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DOI : 10.2240/azojono0114

Multi-Functional Nanoparticles and Their Role in Cancer Drug Delivery – A Review

Priya Pathak and V. K. Katiyar

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This is an AZo Open Access Rewards System (AZo-OARS) article distributed under the terms of the AZo–OARS http://www.azonano.com/oars.asp which permits unrestricted use provided the original work is properly cited but is limited to non-commercial distribution and reproduction.

Submitted: April 10, 2007

Posted: May 11, 2007

Topics Covered

Abstract

Introduction

The Evolution of Nanotechnology

The Vision for Nanoparticles in the Treatment of Cancer

World Scenario: Case of Cancer

The Incidence of Cancer in Our Society

Factors Effecting the Incidence of Cancer

Projected Growth of Cancer in the Future

Structure and Functional Properties of Nanoparticles

Size, Toxicity, Status and Application of Nanoparticles in Cancer Treatment

Types of Biomedical Nanoparticles

Multifunctional Nanoparticles

Lipid/Polymer Nanoparticles

Gold / Magnetic Nanoparticles

Virus Based Nanoparticles

Dry Powder Aerosol

Nanomedicine

Drug Delivery for Cancer Treatment

Drug Delivery Strategies Used to Fight Cancers

Pathways of Nanoparticles in Cancer Drug Delivery

Characteristic Nanoparticles Used for Drug Delievry in Cancer Treatment

The Role of Nanoparticles in Cancer Drug Delivery

Nanodevices: Detection and Cure

Cantilevers

Nanopores

Nanotubes

Quantum Dots (QDs)

Nanoshells

Dendrimers

Biodegradable Hydrogels

Future Herbal Nanoparticles for Cancer

Development and Commercialization of Nanomaterials

Companies Involved with the Commercialization of Nanomaterials for Bio- and Medical Applications

Conclusion

Acknowledgement

References

Contact Details

Abstract

Nanomaterials are at the cutting edge of the rapidly developing area of nanotechnology. The potential for nanoparticles in cancer drug delivery is infinite with novel new applications constantly being explored. Multifunctional nanoparticles play a very significant role in cancer drug delivery. The promising implications of these platforms for advances in cancer diagnostics and therapeutics form the basis of this review.

In the first part, we examine cancer on the world stage, nanoparticles and their structure, functional properties, biomedical applications, nanomedicine, cancer drug delivery and drug delivery strategies using nanoparticles. In the second part, we focus on the various pathways available for cancer drug delivery and the role of nanoparticles in cancer drug delivery. In last part, the use of nanodevices in detection and imaging of cancer are discussed along with the commercialization of nanomaterials. The review provides recent advances in cancer drug delivery.

Introduction

Cancer has a physiological barrier [1,2] like vascular endothelial pores, heterogeneous blood supply, heterogeneous architecture etc. For a treatment to be successful, it is very important to get over these barriers. Cancer represents an enormous biomedical challenge [3] for drug delivery. Cancer treatment is very much dependent on the method of delivery. In the past, cancer patients were using various anticancer drugs, but these drugs were less successful and had major side effects. Nanoparticles have attracted the attention of scientists because of their multifunctional character. The treatment of cancer using targeted drug delivery nanoparticles is the latest achievement in the medical field. 

The Evolution of Nanotechnology

The Nanoscale was initially used by R. P. Feynman, a physicist. In his talk, 1959, called “There’s plenty of room at the bottom. But there’s not that much room - to put every atom in its place - the vision articulated by some nanotechnologists - would require magic fingers”. He was one of the first people to suggest that scaling down to nano level and starting from the bottom was the key to future technology and advancement [4, 5].

The Vision for Nanoparticles in the Treatment of Cancer

In ancient Greek ‘Nano’ means dwarf [6]. Nanotechnology is the creation and utilization of materials, devices, and systems through the control of matter on the nanometer-length scale, i.e. at the level of atoms, molecules, and supramolecular structures. These technologies have been applied to improve drug delivery and to overcome some of the problems of drug delivery for cancer treatment. Several nanobiotechnologies mostly based on nanoparticles, have been used to facilitate drug delivery in cancer. The magic of nanoparticles mesmerize everyone because of their multifunctional character and they have given us hope for the recovery from this disease. Although we are practicing better drug delivery paths into the body, we ultimately seek more accurate protocols to eradicate cancer from our society.

This review focuses on progress in treatment of cancer through delivery of anticancer agents via nanoparticles. In addition, it pays attention to development of different types of nanoparticles for cancer drug delivery.

World Scenario: Case of Cancer

The Incidence of Cancer in Our Society

With more than 10 million new cases every year, cancer has become one of the most devastating diseases worldwide [7]. In 2000, it has been reported by The World Health Organization (WHO), malignant tumors were responsible for 12 per cent of the nearly 56 million deaths worldwide from all causes. Over 22 million people in the world were treated for cancer in 2000, representing an increase of approximately 19 percent in incidence (cases) and 18 percent in mortality since 1990. In many countries, more than a quarter of deaths are attributable to cancer.

Factors Effecting the Incidence of Cancer

In 2000, 5.3 million men and 4.7 million women developed a malignant tumor and altogether 6.2 million died from the disease. The report also reveals that cancer has emerged as a major public health problem in developing countries, matching its effect in industrialized nations. The predicted sharp increase in new cases from 10 million new cases globally in 2000, to 15 million in 2020 9will mainly be due to steadily ageing populations in both developed and developing countries and also to current trends in smoking prevalence and the growing adoption of unhealthy lifestyles.

Projected Growth of Cancer in the Future

In 2005, a total of 7.6million people died of cancer. More than 11 million people are diagnosed with cancer every year. It is estimated that there will be 16 million new cases every year by 2020. Cancer causes 7 million deaths every year or 12.5% of deaths worldwide. Some 60% of all these new cases will occur in the less developed parts of the world. Global cancer rates are expected to increase 50 percent by the year 2020, according to the latest report from the International Agency for Research on Cancer (IARC), a branch of the World Health Organization.

