polymers. Micelles are the best drug delivery system for hydrophobic drugs. Only those chemical have an amphiphilic nature can form micelles in aqueous solution . Micelles are generated when hydrophilic portions surrounding by hydrophobic phase. Micelles are most favorable drug delivery system for poorly water soluble drugs [29-31]. Pharmacokinetics properties of micelles were influenced by size of micelles Nanoparticles, generally accepted range of micelles is 50 – 150 nm, but larger the Nanoparticles size can carry more drug load because of high encapsulation volume . Transport properties of micelles may be influenced by shape of micelles Nanoparticles. Discs and rod shape micelles have more accepted blood circulation properties than spherical particles .
The word dendrimers derived from the Greek word “DENDRON” means tree and “MEROS” means part, so its appearance likes TREE. This technology discovered by Tomalia and coworker in early 1980. Dendritic polymers are newly recognized polymeric structure after linear, cross linked and branch polymer [34-35]. Dendrimers are repetitively branched molecules within the range of 5-10nm. They can be modified as required to carry the drug for targeting site . Dendimers serves suitable pharmacokinetic properties for systematic drug delivery. Structurally, dendrimers have three parts, namely a central core, tiers of multifunctional unit and terminal or end groups.
Dendrimers serves several properties those facilitated various biological applications as following [37-41].
Neutral and negative charge dendrimers are biocompatible while positive charge dendrimers may show toxic effects.
Structure of dendrimers may affect pharmacokinetics properties.
Retention and bio-distribution character may improve by increase water solubility and size of dendrimers by PEGylation.
Therapeutic agent can be attached to functional groups.
Can be modulated for target-specific drug delivery.
Feasibility to develop with defined molecular weight.
Good entrapment efficiency.
Offering surface for functionalization.
Very low polydispersity index.
Very low size (1–5 nm).
Structurally polymersomes are similar as liposomes but compositions are different, polymersome is composed of synthetic polymer/polypeptide amphiphiles and self-assembled. Liposomes drug delivery system is the most widely used drug delivery system for anticancer drug moieties but their short half-life and slow drug release required to develop new alternatives. Synthetic polymers are most promising candidates to exhibit longer half-life and better drug release [42-44], when polymer and liposomes technology works together to design Nanoparticles are called polymersomes Nanoparticles [45-47]. Resulted polymersome Nanoparticles have been shown long half-life, better drug release, enhanced stability and more side chain functioning . As liposomes, hydrophobic membrane and aqueous core of polymersome enables to encapsulate to both hydrophobic and hydrophilic drug moieties. Polymersome Nanoparticles technologies have ability to deliver both hydrophilic and hydrophobic drug in alone or combination .
Protein Nanoparticles are generally with 130 nm size. These particles bound drug with albumin to enhance intrinsic targeting abilities and permeability with retention effect at tumor site . Protein Nanoparticles have gained great attention in nanotechnology because of their low toxicity, biodegradability, metabolizable and easy amenable to surface modification for drug attachment . Various types of proteins are used to prepare protein nanotechnology are water soluble proteins such as bovine, human serum albumin and insoluble proteins such as zein and gliadin [52-53]. The most important advantage of protein Nanoparticles as drug carrier system may target the drug by modified body distribution and improvement of cellular uptake of the substances .
Biological Nanoparticles can be developed from organic and inorganic compounds based on natural biomolecules. Biological Nanoparticles derive from single or multiple assemblies of protein subunits . These are unicellular microorganism with various shapes and sizes. Biological Nanoparticles have capacity to bind with both hydrophilic and hydrophobic drug molecule . Biological Nanoparticles are divided in two categories are: a. delivery of small drug molecules for cancer treatment, b. gene therapy and vaccine applications. These systems are modified by chemical or genetic modification to achieve tumor specific delivery .
