Nano-oncology, the application of Nanomedicine to cancer diagnosis and treatment, has the potential to transform clinical oncology by enhancing the efficacy of cancer chemotherapy for a wide spectrum of invasive cancers. It achieves this by enabling novel drug delivery systems which target the tumour site with several functional molecules, including tumour-specific ligands, antibodies, cytotoxic agents, and imaging probes simultaneously thereby improving tumour response rates in addition to significant reduction of the systemic toxicity associated with current chemotherapy regimens. For this reason, nano-oncology is attracting considerable scientific interest and a growing investment by the global pharmaceutical industry. Several therapeutic nano-carriers have been approved for clinical use and others are undergoing phase II and III clinical trials. This paper describes the current approved formulations, such as liposomes and polymeric nanoparticles, and discusses the overall present status of nano-oncology as an emerging branch of nanomedicine and its future perspectives in cancer and therapy.
Nanotechnology is defined as the development of small devices in a range of 1 to 100 nm. Such nano-structures/devices can offer to the clinical practice of medicine in general, and to oncology in particular, many potentially significant and desirable applications which address unmet clinical needs [
These nano-structures by virtue of the quantum effects acquire at the nanoscale unique physical and chemical properties not present at their macroscale. Additionally, by virtue of molecular scale, they are able to interact with biological systems at cellular level.
The current focus of new technologies is to design and develop novel pharmaceutical formulations or drug carriers, which are both size- and site-specific aimed at targeted delivery of the active drug to the tumour site whilst evading clearance by the reticuloendothelial system (RES).
The ideal
Such CDDSs overcome the problems encountered when cytotoxic agents are administrated systemically as these chemotherapeutic drugs lack specificity and thus cause significant damage to noncancerous tissues (systemic toxicity), including bone marrow suppression, hair loss (alopecia) and gut mucosal damage. Lack of specificity for cytotoxicity of these drugs is further compounded by escalating doses required in chemotherapy for solid cancers because of their rapid excretion and low therapeutic index [
Goals of targeted nanoscale drug delivery systems.
Characteristic of an ideal carrier for cancer therapy: | |
Biocompatible and biodegradable | |
Facilitate cellular uptake and intracellular trafficking | |
Retain the drug at the target site for the desired period of time | |
Protect the drug from the degradation and from premature | |
clereance | |
Ensure minimal drug leakage during transit to target | |
Decrease drug localisation in sensitive, non target tissue | |
Increase drug localisation in the tumour | |
(a) Passive targeting | |
(b) Active targeting |
The following sections provide an overview of the arsenal of most promising nano-carriers, underlined by their current established clinical usage and evaluation in on-going clinical trials.
Liposomes have a long history as drug carrier systems because of their easy preparation, acceptable toxicity, and biodegradability profiles [
Because liposomes are of the order of 400 nm in size they are rapidly cleared by mononuclear phagocytic system (MPS) which requires preliminary opsonisation by the immune system. A useful method for evading opsonisation of carriers was developed at Rutgers University in the 1960s by a process called PEGylation: a biocompatible polymer, poly(ethylene glycol) (PEG; [CH2CH2O]n), is conjugated to the drug carrier [
Liposomes can be classified as first generation or naked liposomes with an unmodified phospholipid surface, second generation or stealth liposomes with a layer of hydrophilic carbohydrates or polymers, usually PEG, onto the surface of the vesicles, and third generation liposomes that incorporate surface ligands to improve the therapeutic index of the drug by increasing the selectivity and the specificity of the complex. Figure
Diagram of bilayered membrane structure. The internal core entraps hydrophilic drug, while lipid soluble drugs are entrapped between the hydrophobic tails of the phospholipids. The outer surface can be functionalized with PEG and ligands for active targeting.
Delivery devices made from biodegradable polymers are an attractive option as carriers of therapeutic drugs in cancer therapy. Polymeric nanoparticles (NPs) (Figure
A schematic representation of polymeric particle as drug carrier: drug is entrapped in polymeric matrix and functional moieties lead to active targeting.