Structure and Functional Properties of Nanoparticles

A nanometer is one-billionth of a meter (10-9 m); a sheet of paper is about 100,000 nanometers thick. These nanoparticles give us the ability to see cells and molecules that we otherwise cannot detect through conventional imaging. The ability to pick up what happens in the cell, to monitor therapeutic intervention and to see when a cancer cell is mortally wounded or is actually activated is critical for the successful diagnosis and treatment of this disease.

For drug delivery in cancer we have “Nano scale devices”.  Nanoscale devices [8] are 102 to 104 times smaller than human cells but are similar in size to large biomolecules such as enzymes and receptors. Nanoscale devices smaller than 50 nm can easily enter most cells, and those smaller than 20 nm 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. According to The National Cancer Institute, Nanoparticulate technology can prove to be very useful in cancer therapy allowing for effective and targeted drug delivery by overcoming the many biological, biophysical and biomedical barriers that the body stages against a standard intervention such as the administration of drugs or contrast agents. Nanoscale constructs can serve as customizable, targeted drug delivery vehicles capable of ferrying large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells, greatly reducing or eliminating the often unpalatable side effects that accompany many current cancer therapies. Several nanotechnological approaches have been used to improve delivery of chemotherapeutic agents to cancer cells with the goal of minimizing toxic effects on healthy tissues while maintaining antitumor efficacy. Some nanoscale delivery devices, such as dendrimers (spherical, branched polymers), silica-coated micelles, ceramic nanoparticles, and cross linked liposomes can be targeted to cancer cells. This increase the selectivity of drugs towards cancer cells can and will reduce the toxicity to normal tissue [9].

Size, Toxicity, Status and Application of Nanoparticles in Cancer Treatment

Nanoparticle size, toxicity, status and application [10] are discussed in Table 1.

Table 1. Nanoparticle size, toxicity, status and application.

Nanoparticle

Size

Toxicity

Status

Application

Liposome

100-200nm

Low

Clinical use

Delivery

Small polymer

~200kDa

Low

Research

Delivery

Dendrimer

2-6nm depending on generation number

Variable depending on cell type

Phase I

Delivery

Virus

30-100nm

High

Phase II

Delivery

Hybrid System

 

 

 

 

QD – Virus

Variable

-

Research

Imaging delivery

Metal core dendrimers

2-4nm for gold

-

Research

Delivery

Nanoshells

60-400nm

Non-toxic

Research

Imaging, treatment

Quantum Dots

2-10nm

Toxic

Commercial

Sensing, Imaging

Carbon nantoubes

 

Expected to be non-toxic

Research

Delivery, sensing

Single-walled

1-2nm diameter, variable length

 

 

 

Multi-walled

20-25nm diameter, variable length

 

 

 

Nanowires

Variable length/diameter

NA

Research

Sensing

Types of Biomedical Nanoparticles

Although the number of different type of nanoparticles is increasing rapidly, most can be classified into two major types. Particles that contain organic molecules as a major building material and those that use inorganic elements, usually metals, as a core

•        Inorganic nanoparticles

•        Organic nanoparticles

Liposomes, dendrimers, carbon nanotubes, emulsions, and other polymers are a large and well-established group of organic particles. Use of these organic nanoparticles [11] has already produced exciting results. Liposomes are being used as vehicles for drug delivery in different human tumors, including breast cancer. Dendrimers, used in MRI as contrast agents, have aided visualisation of various pathological processes. Conjugated with pharmacological agents and targeting molecules, organic nanovectors are potent vehicles for drug delivery and selective imaging of different human cancers. Most inorganic nanoparticles share the same basic structure. This consists of a central core that defines the fluorescence, optical, magnetic, and electronic properties of the particle, with a protective organic coating on the surface [11]. This outside layer protects the core from degradation in a physiologically aggressive environment and can form electrostatic or covalent bonds, or both, with positively charged agents and biomolecules that have basic functional groups such as amines and thiols. Several research groups have successfully linked fluorescent nanoparticles to peptides, proteins, and oligonucleotides.

Multifunctional Nanoparticles

Nanoparticles have a further advantage over larger microparticles, because they are better suited for intravenous (i.v.) delivery. The smallest capillaries in the body are 5–6 mm in diameter. The size of particles being distributed into the bloodstream must be significantly smaller than 5 mm, without forming aggregates, to ensure that the particles do not form an embolism. Nanoparticles can be used to deliver hydrophilic drugs, hydrophobic drugs, proteins, vaccines, biological macromolecules, etc. They can be formulated for targeted delivery to the lymphatic system, brain, arterial walls, lungs, liver, spleen, or made for long-term systemic circulation. Therefore, numerous protocols exist for synthesizing nanoparticles based on the type of drug used and the desired delivery route. Once a protocol is chosen, the parameters must be tailored to create the best possible characteristics for the nanoparticles.

Four of the most important characteristics of nanoparticles are their size, encapsulation efficiency, zeta potential (surface charge), and release characteristics. Different nanoparticles have been discussed below.