Various type of Nanoparticles are used as drug delivery such as silica Nanoparticles , quantum dots [59-60], metal Nanoparticles , and lanthanide Nanoparticles [62-63], Inorganic Nanoparticles are generally metal based particles. These may synthesized with near monodispersity. These Nanoparticles have ability to energy convert into heat at some specific conditions . Metallic Nanoparticles are used as drug delivery system since last few decades but now days this technology is a favorable drug delivery system for anticancer drugs because these technology have various advantages such as efficiency of drugs, biocompatibility, drug loading, nontoxic to normal cells and easily reached to targeted tumor sites. This technology used various metals to synthesized Nanoparticles like gold, silver, iron oxide. Gold Nanoparticles are synthesized in various size range but commonly used ranges are 2-100 nm. Cellular uptake of these particles is inversely prepositional to their size and larger particle i.e. 80-100 nm does not diffuse in to tumor site and stay near the blood vessels [65-66]. These particle sizes depend on the thiol/gold ratio during the synthesis, as the thiol amount increases particle size decreases [67-68]. In this era various types of gold Nanoparticles take place in research such as gold nanoshells, gold nanosphere, gold nanorods and gold nanocages . Another newest inorganic Nanoparticles technology for cancer therapy was developed as silver Nanoparticles.
Hybrid Nanoparticles are the advancement of liposome and micelles. These are composed of two different materials that form core and corona structure. Core contains metallic or polymeric material while corona contains lipid layer that worked as protecting membrane. As we have discussed in earlier in part of liposome that the drug moieties are attached on the surface of liposome or incorporated into hydrophilic phase to enhance retention time of drug to cancer cell. But at this time liposome decorated with paramagnetic molecules and enable to detection of angiogenesis [70-71]. So in these cases hybrid Nanoparticles technologies is required. Various types of inorganic material such as gold Nanoparticles and iron oxide Nanoparticles able to improve image contrast . That’s by gold Nanoparticles and iron oxide Nanoparticles are encapsulated in liposome, hydrophilic gold Nanoparticles are encapsulated in hydrophilic phase and hydrophobic gold Nanoparticles are inserted in hydrophobic membrane.
Advancement of nanoparticle preparation methods
The mode of preparation of Nanoparticles plays a vital role to achieve the properties of Nanoparticles. The selection of these methods depends on the physical and chemical properties of drug and polymer. Scientist worked from ancient time to prepare Nanoparticles via various methods and their modifications, these methods and their modifications are listed below.
Emulsion-Solvent evaporation method
This method is widely used method for preparation of Nanoparticles. This method consist two steps a. emulsification of polymer solution into water phase b. evaporation of solvent until Nanoparticle precipitation. Prepared Nanoparticles are collected by ultracentrifugation as washed with distilled water  (Figure 1).
Modified Emulsion-Solvent Evaporation Method (Table 1).
Salting out method (Figure 2)
Modified Salting Out Method (Table 2)
Solvent/emulsions diffusion method (Figure 3)
Modified Solvent/emulsions diffusion method (Table 3)
Dialysis method (Figure 4)
Modified Dialysis method (Table 4)
Precipitation method (Figure 5)
Modified Precipitation Method (Table 5)
Patent filled by inventors to prepared nanoparticles
Researchers developed new formulations and their methods to achieve their goals, latest worked done by various researchers listed here (Table 6).
As summarized above, new scientific approaches serves advanced technologies and overcome various challenges i.e toxicity, absorption, tumor site targeting, solubility, drug resistance, dose requirement etc. The ultimate goal of developing new technologies should be change the way of cancer treatment and overcome the challenges. Development of Nanoparticles drug delivery system is a future hope with great impact on cancer treatment approaches. Because researchers realize that Nanoparticles drug delivery may be stabilized to treat various type of cancer. Nanoparticles as drug delivery system are prepared to improve therapeutic and pharmacological properties of conventional drug delivery system. Drug molecule incorporated in Nanoparticles offers controlled release and possibilities to targeting to tumor site as well as protection of drug from degradation. Drug conjugations with Nanoparticles are more effective and selective and low toxic to healthy cells as well as required low therapeutic dose. Nowadays, various Nanoparticles based drug delivery is currently under preclinical evaluation phases. Some of Nanoparticle technologies have few limitations but these have possibility to improve with small modifications.
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