Polymeric micelle core-shell structure and drug encapsulation (reproduced from [
Synthetic polymers, which include poly(lactic acid) (PLA) [
When systemically administered, nanoparticles are generally more stable than liposome but are limited by poor pharmacokinetic properties that is, uptake by the RES. As with liposomes, the surface of nanoparticles can be coated with molecules, or intercalated into their structure, to increase pharmacokinetics and even enable targeting for delivery and imaging purpose [
Polymeric micelles are biodegradable spherical nano-carriers with a usual size range of 10–200 nm. They are formed by self-assembly of block copolymers consisting of two or more polymer chains with different hydrophobicity. These copolymers spontaneously assemble to form a core-shell structure in an aqueous media to minimize the system’s free energy (Figure
Micelles are considered ideal drug delivery vehicles because they provide a set of important advantages. The hydrophobic core can be used to carry pharmaceuticals, especially lipophilic drugs which are solubilized and physically entrapped in the inner region with high loading capacity. It must be remembered that hydrophobic drugs can only be administered intravenously after addition of solubilizing adjuvants like ethanol or Cremophor EL, which often induce toxic side effects. The incorporation of these drugs in micelles avoids the use of adjuvants. The hydrophilic shell not only provides a steric protection that increases micellar stability in blood, but also provides functional groups suitable for further micelle modification. Polymeric micelles can simultaneously codeliver two or more therapeutic agents and are capable of releasing drugs in a regulated manner. The encapsulated drugs can be released through erosion of the biodegradable polymers, diffusion of the drug through the polymer matrix, or polymer swelling followed by drug diffusion. External conditions such as change of pH and temperature can also induce drug release from micelles. Moreover, the surface modification of micelles with ligands such as antibodies, peptides, or other small molecules can be used for targeted delivery and uptake of these nano-carriers, thereby reducing their systemic toxicity and improving their specificity and efficacy [
Dendrimers are spherical, highly branched, and synthetic macromolecules with adjustable size and shape. They contain multiple layers with active end groups, also known as generations, that extend outwards from an initiator core called generation zero (Figure
Structure of a dendrimer.
The most commonly studied dendrimers belong to the family of PAMAM (polyamidoamine) dendrimers. These polymers have shown great potential for drug delivery because they are biodegradable and biocompatible and have high water solubility [
Gold nano-shells are nanospheres composed of an ultrathin layer of gold around a dielectric core, typically silica. The size of these nanoparticles ranges from 50 to 500 nm in diameter but the outer shell can be only few nanometers thick. Gold nano-shells have peculiar optical properties due to their unique interaction with light and related to a nanotechnological phenomenon known as surface plasmon resonance (SPR). In this process, the conducting surface electrons of the metal nano-shell oscillate collectively in the presence of the oscillating magnetic field of light. After absorption of radiation, the surface plasmon decays radiatively resulting in light emission or nonradiatively as heat. The SPR effect depends on nanoparticle size and shape (Figure
Extinction spectra of gold nano-shells depending on the core: shell diameter ratio (reproduced from [
Gold nano-shells can be used for medical applications because they are resistant to corrosion, are physiologically inert and thus quite safe [
The ability of gold nano-shells to scatter light can also be used for imaging, thus allowing the detection and diagnosis of cancer. In particular, gold nano-shells have been useful as
SPIOs are nanoparticles usually composed of Fe3O4 (magnetite) with a size of less than 20 nm [
Like gold nano-shells, SPIOs are attracting particular interest as hyperthermia agents for cancer thermal ablation. It is known that oscillating magnetic fields (in the range of kHz–MHz) applied to SPIOs result in generation of heat because of the great relaxation loss of the single magnetic domain. Energy can be dissipated through Brownian relaxation (heat due to total particle oscillation) or Neél relaxation (heat due to the rotation of the magnetic moment in the oscillating magnetic field) [
The peculiar magnetic properties of SPIOs can also be useful for cancer diagnosis and detection by magnetic resonance imaging (MRI), an important medical imaging technique depending on signals from water protons of the body. By virtue of their large magnetic moment, SPIOs can enhance image contrast in MRI, thus producing distinct images and allowing the discrimination between neoplastic and healthy tissues. Several SPIOs have been in long established clinical use as contrast agents for MRI [
Many liposomal formulations of anticancer drugs have been approved for human use and are already available on market. The list of the cytotoxic agents marketed for clinical use by various pharmaceutical companies are shown in Table
Examples of liposomes available on the market and in clinical use.