Lipid/Polymer Nanoparticles

Positively charged lipid-based nanoparticles are known to trigger strong immune responses when injected into the body. This can be problematic when attempting to use this type of nanoparticle as a drug delivery vehicle. Lipid-based cationic nanoparticles [12] are a new promising option for tumor therapy, because they display enhanced binding and uptake at the neo-angiogenic endothelial cells, which a tumor needs for its nutrition and growth. By loading suitable cytotoxic compounds to the cationic carrier, the tumor endothelial and consequently also the tumor itself can be destroyed. For the development of such novel anti-tumor agents, the control of drug loading and drug release from the carrier matrix is essential. Structural investigation of drug/lipid membranes may give valuable information about the organization of drugs in lipid matrices. Screening of different matrices for a given drug may be useful for fast and efficient optimization of drug/lipid combinations in pharmaceutical development. In a new therapeutic approach, targeted drug delivery is performed not to the tumor itself, but to the neo-angiogenic blood vessels that the tumor stimulates to grow for its nutrition. This procedure is based on the observation that cationic liposomes show enhanced binding and uptake at tumor endothelial cells. In this context Munich Biotech AG has developed a series of cationic, lipid based, nanoparticulate agents for tumor therapy and diagnosis. The therapeutic agents consist of a cytotoxic compound, such as Paclitaxel, which is loaded into the lipid matrix of the cationic carrier. For efficient development of such pharmaceutical formulations, it is useful to obtain an insight into the physico-chemical constraints of drug loading and drug release from the lipid matrix. Structural investigation of drug/lipid membranes, for example by X-ray scattering techniques, can give valuable information about the organization of a drug in the membrane, and it can help to optimize a lipid matrix with respect to its solubilizing potency of a given drug. In this work, attention was given to the organization of Paclitaxel in matrices of cationic and zwitterionic lipid membranes. Polymeric nanoparticle, are stable and non-phototoxic upon systemic administration. Upon cellular internalization, the photosensitizer is released from the nanoparticle and becomes highly phototoxic. Irradiation with visible light results in cell-specific killing of several cancer cell lines [13]. 

Gold / Magnetic Nanoparticles

In practice, gold nanoparticles are the most commonly used nanoparticles for diagnostics and drug delivery. The unique chemical properties of colloidal gold make it a promising targeted delivery approach for drugs or gene specific cells. Gold and silica composite nanoparticles have been investigated as nanobullets for cancer [14,15]. Researchers are also using magnetic nanoparticles for cancer drug delivery. The use of magnetic nanoparticles [16] in cell biology was first proposed in the early 1990s, and their use has made the separation of cells or molecules such as proteins, peptides and DNA considerably easier.

In medicine, nanoparticles first found use in the diagnosis of tumors in the liver and spleen using magnetic resonance tomography.  In cancer therapy a major difficulty is to destroy tumor cells without harming the normal tissue. Radiotherapy attempts to focus irradiation on the tumor, but nevertheless damages healthy tissue which cannot always be protected in the desired way. Magnetic drug targeting employing nanoparticles as the carrier is a promising cancer treatment avoiding side effects of conventional chemotherapy [17]. There is also a very significant role of hyperthermia in cancer drug delivery .There is increasing evidence that hyperthermia at 40–43°C enhances the uptake of therapeutic agents into cancer cells and provides an opportunity for improved targeted drug delivery[13]. Using nanoparticles (NPs) for drug delivery of anticancer agents [18] has significant advantages such as the ability to target specific locations in the body, the reduction of the overall quantity of drug used, and the potential to reduce the concentration of the drug at non target sites resulting in fewer unpleasant side effects.

Furthermore, certain type of nanoparticles showed some interesting capacity to reverse multi drug resistance (MDR) which is a major problem in chemotherapy. The use of nanoparticles as drug delivery vehicles for anticancer therapeutics has great potential to revolutionise [19] the future of cancer therapy. As tumor architecture causes nanoparticles to preferentially accumulate at the tumor site, their use as drug delivery vectors results in the localization of a greater amount of the drug load at the tumor site; thus improving cancer therapy and reducing the harmful nonspecific side effects of chemotherapeutics. In addition, formulation of these nanoparticles with imaging contrast agents provides a very efficient system for cancer diagnostics.  

Virus Based Nanoparticles

In the latest research development virus-based nano-particles are being extensively investigated for nanobiotechnology applications [20, 21, 22, 23]. Viruses [10] have long been envisaged as nanoparticle vectors suitable for drug delivery, vaccines, and gene therapy. Recently, viruses have been explored as nano-containers for specific targeting applications. However these systems typically require modification of the virus surface using chemical or genetic means to achieve tumor-specific delivery. The latest technology developed engineered virus (nanoparticles) for cancer treatment [21]. Viruses by their extraordinarily nature are well-defined nanoparticles, and several teams of investigators are taking a cue from nature and developing non-infectious, engineered viral nanoparticles for use as multifunctional nanoscale devices.

The plant virus known as (CPMV) cowpea mosaic virus (CPMV and FHV are among the smallest viruses with diverse nanostructures extensively investigated, and are strategically more suitable for rapid dispersal within tumors than adenoviruses three times their size) has become a research favorite, in large part because it is relatively easy to produce in large amounts, and the virus is benign to humans and other animals. In addition, researchers have developed methods of altering the virus’s coat protein to give it chemical functionality that might be useful for adding targeting and drug delivery capabilities to these nanoparticles. Now, there’s another reason to study CPMV particles as potential biomedical nanodevices. M. Manchester, M.G. Finn, and their colleagues at the Scripps Research Institute have shown that CPMV nanoparticles can pass intact through the stomach’s hostile environment and be taken into the bloodstream through the intestines. As a result, CMPV nanoparticles could provide a means of administering anticancer drugs and tumor imaging agents orally, rather than by injection. This work appeared in the journal Virology. In most studies, researchers produce CPMV nanoparticles using a system that makes just the proteins that the virus uses to make its outer shell – these proteins self-assemble to make the virus’s shell. But to learn what would happen to CPMV particles as they pass through the digestive system, the researchers used the fully formed virus, complete with its RNA genetic material. Having the RNA present allowed the investigators to use PCR-based technology to detect a very small number of particles no matter what part of the body they reached. Indeed, after feeding mice cowpea leaves infected with the virus, the investigators found virus particles distribute widely throughout the animal’s bodies. Subsequent studies using analytical techniques to detect the virus coat proteins confirmed that the virus particle, and not just its genetic material, had passed through the stomach, been absorbed through the intestines, and distributed itself throughout the animal. Nearly identical results were obtained when the virus was injected directly into the bloodstream of the test animals, supporting the idea that virus particles were able to pass through the intestines unaltered. In vitro experiments also showed that engineered CPMV particles are stable in conditions that mimic the acidic conditions of the stomach. Taken together, these data sets support the notion that engineered, synthetic plant virus particles could prove useful in delivering drugs and imaging contrast agents to tumors. Previous work by the Manchester and Finn groups has already shown that it is possible to attach tumor-targeting molecules to the surface of engineered viral nanoparticles and to load various drug-type molecules into the interior of the virus particles.

