Liposomes and inorganic nanoparticles for drug delivery and cancer

Review

Liposomes and inorganic nanoparticles for drug delivery and cancer imaging

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Recently, there have been several advancements in material sciences and nanosciences. At the moment these new techniques are slowly entering into clinical settings in drug delivery and imaging. In this review we will look more closely at the applications that are at the forefront of this translation and examine critical aspects that are involved in the process. Nanoparticles have been increasingly used in clinical settings for drug delivery over the past two decades. Lipid-based nanoparticles are front-runners of the technology, but other innovative strategies, such as small inorganic nanoparticles, are entering to the field, in particular for imaging applications. Lipid-based nanoparticles can be metabolized and consumed by the body and are regarded as safe for clinical use. Lipid-based particles are usually large with hydrodynamic diameters of approximately 100–200 nm; however, phospholipid-containing particles such as microbubbles with diameters as low as 10 µm in size and micelles with diameters of 10–40 nm can also be used. Hollow liposomes with a large aqueous inner cavity can carry high payloads of drugs and imaging moieties, but can result in lower tissue penetration rates and are easily trapped by liver kupffer cells. New classes of particles with hydrodynamic diameters of 40 kDa and nanoparticles accumulate nonspecifically in areas with increased vascular permeability such as tumors and inflamed tissue. This future science group

Liposomes & inorganic nanoparticles for drug delivery & cancer imaging However, phagocytosis has been used to track macrophages nonspecifically. of targeting & therapeutic moieties Nanodelivery systems consist of a carrier to which targeting and therapeutic moieties are attached. Cohesion of the three components can be affected by, for example, enzymatic cleavage or environmental conditions such as pH, primarily leading to the release of moieties conjugated to the surface of the nanocarriers. However, integrity of the ligand–drug matrix entity is a prerequisite for targeted delivery. If the drug disintegrates from its carrier, adverse side effects may increase or the local dose may decrease. If the ligand that ensures specific binding of the nanoprobe is released, only nonspecific events, for example those based on the EPR effect, will provide accumulation in tumors or inflamed tissue. All of these potential events can endanger efficient therapy. Therefore, stability of any new nanocarrier has to be proven in vivo.

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of payload release An integral feature of targeted therapy is the release of the therapeutic moieties at the site of interest. This can be achieved by incorporation and digestion of the nanocarriers by the diseased cells, by enzymatic activation of a prodrug conjugated to the carrier surface, or by diffusion of the drug out of the carrier matrix. However, balance of safe encapsulation during systemic passage and sufficient release at the site of action is not trivial. This issue can be addressed by conjugating the active moieties to the surface, but it has to be proven that the drug is still active after the conjugation procedure, that it is not cleaved off in the circulation (see above), and that the adverse side effects caused by ectopic activity are tolerable. Nanodelivery systems that are activated at the site of action by disease-specific reactions would be favorable.

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process is described as the enhanced permeation and retention (EPR) effect [9,10] . It was shown that the EPR effect alone is sufficient to visualize subcutaneous tumors in a mouse model nonspecifically by positron emission tomography imaging [11] , and the EPR effect is the main mechanism by which the clinically used liposomal formulations of drugs accumulate in tumors [10–15] . The majority of tumor vessels have been reported to have an average pore size ranging from 380 to 780 nm, which limits the upper size of the EPR effect-based drug delivery but also all the targeted systems that rely on specific targeted drug-delivery relaying to the tumor-cell binding. Nevertheless, endothelial cells provide targets for larger specific nanoparticles [18,19] . Although useful for passive accumulation of drugs or imaging agents in tumors or areas of inflammation and cancer, the EPR effect increases the nonspecific background significantly for any specific approach. Elaborate controls are needed to distinguish between effects caused by specific targeting or by EPR. There is data available demonstrating that the amount of EPR effect depends mainly on the physicochemical characteristics of the macromolecules/ nanoparticles and less on the tumor morphology and vascularization [10] . However, more data is needed to fully understand the underlying mechanisms, and potentially use the EPR effect in a more sophisticated way for drug delivery to tumors and areas with inflammatory activity. Until then, any macromolecular or nanoparticle system using site-specific targeting or activation needs to accurately control for nonspecific accumulation of the vehicles via the EPR effect.