Composition | Trade name | Company | Indication | Administration |
---|---|---|---|---|
Liposomal daunorubicin | DaunoXome | Gilead Sciences | Kaposi’s sarcoma | intravenous |
Stealth liposomal doxorubicin | Doxil/Caelyx | Ortho Biotech, Schering-Plough | Kaposi’s Sarcoma; refractory ovarian cancer; refractory breast cancer | intramuscular |
Liposomal doxorubicin | Myocet | Zeneus | Metastatic breast cancer in combination with cylophosphamide | intravenous |
Liposomal muramyl Tripeptide phosphatidyl Ethanolamine | MEPACT | Taked | Osteosarcoma | intravenous |
Cytarabine | Depocyt | SkyePharma PLC | Lymphomatous meningitis | intrathecal |
Liposomal vincristine | Onco-TCS | Inex Enzon | Non-hodgking lymphoma | intravenous |
The first liposome formulations approved by the regulatory authorities were Doxil and Myocet. Both products contain the cytotoxic drug doxorubicin, a chemotherapeutic agent used widely in the treatment of breast, ovarian, bladder, and lung cancers. The two liposomal formulations, Myocet and Doxil, differ in PEG coating: Doxil is a PEG-liposome formulation designed to prolong blood circulation time. Free doxorubicin has an elimination half-life time of 0.2 h. This value is prolonged to 2.5 h and 55 h for Myocet and Doxil, respectively (Table
Values for half-life and AUC for two liposomal formulations and free doxorubicin.
Half-life time | AUC | |
---|---|---|
Free doxorubicin | 0.2 h | 4 |
Myocet | 2.5 h | 45 |
Caelyx/Doxil | 55 h | 900 |
Liposomal encapsulation and consequently polymer coating can substantially affect a drug’s functional properties relative to those of the unencapsulated drug. Harris et al., have reported on the advantages of Myocet over free doxorubicin in terms of cardiotoxicity by evaluating two parameters: the incidence of cardiac events and congestive heart failure with significant decrease of cardiac events and congestive cardiac failure of 16% and 6%, respectively [
Effect of Myocet on cardiotoxicity than free doxorubicin.
Incidence of cardiac events | Congestive Heart failure | |
---|---|---|
Free doxorubicin | 29% | 8% |
Myocet | 13% | 2% |
Myocet is currently used in the chemotherapy of breast cancer in combination with other chemotherapeutic agent (cyclophosphamide). Doxil is used to treat women with metastatic breast cancer who have an increased risk of heart damage, in patients with advanced ovarian cancer and in AIDS-related Kaposi's sarcoma.
Other liposomal systems have been approved and are currently on the market such as MEPACT, DepoCyt and Onco-TCS. MEPACT is a liposomal formulation of mifamurtide, an immune modulator proposed for clinical use in adjuvant chemotherapy of children and young adults with high grade resectable non-metastatic osteosarcoma.
DepoCyt, used in the treatment of lymphomatous meningitis, is a sustained-release liposomal formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF). Onco-TCS is a non-PEGylated liposomal formulation (about 50 nm in diameter) of daunorubicin and vincristine. DaunoXome is a liposomal preparation of daunorubicin, formulated to maximize the selectivity of daunorubicin in AIDS related Kaposi's sarcoma. As with Myocet, both the pharmacokinetic parameters and incidence of side effects are decreased by DaunoXome (Tables
Pharmacokinetic parameters of DaunoXome compared to free daunorubicin.
Half-life time (h) | Plasma Clereance (mL/min) | |
---|---|---|
Conventional daunorubicin | ||
DaunoXome |
Comparative toxicity (neuropathy and alopecia) of DaunoXomeand free daunorubicine.
Neuropathy (%) | Alopecia (%) | |
---|---|---|
Conventional daunorubicin | 41 | 36 |
DaunoXome | 13 | 8 |
Drug-encapsulated liposomes dominate clinical trials designed to study the effects of these CDDS in overcoming rapid clearance from the blood by phagocytic cell of the RES and thus improving the therapeutic index.
The main liposome formulations currently in clinical trials are listed in Table
Liposomes in clinical trials.