A research team from Yonsei University uses a genetically-engineered form of the adenovirus, which normally causes colds. The adenovirus was implanted with a human gene that is related to the production of relaxin, a hormone associated with pregnancy. When injected into cancerous tumors, the virus quickly multiplies in the cancer cells and kills them. The new adenovirus can target only cancer cells and does not harm normal cells [24].

Dry Powder Aerosol

An approach regarding drug delivery has been taken by Dr. Lobenberg, University of Alberta, i.e. a lung cancer treatment using nanoparticles in dry powder aerosol form. Drug-loaded nanoparticles carried by dry powders [25] showed a concentration related increased cytotoxicity in vitro. This study supports the approach of local lung cancer treatment using nanoparticles as a drug delivery vector. The development of inhalable nanoparticles loaded with bioactive molecules is a new delivery platform which can allow targeting of lung specific diseases in the future. Loebenberg explained that the drug sits in powder form in the inhaler, which is similar to the device that asthmatics use.

Nanomedicine

When we think about nanomedicine then the first thing that comes to our mind is exactly why nanomedicine?

One of the main goals of nanomedicine is to create medically useful nanodevices that can function inside the body. Additionally, nanomedicine will have an impact on the key challenges in cancer therapy such as localized drug delivery and specific targeting. Among the recently developed nanomedicine and nanodevices, quantum dots, nanowires, nanotubes, nanocantilevers, nanopores, nanoshells and nanoparticles are potentially the most useful for treating different types of cancer. Nanoparticles [9] can be in the form of nanospheres (matrix systems in which drugs are dispersed throughout the particle) and nanocapsules (where the drug is confined in an aqueous or oily cavity surrounded by a single polymeric membrane). Nanomedicines [26] are a recent off-shoot of the application of nanotechnology to medical and pharmaceutical challenges, but have in fact been around for much longer in the guise of drug delivery systems. Nanomedicines that facilitate uptake and transport of therapeutically active molecules (‘delivery systems’) tend to be based on supramolecular assemblies of drug and functional carrier materials. The use of nanomedicines facilitates the creation of dose differentials between the site of the disease and the rest of the body, thus maximizing the therapeutic effect while minimizing non-specific side-effects. Nanomedicine, the use of nanometer-sized particles and systems to detect and treat diseases at the molecular level plays an essential role in achieving the federal governments stated goal of eliminating suffering and death from cancer, the second leading cause of death in the United States, by 2015 [27].

Drug Delivery for Cancer Treatment

Core features of cancer cell

                   ----Abnormal growth control

                                 ----- Improved cell survival

                                        ----Abnormal differentiation

                                                ----Unlimited replicated potential

                                                      ----Host-tumor symbiosis  

Transport of an anticancer drug in interestium [28] will be governed by physiological (i.e. pressure) and physiochemical (i.e. composition, structure and charge) properties of the interestium and by the physiochemical properties of molecules (size, configuration, charge and hydrophobicity) itself. Thus, to deliver [9] therapeutic agents to tumor cells in vivo, one must overcome the following problems:

•        Drug resistance at the tumor level due to physiological barriers (non cellular based mechanisms),

•        Drug resistance at the cellular level (cellular mechanisms),

•        Distribution, biotransformation and clearance of anticancer drugs in the body.

A strategy could be to associate antitumor drugs with colloidal nanoparticles, with the aim to overcome non-cellular and cellular based mechanisms of resistance and to increase selectivity of drugs towards cancer cells while reducing their toxicity towards normal tissues. There are different drug delivery strategies that have been used to fight with cancer which are discussed in this paper.

Drug Delivery Strategies Used to Fight Cancers

There are a variety of different delivery strategies [29] that are either currently being used or are in the testing stage to treat human cancers (Table2) which are discussed in this paper.

Table 2. Different drug delivery strategies.

Variety of different drug delivery strategies

Direct Introduction of anticancer drugs into tumor

•        Injection Directly into the tumor

•        Tumor necrosis therapy

•        Injection into the arterial blood supply of cancer

•        Local injection into the tumor for radiopotentiation

•        Localized delivery of anticancer drugs by electroporation (Electrochemotherapy)

•        Local delivery by anticancer drugs implants

Routes of Drug delivery

•        Intraperitoneal

•        Intrathecal

•        Nasal

•        Oral

•        Pulmonary inhalation

•        Subcutaneous injection or implant

•        Transdermal drug delivery

•        Vascular route: intravenous, intra-arterial

Systematic delivery targeted to tumor

•        Heat-activated targeted drug delivery

•        Tissue-selective drug delivery for cancer using carrier-mediated transport systems

•        Tumor-activated produrg therapy for targeted delivery of chemotherapy

•        Pressure-induced filtration of drug across vessels to tumor

•        Promoting selective permeation of the anticancer agent into the tumor

•        Two-step targeting using bispecific antibody

•        Site-specific delivery and light-activation of anticancer proteins

Drug delivery targeted to blood vessels of tumor

•        Antiangiogenesis therapy

•        Angiolytic therapy

•        Drugs to induce clotting in blood vessels of tumor

•        Vascular targeting agents

Special formulations and carriers of anticancer drugs

•        Albumin based drug carriers

•        Carbohydrate-enhanced chemotherapy

•        Delivery of proteins and peptides for cancer therapy

•        Fatty acids as targeting vectors linked to active drugs

•        Microspheres

•        Monoclonal antibodies

•        Nanoparticles

•        Pegylated liposomes (enclosed in a polyethylene glycol bilayer)