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Phagocytosis

Nanoparticles are internalized preferentially by macrophages depending on the dose and physicochemical characteristics of the nanoprobes [21] . This leads to accumulation in the reticuloendothelial system with the highest uptake predominantly in the liver, followed by spleen and bone marrow [6] . Therefore, the liver is typically the dose-limiting organ in targeted therapy with nanodelivery systems. In terms of imaging applications, phagocytosis is the main component of the nonspecific background of any nanodelivery system. This is an issue present in any cell-tracking approaches, for example in stem cell therapies. It is therefore an important goal to be able to distinguish between signals from viable injected cells and cell remnants internalized by resident macrophages [22] . future science group

Theranostics Besides using particles solely for drug-delivery purposes, particles can also carry additional payload, that is. an imaging agent. The imaging moiety together with drug-delivery function creates a theranostic agent. For the application of nanoparticles in drug-delivery systems (DDS), evaluation of the fate of nanoparticles in vivo is important. Biodistribution has usually been evaluated invasively in sacrificed animals after injection www.future-science.com

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Review | Heneweer, Gendy & Medina Molecular imaging: Usage

charge and potentially the size of the particle. Therefore, new development cycles and evaluations would become necessary for validation. There are several novel and interesting theranostic applications nearing clinical trials. To highlight a few examples, gold nanoshells (Aurolase) have recently been used (1.25 × 109 nanoshells/g body weight) in animals. These nanoshells have been shown to eliminate neck and throat cancers when injected intravenously and allowed to accumulate in the tumor by EPR [23] . Following injection of the nanoparticles, laser irradiation at 808 nm causes a temperature increase of 20°C and tumor ablation. Microbubbles that are used for ultrasound imaging and can be triggered to release the content by ultrasound pulse. CTT peptide targeted liposomes have been used for imaging tumors and to target drug molecules to gelatinase-containing tumors as well as for drug delivery (F igure 1) [1,4] . Gold surfaceenhanced Raman scattering nanoparticles can be used as markers of colon cancer when targeting either affibodies or small peptides, which this can lead to a molecular imaging-guided colonosocopy [24,25] . Small (under 10 nm in diameter) organic silica nanoparticles, such as RGD-C-dots that are efficiently cleared from the blood mainly through the kidneys, have new characteristics that can be utilized in clinical settings There are ongoing clinical trials being conducted with these particles, and these ultrasmall inorganic nanoparticles have a great future in theranostic approaches. In particular, where a treatment isotope such as 131I is used after strong specific binding to the tumors visualized with 124I-labeled targeted particle. Other clear advancements will be in intraoperational settings where the multimodality can be utilized by surgeons in the cases of difficult sentinel lymph node or metastasis tracking. In such circumstances, the PET-CT can be used for locating the lymph nodes with metastasis pre-operation, following optical recognition of the nodes using surgical microscopy during operation [53] .

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of imaging techniques to reveal molecular -level incidences in animals or humans on a macromolecular scale.

of radiolabeled nanoparticles. Imaging enables non-invasive determination of nanoparticles fate. Exact position information is hard to obtain by using PET or single photon emission computed tomography so additional methods such as CT or MRI has to be used to get structural data from the animal almost simultaneously following co-alignment of the two data sets. This technique enables the evaluation of realtime trafficking of liposomes and other nano particles, and can be applicable to diagnostic imaging. Nanoparticles can be surface labelled with various methods, such as iodination of tyrosines that are coupled to the lipids of the liposomes or directly to the surface of nanoparicles or by DTPA conjugates labelled with radiometals. The payload can be directly radio labeled with a different isotope than the carrier nanoparticle to reveal the exact location of the drug and the carrier at a different timepoint. In this way, the fate of the carrier can be separated from the fate of the payload drug and exact free and active late-time drug doses can be measured in different organs. A good example is EGFR inhibitor SKI-243 with I-124 where the drugs binding to the receptors has been evaluated by PET and the liposomal versions fate is examined by using I-131/I-124-labelled drug and a liposome [4] . What was essential finding was that the overall elimination of the drug was slower and the drug accumulation by EPR increased the drug content in the tumor, but it was not clear if the actual receptor occupancy of the drug was increased by this. It is important to do these type of studies with all nanoparticle DDS, at least during drug development and perhaps even with the patients in the beginning and in the end of the treatment. These receptor-specific labeled drug agents can diagnose and treat the respective disease, and monitor the therapy efficiency simultaneously. The integration of diagnostic imaging capability with therapeutic efficacy is especially important in personalized medicine as well as in the early steps of developing a new nanodelivery tool. The theranostic approach can be monitored by imaging a labeled DDS or by transforming an imaging nanoparticle into a DDS. This is due to the relative ease by which a small reporter molecule can be included in a relatively large nanoparticle to visualize its journey in the body. On the other hand, a large degree of chemical engineering is needed to change an imaging nanoparticle to a drug-delivery particle, and this process will most likely change the surface

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Key Term

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Therapeutic Delivery (2012) 3(5)