Compound | Name | Status | Indication |
---|---|---|---|
Liposomal cisplatin | SPI-77 | Phase III | Non-small cell lung cancer |
Liposomal interleukin 2 | Oncolipin | Phase I | Non-hodgking lymphoma |
Liposomal annamycin | L-Annamycin | Phase I | Acute lymphocytic leukemia |
Liposomal oxaliplatin | Aroplatin | Phase II | Advanced colorectal cancer |
Liposomal lurtotecan | OSI-211 | Phase II | Ovarian cancer |
Cationic liposomal c-Raf AON | LErafAON | Phase I/II | Various |
Cationic liposomal EI A pDNA | PLD-EIA | Phase I/II | Breast, Ovarian |
Thermosensitive liposomal doxorubicin | Thermodox | Phase III | Breast, liver |
Aroplatin is a novel liposomal third generation formulation of cisplatin (platinum). Its antitumour activity has been demonstrated in the treatment of colorectal cancer. SPI-77, a pegylated liposomal formulation of cisplatin developed specifically to reduce systemic toxicity and improve cisplatin delivery, is currently undergoing a phase III clinical trial [
A new targeting strategy consisting in “activable” nano-carrier is also being evaluated in a clinical trial. The liposomal formulation developed by Needham and Dewhirst’s groups at Duke (USA) underwent further pharmaceutical development by the biopharmaceutical company Celsion, which has now reached the stage of phase III clinical trial and is marketed as Thermodox. Two main studies are currently on-going combining Thermodox with hyperthermia in patients with loco-regional breast carcinoma of the chest wall and Thermodox with radiofrequency ablation in patients with primary or metastatic liver cancer. Results of these trials have not yet been published. However, the reported results to date have indicated the need for confirmatory clinical phase III trials in patients with liver cancer patients (
Another strategy adopted to increase the accumulation of liposomes in the desired tumour tissue is by attaching targeting ligands such as antibodies, peptides, and small molecules (i.e., folate, transferrin) to the liposome surface. The targeted liposome formulations involved in clinical trials are summarized in Table
Examples of targeted liposome in clinical trials.
Compound | Therapeutic agent | Status | Targeting agent |
---|---|---|---|
MCC-465 | Doxorubicin | Phase I | F(ab’)2 fragment of human antibody GAH |
MBP-426 | Oxaliplatin | Phase II | Transferrin |
SGT-53 | Plasmid DNA with p53 gene | Phase I | Transferrin receptor antibody fragment |
CALAA-01 | Small interfering RNA | Phase I | Transferrin |
Two examples of liposomal formulations for targeted drug/gene delivery are MBP-426 and SGT-53, which are currently undergoing phase I and phase II of clinical trials. They utilize transferrin and an antitransferrin receptor single-chain antibody fragment as targeting moieties, respectively.
MBP-426, transferrin-conjugated liposomal oxaliplatin formulation, was developed to improve the safety and efficacy of oxaliplatin through the prolongation of drug plasma circulation time and thus bioavailability and by targeting transferrin receptor on tumour cell.
Many human tumours possess loss or mutation of wild-type p53 (wtp53). In addition to playing a crucial role in cell cycle control, the p53 gene is a critical component in two of the pathways involved in regulating tumor cell growth: cell death (apoptosis) and the regulation of angiogenesis. The loss of such critical tumour suppressor activity is believed to be responsible for p53's involvement in such a broad array of human tumors and resistance to chemo/radiotherapy. SGT-53 is a complex composed of a wild-type p53 gene (plasmid DNA) encapsulated in a liposome that is targeted to tumor cells by means of an antitransferrin receptor single-chain antibody fragment (TfRscFv) attached to the outside of the liposome.
The majority of polymeric nanoparticles are still in preclinical phase of development but have potential for targeted drug delivery of anticancer drugs owing to the ease with which ligands can be attached (Table
Examples of polymeric nanoparticles in clinical trials.
Compound | Name | Status | Indication |
---|---|---|---|
Albumin-paclitaxel | Abraxane | Approved | Metastatic breast cancer |
Doxorubicin | Transdrug | Approved | Hepatocarcinoma |
Paclitaxel | Nanoxel | Phase I | Advanced breast cancer |
Paclitaxel | Paclimer | Phase I | Various |
Albumin-bound nanoparticles of paclitaxel (Abraxane) have been successfully used to deliver paclitaxel for the treatment of metastatic breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. The advantages with the use of Abraxane include (i) albumin is nontoxic and well tolerated by immune system because it is a plasma protein (molecular weight of 66 kDa); (ii) its use eliminates the need for toxic solvent (Cremophor EL polyoxyethylated castor oil) which has been shown to limit the dose of Taxol that can be administered [
In cancer chemotherapy, a multitude of pre-clinical studies on polymeric micelles has been published, which have shown that micelle-based drug delivery is advantageous over free drug delivery in laboratory animals, resulting in less adverse effects and toxicity to nontargeted areas. To-date, five products for anticancer therapy has been investigated in clinical trials, of which Genexol-PM has FDA approval for use in patients with breast cancer (Table
Polymeric micelles in clinical trials.