•        Polyethylene glycol (PEG) technology

•        Single-chain antigen-binding technology

Transmembrane drug delivery to intracellular targets 

•        Cytoporter

•        Receptor-mediated endocytosis

•        Transduction of proteins and Peptides

•        Vitamins as carriers for anticancer agents

Biological Therapies

•        Antisense therapy

•        Cell therapy

•        Gene therapy

•        Genetically modified bacteria

•        Oncolytic viruses

•        RNA interference

Pathways of Nanoparticles in Cancer Drug Delivery

Nanotechnology has tremendous potential to make an important contribution in cancer prevention, detection, diagnosis, imaging and treatment. It can target a tumor, carry imaging capability to document the presence of tumor, sense pathophysiological defects in tumor cells, deliver therapeutic genes or drugs based on tumor characteristics, respond to external triggers to release the agent and document the tumor response and identify residual tumor cells. Nanoparticles are important because of their nanoscaled structure but nanoparticles [30] in cancer are still bigger than many anticancer drugs. Their “large” size can make it difficult for them to evade organs such as the liver, spleen, and lungs, which are constantly clearing foreign materials from the body. In addition, they must be able to take advantage of subtle differences in cells to distinguish between normal and cancerous tissues. Indeed, it is only recently that researchers have begun to successfully engineer nanoparticles that can effectively evade the immune system and actively target tumors. Active tumor targeting of nanoparticles involves attaching molecules, known collectively as ligands to the outsides of nanoparticles. These ligands are special in that they can recognize and bind to complementary molecules, or receptors, found on the surface of tumor cells. When such targeting molecules are added to a drug delivery nanoparticle, more of the anticancer drug finds and enters the tumor cell, increasing the efficacy of the treatment and reducing toxic effects on surrounding normal tissues. Although the past 30 years of innovation in nanotechnology has removed much of the “magic” to yield 21st century “smart bombs” capable of carrying a whole host of new anticancer drugs directly to tumors, we are still searching for the ideal delivery nanosystem. Nanotechnology studies [31] are not new. In essence, all drug molecules can be considered as Nanoengineered structures. What is new is the inclusion of a number of other nano-based approaches to medical studies.

Characteristic Nanoparticles Used for Drug Delievry in Cancer Treatment

Characteristics [15] of nanoparticles used for drug delivery in cancer are discussed in Table-3.

Table 3. Characteristics of nanoparticles used for drug delivery for cancer.

Structure

Size

Role in drug delivery

Carbon magnetic Nanoparticles 

40-50 nm

For drug delivery and targeted cell destruction

Dendrimers

1-20 nm

Holding therapeutics substances such as DNA in their cavities

Ceramics Nanoparticles

~ 35 nm

Accumulate exclusively in the tumor tissue and allow the drug to act as sensitizer for photodynamics therapy without being released

Chitosan nanoparticles

110-180 nm

 

High encapsulation efficiency. In vitro release studies show a burst effect flowed by a slow and continuous release.

Liposomes

25-50 nm

A new generation of liposomes that incorporate fullerenes to deliver  drug that are not water soluble ,that tend to have large molecules

Low density lipoprotein

20-25 nm

Drug solublized in the lipid core or attached to the surface

Nanoemulsions

20-25 nm

Drug in oil/or in liquid phases to improve absorption

Nanolipispheres

25-50 nm

Carrier incorporation of lipophilic and hydrophilic drugs

Nanoparticles composites

~ 40 nm

Attached to guiding molecules such as Mabs for targeted drug delivery

Nanoparticles

25-200 nm

Act as continuous matrices containing dispersed or dissolved drug

Nanopill/micelle

20-45 nm

Made for two polymer molecules-one water-repellent and the other hydrophobic that self assemble into a sphere called a micelle that can deliver drugs to specific structures within the cell

Nanospheres

50-500 nm

Hollow ceramic nanospheres created by ultrasound

Nanovesicles

25-3000 nm

Single or multilamellar bilayer spheres containing the drugs in lipids

Polymer nanocapsules

50-200 nm

Used for enclosing drugs

The Role of Nanoparticles in Cancer Drug Delivery

Nanoparticles and other nanostructures appear to hold great promise for the future of cancer treatment. In experimental studies, primarily in animal models, nanoparticles appear to be able to selectively deliver high concentrations of antitumour drugs to tumor cells.  The high concentrations of toxic agents seem to persist for long periods within tumor cells and have more potent antitumour effects and less toxicity than their systematically administered counterparts. Nanoparticles are much more successful at delivering anticancer agents during drug delivery to cancer cells or tissues.

Cancer disease challenging nanoparticles may be defined as being submicronic (< 1 µm) colloidal systems generally, but not necessarily, made of polymers (biodegradable or not). According to the process used for the preparation of the nanoparticles, nanospheres or nanocapsules can be obtained. Unlike nanospheres (matrix systems in which the drug is dispersed throughout the particles), nanocapsules are vesicular systems in which the drug is confined to an aqueous or oily cavity surrounded by a single polymeric membrane. Nanocapsules may, thus, be considered as a ‘reservoir’ system. If designed appropriately, it may act as a drug vehicle able to target tumor tissues or cells, to a certain extent, while protecting the drug from premature inactivation during its transport. Indeed, at the tumor level, the accumulation mechanism of intravenously injected nanoparticles relies on a passive diffusion or convection across the leaky, hyperpermeable tumor vasculature. The uptake can also result from a specific recognition in the case of ligand decorated nanoparticles (‘active targeting’). Understanding and experience from other technologies such as Nanotechnology, Advanced Polymer Chemistry, and Electronic Engineering, are being brought together in developing novel methods of drug delivery. The current focus in development of cancer therapies [15] is on targeted drug delivery to provide therapeutic concentrations of anticancer agents at the site of action and to spare the normal tissues. Cancer drug delivery is no longer simply packaging the drug in new formulations for unlike routes of delivery. Targeted drug delivery to tumors can increase the selectivity for killing cancer cells, decrease the peripheral/systemic toxicity and can permit a dose escalation. So targeted drug delivery will be more advantageous. These days drug delivery using micro/nano particles has been shown to have great potentials for achieving controlled and targeted therapeutic effects. The carrier particles have specific transportation and extravasation [14] behaviors determined by their chemical structure, size, and surface properties etc. These characteristics are vital for the pharmacokinetics and pharmacodynamics of drugs being carried. To reach cancer cells in a tumor, a blood borne therapeutic molecule or cell must make its ways into the blood vessels of the tumor and across the vessel wall into interstitium, and finally migrate through the interstitium. For a molecule of given size, charge, and configuration, each of these transport processes may involve diffusion and convection [2]. In the year 2002, there was a very fascinating article published in Science entitled “Nanoparticles Cut Tumors’ Supply Lines”. In which, hungry tumors [32] need new blood vessels for sustenance to deliver the goods. Cancer researchers have spent years working to starve tumors by blocking this blood vessel growth, or angiogenesis, with mixed success. The researchers packed a tiny particle with a gene that forces blood vessel cells to self-destruct, then they “mailed” the particle to blood vessels feeding tumors in mice. This is the latest achievement in the field of cancer treatment which is giving new hope for cancer patients who are suffering from angiogenesis. Targeted drug delivery is an invaluable need in pharmacology. Such an approach is particularly important in tumor therapy as the compounds are very toxic, and if they act on cells other than tumor cells, severe side effects are encountered. Any means that enables the increase of the ratio of the drug, which is delivered to the target site, will help to reduce such side effects.

Nanodevices: Detection and Cure

“Smart” dynamic nanoplatforms have the potential to change the way cancer is diagnosed, treated, and prevented. There are two basic approaches for creating nanodevices. Scientists refer to these methods as the top-down approach and the bottom-up approach. The top-down approach involves molding or etching materials into smaller components. This approach has traditionally been used in making parts for computers and electronics. The bottom-up approach involves assembling structures atom-by-atom or molecule-by-molecule, and may prove useful in manufacturing devices used in medicine. Most animal cells are 10,000 to 20,000 nanometers in diameter. This means that nanoscale devices (less than 100 nanometers) can enter cells and the organelles inside them can interact with DNA and proteins. Tools developed through nanotechnology may be able to detect disease in a very small amount of cells or tissue. They may also be able to enter and monitor cells within a living body. In order to successfully detect cancer at its earliest stages, scientists must be able to detect molecular changes even when they occur only in a small percentage of cells.  This means the necessary tools must be extremely sensitive. The potential for nanostructures to enter and analyze single cells suggests they could meet this need.

Cantilevers

Nanoscaled cantilevers like springs are being developed using electron-beam lithography for an ultra sensitive bioassay. The flexible nature of the technology has the potential to offer high-throughput detection of proteins, DNA and RNA for a broad range of applications ranging from disease diagnosis to biological weapons detection. Through e-beam lithography [33] and lift-off processes, arrays of nano-cantilevers have been fabricated. These arrays can be used as non-invasive and ultra-sensitive bio-assays, and provide an opportunity to increase the sensitivity of detection of tumor-associated antigens with a smaller sample size and at much earlier stages of disease progression compared to current medical diagnostic technologies. Cantilevers can improve cancer detection and diagnosis. These tiny levers, which are anchored at one end, can be engineered to bind to molecules that represent some of the changes associated with cancer. They may bind to altered DNA sequences or proteins that are present in certain types of cancer. When these molecules bind to the cantilevers, surface tension changes, causing the cantilevers to bend.  By monitoring the bending of the cantilevers, scientists can tell whether molecules are present. Scientists hope this property will prove effective when cancer-associated molecules are present even in very low concentrations-making cantilevers a potential tool for detecting cancer in its early stages.

Nanopores

Another interesting nanodevice is the nanopore. Improved methods of reading the genetic code will help researchers detect errors in genes that may contribute to cancer. Scientists believe nanopores, tiny holes that allow DNA to pass through one strand at a time, will make DNA sequencing more efficient. As DNA passes through a nanopore, scientists can monitor the shape and electrical properties of each base, or letter, on the strand. Because these properties are unique for each of the four bases that make up the genetic code, scientists can use the passage of DNA through a nanopore to decipher the encoded information, including errors in the code known to be associated with cancer.

Nanotubes

Another nanodevice that will help identify DNA changes associated with cancer is the nanotube. Nanotubes are carbon rods about half the diameter of a molecule of DNA that can not only can detect the presence of altered genes, but they may help researchers pinpoint the exact location of those changes. Carbon nanotubes (CNTs) are remarkable solid state nanomaterials [34] due to their unique electrical [35] and mechanical properties [36]. The electronic properties of nanotubes combined with biological molecules such as proteins could make miniature devices for biological sensing applications. The research of carbon nanotube functionalization has intensified due to their great potential for biomedical and biotechnological applications. Organic modification of carbon nanotubes generate multiple sites for the attachment of bioactive molecules, and the modified nanotube could be used as a biosensor or a novel delivery system. Carbon Nanotubes Target Tumors [37] in the first experiment of its kind Investigators at the Center for Cancer Nanotechnology Response (CCNE-TR), based at Stanford University. Experiments have shown that single-walled carbon nanotubes (SWCNTs) wrapped in poly(ethylene glycol), or PEG, can successfully target tumors in living animals.