Polymeric micelle | Block copolymer | Drug | Diameter (nm) | Indication | Clinical phase |
---|---|---|---|---|---|
NK012 | PEG-PGlu(SN-38) | SN-38 | 20 | Breast cancer | II |
NK105 | PEG-P(aspartate) | Paclitaxel | 85 | Advanced stomach cancer | II |
SP1049C | Pluronic L61 and F127 | Doxorubicin | 22–27 | Adenocarcinoma of esophagus, gastro esophageal junction and stomach | III |
NC-6004 | PEG-PGlu(cisplatin) | Cisplatin | 30 | Solid tumors | I/II |
Breast cancer | I | ||||
Pancreatic cancer | V | ||||
Genexol-PM | PEG-P(D,L-lactide) | Paclitaxel | 20–50 | Non-small-cell lung cancer in combination with carboplatin | II |
Pancreatic cancer in combination with gemcitabine | I/II | ||||
Ovarian cancer in combination with carboplatin |
Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel (Taxol) consisting of two block copolymers: poly-(ethylene glycol), which is useful as a non-immunogenic carriers, and the core-forming poly-(D,L-lactide) that allows the solubilization of the hydrophobic drug. Preclinical
In this paper, we have focused on the main achievements obtained with organic and inorganic nanoparticles in cancer therapy, but we must also consider their drawbacks, current limitations, and the important challenges for the future development of nano-oncology. Additionally, aspects of higher performance, nanosafety, and regulatory issues need to be addresses in the near future.
The first requirement relates to improvement of the targeting efficacy of nano-vectors to specific cancers and their immediate microenvironment in order to concentrate delivery of the cytotoxic agents to the tumor site. Targeting methods involve the conjugation of specific recognition molecules to the surface of nano-vectors. Another requirement is the development of effective triggers for release of the cytotoxic drugs, for example, nano-carriers which release their payload of active drugs at the intended site by external energy (e.g., light and electromagnetic fields) or environmentally responsive by conditions preferentially expressed at tumor site (e.g., low pH) [
The ideal system would be attained by the design and development of “smart” multifunctional nanoparticles concurrently able to image, target, and treat tumours imaging (Figure
Structure of a smart multifunctional nanoparticle (reproduced from [
Before this can be materialized, however, there is an urgent need to resolve the outstanding issues relating to safety of nanoparticles and material, which have to be engineered for biocompatibility, biodegradability, and nontoxicity to enable safe use in patients. Unfortunately, little is known about the fate of nanoparticles in human body. As the size and surface properties of nano-vectors allow them to reach locations denied to larger particles, their bio-distribution may be different from the expected and may result in accumulation in nontarget organs (such as liver, spleen and bone marrow), with possible undesired toxic effects [
Additionally, as with many applications in the nanofield, currently there is no internationally agreed regulation and legislation related to the development and subsequent clinical introduction of nanobased drug delivery systems [
Research is essential to the future progress of nanomedicine and the realization of its potential in the treatment of various life-threatening disorders and others which severely impair the quality of life, and this research should encompass all aspects of nanosafety rather than the more limited field of nanotoxicity. The European Union has recognized the importance of this by establishing the “Nanosafety Network”, by commissioning various reports and inclusion of Health Technology Assessment (HTA) calls within its more recent invitation for research projects within Framework 7 Programme. The two key issues are thus (i) improved knowledge on nanosafety and improved methods of HTA which, in addition to the conventional HTA measures, include additional nano-technology-related outcome measures. In turn these measures should provide the basis for effective regulation of newer nanomedicine products for healthcare.
Aside from regulatory and safety issues the translation of nanomedical products into clinical practice will remain restricted until the current limitations such as their selectivity, efficacy in protected drug carriage and release at the intended are resolved or improved by basic biological and in-vivo animal studies. Their full potential will then be realized as standard drug delivery systems for routine cancer chemotherapy. With the progress made in this field to-date, it is likely that in the not-distant future, nanoparticles-based approaches will usher a new era of personalized oncology, tailored to the phenotypical characteristics of the individual patient and his or her cancer—this is the ultimate objective for curative cancer chemotherapy and nano-oncology may be the means to provide this.
The authors acknowledge the grant support from EU FP6/CNR (NanoSci-E+ transnational call) for the MARVENE project (magnetic nanoparticles for nerve regeneration) and Fondazione Cassa di Risparmio di Pisa (CARIPI) for the NANODIAB-1 project (Role of multilayer nanoencapsulation, anti-inflammatory nano-structures, and selective nanoparticle-guided homing in human islet transplantation for the treatment of type 1 diabetes).