Quantum Dots (QDs)

Quantum dots [26] are unique in their far reaching possibilities in many avenues of medicine. A QD is a fluorescent nanoparticle that has potential to be used as a sensitive probe for screening cancer markers in fluids, as a specific label for classifying tissue biopsies and as a high resolution contrast agent for medical imaging, which is capable of detecting even the smallest of tumors. These particles have the unique ability to be sensitively detected on a wide range of length scales, from macroscale visualization, down to atomic resolution using electron microscopy. Using Quantum dots (QDs), the drug delivery particles are injected in to blood stream until they find the cancer cells, to which the antibodies adhere. Infrared light shining on the suspected cancer site penetrates the tissues and cause the quantum dots to radiate photons. The photons pinpoint the cancer cell’s location and also cause the release of the Taxol (an anticancerous drug), which can then attack and kill the cancer cells. Quantum dots are tiny crystals that glow when stimulated by ultraviolet light. The wavelength, or color, of the light depends on the size of the crystal. Latex beads filled with these crystals can be designed to bind to specific DNA sequences. By combining different sized quantum dots within a single bead, scientists can create probes that release distinct colors and intensities of light. When the crystals are stimulated by UV light, each bead emits light that serves as a sort of spectral bar code, identifying a particular region of DNA. The diversity of quantum dots will allow scientists to create many unique labels, which can identify numerous regions of DNA simultaneously. This will be important in the detection of cancer, which results from the accumulation of many different changes within a cell.  Another advantage of quantum dots is that they can be used in the body, eliminating the need for biopsy.  Nanotechnology may also be useful for developing ways to eradicate cancer cells without harming healthy, neighboring cells. Scientists hope to use nanotechnology to create therapeutic agents that target specific cells and deliver their toxin in a controlled, time-released manner.

Nanoshells

Nanoshells are layered colloids with a nonconducting nanoparticle [38] core covered by a thin metal shell, whose thickness can be changed to precisely tune the plasmon resonance. Proteins that bind only with tumor cells can be attached to the surface, creating tumor-seeking nanoparticles. By tuning the shells to strongly absorb 820 nm NIR light, where optical transmission through body tissue is optimal and harmless, low-power extracorporeally applied laser light shone at the patient induces a response signal from injected nanoshells clustered around a tumor. Increasing the laser power to a still moderately low exposure heats the nanoshells just enough to destroy the tumor without harming healthy tissue. On exposure to 35 W/cm2 NIR light, human breast carcinoma cells incubated with nanoshells in vitro undergo photothermally induced morbidity. Cells without nanoshells display no loss in viability. Likewise, in vivo studies under magnetic resonance guidance reveal that exposure to low-dose (4 W/cm2) NIR light in solid tumors treated with nanoshells incur a temperature increase of 37.4±6.6°C within 4-6 minutes. The tissue displays coagulation, cell shrinkage, and loss of nuclear staining, indicating irreversible thermal damage. Controls treated without nanoshells demonstrated significantly lower temperatures and appeared undamaged. Miniscule beads coated with gold are also Nanoshells. By manipulating the thickness of the layers making up the nanoshells, scientists can design these beads to absorb specific wavelengths of light. The most useful nanoshells are those that absorb near-infrared light, which can easily penetrate several centimeters of human tissue. The absorption of light by the nanoshells creates an intense heat that is lethal to cells.

Researchers can already link nanoshells to antibodies that recognize cancer cells. Scientists envision letting these nanoshells seek out their cancerous targets, then applying near-infrared light. In laboratory cultures, the heat generated by the light-absorbing nanoshells has successfully killed tumor cells while leaving neighboring cells intact. To achieve tumor-targeted drug delivery, nanoparticle systems must address technical and biological concerns that influence their distribution.

Dendrimers

Highly branched, monodisperse macromolecules [39] (Hyperbranched molecules) or “Dendrimers” were discovered in the early 1980’s by D. Tomalia and co-workers [40]. Dendrimers are a new class of polymeric materials. They have potential to link treatment with detection and diagnosis. Dendrimers are man-made molecules about the size of an average protein, and have a branched shape. This shape gives them vast amounts of surface area to which scientists can attach therapeutic agents or other biologically active molecules. A single dendrimer can carry a molecule that recognizes cancer cells, a therapeutic agent to kill those cells, and a molecule that recognizes the signals of cell death. Researchers hope to manipulate dendrimers to release their contents only in the presence of certain trigger molecules associated with cancer. Following drug release, the dendrimers may also report back whether they successfully killed their targets or not.  The structure of these materials has a great impact on their physical and chemical properties. As a result of their unique behavior dendrimers are suitable for a wide range of biomedical and industrial applications. Dendrimers are going to be very helpful in cancer treatment. Dendrimers can act as carriers, called vectors in gene therapy. Vectors transfer genes through the cell membrane into the nucleus. Currently liposomes and genetically engineered viruses have been mainly used for this purpose. The unique properties [41] of dendrimers, such as their high degree of branching, mutivalency, globular architecture and well defined molecular weight, make them promising new scaffolds for drug delivery. Recent progress has been made in the application of biocompatible dendrimers to cancer treatment, including their use as delivery systems for potent anticancer drugs such as cisplatin and doxorubicin, as wall as agents for both boron neutron capture therapy and photodynamics therapy. Although the additional effort required for the stepwise synthesis of large dendrimers means that these molecules must possess distinct advantages over their linear polymer analogs to be useful in practical terms. Recent research has shown that dendrimers do indeed have many unique features that warrant further exploration in drug discovery.

Biodegradable Hydrogel

One of the latest approaches towards drug delivery uses hydrogels. Hydrogels [42] can be used in various biomedical applications such as drug delivery systems, biosensors, contact lenses, catheters, and wound dressings. Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids. The networks are composed of homopolymers or copolymers, and are insoluble due to the presence of chemical crosslinks (tie-points, junctions), or physical crosslinks, such as entanglements or crystallites. Hydrogels exhibit a thermodynamic compatibility with water, which allows them to swell in aqueous media. They are used to regulate drug release in reservoir-based, controlled release systems or as carriers in swellable and swelling-controlled release devices. Researchers are using biodegradable hydrogels for cancer treatment.

Future Herbal Nanoparticles for Cancer

The whole world is practicing herbal medicine to avoid maximum side effects and for better treatment. The science of Ayurveda [43] is supposed to add a step on to curative aspects of cancers. There are many herbs like Aswagandha, Amla, Basil, Rakta vrntaka (Tomato), Neem, Turmeric etc with anticancerous properties. Antioxidants play an important role in mitigating the damaging effects of oxidative stress on cells. Lycopene, a carotenoid, has received considerable scientific interest in recent years. They have demonstrated a very special role in the curing of cancer. In the past several years, two lines of emerging evidence have supported a role for lycopene in the prevention of certain malignancies, especially prostate cancer [44]. Tomato is a rich source of lycopene [45]. The first, antioxidant properties of lycopene (Lycopersicon esculentum) have been established [46]. Given the relatively high concentrations of lycopene in the tissues of many individuals, and the potential role of oxidative stress in the formation or progression of cancers, a potential anticancer influence of lycopene has been hypothesized. Secondly, a number of epidemiologic studies have suggested that individuals with a relatively high intake of lycopene, particularly from tomato products, have a lower risk of prostate cancer [47]. In the future, the concept of herbal nanoparticles for cancer drug delivery may also fascinate some potential research groups and potentially create attention-grabbing results.

Development and Commercialization of Nanomaterials

Drug delivery techniques were established to deliver or control the amount, rate and, sometimes location of a drug in the body to optimize its therapeutic effect, convenience and dose. Combining a well established drug formulation with a new delivery system is a relatively low risk activity and can be used to enhance a company’s product portfolio by extending the drug’s commercial life-cycle. Although not exhausting, this is a representative selection reflecting current industrial trends. Most companies are developing pharmaceutical applications, mainly for drug delivery. Most major and established pharmaceutical companies have internal research programs on drug delivery that are on formulations or dispersions containing components down to nano sizes. With the total global investment in nanotechnologies currently at € 5 billion, the global market is estimated to reach over € 1 trillion by 2011-2015. Nano and Micro technologies are part of the latest advanced solutions and new paradigm for decreasing the discovery and development time for new drugs and potentially reducing the development costs.

Companies Involved with the Commercialization of Nanomaterials for Bio- and Medical Applications

Examples of companies [48] commercializing nanomaterials for bio- and medical applications are given in Table 4.

Table 4. Companies commercialising nanomaterials for bio- and medical applications.

Company

Major area of activity

Technology

Advectus Life Science Inc.

Drug delivery

Polymeric nanoparticles engineered to carry anti-tumor drug across the blood-brain barrier

Alnis Bioscinces,  Inc.

Bio-pharmaceutical

Biodegradable polymeric nanoparticles for drug delivery

Argonide

Membrane filtration

Nanoporous ceramic materials for endotoxin

Biophan Technologies, Inc.

MRI shielding

Nanomagnetic /carbon composite materials to shield medical devices from RF fields

Capsulation Nanoscience AG

Pharmaceutical coating to improve solubility of drugs

Layer-by-layer poly-electrolyte coating, 8-50 nm

Eiffel Technologies

Drug delivery

Reducing size of the drug particles to 50-100 nm

Evident Technologies

Luminescent biomarkers

Semiconductor quantum dots with amine or carboxyl groups on the surface, emission from 350-2500 nm

Immunicon

Tracking and separation of different cell type

Magnetic core surrounded by a polymeric layer coated with antibodies for capturing cell

NanoBio Cortporation

Pharmaceutical

Antimicrobial nano emulsions

NanoCarrier Co., Ltd

Drug delivery

Micellar nanoparticles for encapsulation of drugs, proteins, DNA

NanoPharm AG

Drug delivery

Polybutyilcyanocrylate nanoparticles are coated with drug and then with surfactant can go across the blood brain barrier

Nanoprobes, Inc.

Gold nanoparticles for biological markers

Gold nanoparticles bio-conjugates for TEM and/or fluorescent microscopy

Nanoshpere, Inc.

Gold biomarkers

DNA barcode attached to each nanoprobes for identification purposes, PCR used to amplify the signals, also catalytic silver deposition to amplify the signal using surface plasmon resonance

NanoMed Pharmaceutical, Inc.

Drug delivery

Nanoparticles for drug delivery

Conclusion

Nanotechnology is definitely a medical boon for diagnosis, treatment and prevention of cancer disease. It will radically change the way we diagnose, treat and prevent cancer to help meet the goal of eliminating suffering and death from cancer. Although most of the technologies described are promising and fit well with the current methods of treatment, there are still safety concerns associated with the introduction of nanoparticles in the human body. These will require further studies before some of the products can be approved. The most promising methods of drug delivery in cancer will be those that combine diagnostics with treatment. These will enable personalized management of cancer and provide an integrated protocol for diagnosis and follow up that is so important in management of cancer patients. There are still many advances needed to improve nanoparticles for treatment of cancers. Future efforts will focus on identifying the mechanism and location of action for the vector and determining the general applicability of the vector to treat all stages of tumors in preclinical models. Further studies are focused on expanding the selection of drugs to deliver novel nanoparticle vectors. Hopefully, this will allow the development of innovative new strategies for cancer cures.

Acknowledgement

The work is supported by Department of Science and Technology, India. Authors are very grateful for the hospitality of the Indian Institute of Technology Roorkee. Special thanks to Dr. Rakesh K. Jain, Andrew Werk Cook Professor of Tumor Biology for his literature help.

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Contact Details

Ms. Priya Pathak

Centre of Nanotechnology
Indian Institute of Technology Roorkee
Roorkee-247667, Uttarakhand
India

Email – Priya_biomath@yahoo.co.in

Prof. V. K. Katiyar

Dept. of Mathematics
Indian Institute of Technology Roorkee
Roorkee-247667, Uttarakhand
India

 

Date Added: May 14, 2007 | Updated: Jul 15, 2013
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