Organic NPs & micelles Liposomes are self-assembled vesicles composed of a lipid bilayer, which forms a closed shell surrounding an internal aqueous phase. The size, charge, components and molecular modifications of liposomes are easily controlled. One of the advantages of liposomes as drug carriers is that they can carry both hydrophilic and hydrophobic molecules (Figure 2) . On the other

Liposomes

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Liposomes & inorganic nanoparticles for drug delivery & cancer imaging

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CTT2-SL SL Doxorubicin Buffer

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liver and spleen uptake rates, and are generally regarded as safe nanoparticle species with long or ultra-long circulation time when PEGylated, favorable lipid to drug ratios and highly biodegradability. Studies suggest that liposomes are convenient vehicles for targeted drug delivery. There are fewer reports of imaging uses of liposomes, although the amount of articles regarding

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hand, liposomes have a surface that can be used for attachment of various targeting ligands and reporters (Figure 3) . Liposomes and micelles are common nanostructures in clinical use for drug delivery. By preferentially enhancing localization of pharmaceutical activity in the organ/tissue of interest, their use has the potential to reduce the required systemic dose of drugs, thus minimizing risks of adverse side effects while increasing treatment efficacy. Liposomes have been generated in several institutions and companies in multiple settings and in different formulations in GMP conditions for clinical use and they are generally well tolerated [26] . Currently, a large amount of research is being conducted to improve drug delivery by introducing targeted or functional delivery systems. Liposomes and micelles are among the most common nanostructures used in clinical drug-delivery applications. Among the first clinically approved liposomal delivery systems in cancer was a doxorubicin containing liposome together with SMANCS. There is a growing body of liposomal applications approved for cancer research (Table 1) and more still in the early clinical stages (Supplementary Table 1) . Currently, the total amount of liposomal and micellar formulations in different clinical stages in all applications in developed and in developing countries likely exceeds several hundred. These formulations usually have high

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Figure 1. Kaplan–Meier plot of the survival of tumor-bearing mice. Mice were treated with doxorubicin (9 mg/kg) administered by MMP9/2 targeting CTTHWGFTLC-peptide conjugated liposomes (CTT2-SL). Control groups were injected with doxorubicin (9 mg/kg) or saline dilution buffer. Injections for each treatment group were made at days 0, 3 and 6. Reprinted with permission from [7] .


Figure 2. Cross-section of targeting liposomes. Reprinted with permission from [1] . © Bentham Direct (2004).

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Figure 3. Surface modifications for nanoparticles [74] .

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liposomal imaging has been doubled in the last 5 years. In particular, MRI and optical imaging are quickly gaining popularity in this field, followed to a lesser extent by radio imaging. For example, incorporation of tyrosine kinase inhibitors such as dasatinib EGFR inhibitors (e.g., Iressa® or Tarceva®), within micellar/liposomal formulations offers distinct advantages over the native drug itself in terms of improved drug solubility and tolerability in mice, and potentially produces more favorable pharmacokinetic and tumor uptake kinetic profiles. Mono- and hetero-functional polyethylene glycol-moieties have been used to prolong circulation times.

Table 1. Approved nanoparticles in cancer. Compound

Name

Indication

Liposomal doxorubicin Liposomal daunorubicin Liposomal vincristine Liposomal cisplatin Styrene maleic acid and neocarzino–statin copolymer in ethiodol

Myocet, caelyx and doxil Daunoxome Onco TCS SPI-77 SMANCS/lipiodol, zinostatin stimalamer

KS, breast and ovarian KS Non-Hodgkin lymphoma Lung Hepatocellular carcinoma

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They also provide binding sites on their surface to attach additional imaging or targeting molecules to the nanoparticles [4] . Thermosensitive

liposomes Thermosensitive liposomes (TSLs) are DDSs that allow controlled release of their payloads resulting from regional hyperthermia [27,28,29] . In this process, lipids change from a gel to a liquid state at a species-specific temperature, called a transition temperature (Tm). Every lipid molecule in the liquid phase requires more space than in the solid phase due to the additional freedom of the lipid molecules in the membrane. Key for development of TSLs is the combination of a lipid species with a low Tm, such as 1,2-dipalmitoyl-sn-glycero-3phosphocholine (Tm = 42°C) with that of a species with a slightly higher Tm such as 1,2-distearoylsn-glycero-3-phosphocholine (Tm = 46°C) [20] . The 1,2-distearoyl-sn-glycero-3-phosphocholine component stabilizes the liposome, while the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine part transits from gel to liquid state during application of thermal energy [30] . This technique increases the permeability of the liposomes. future science group

Liposomes & inorganic nanoparticles for drug delivery & cancer imaging delivery systems for gene therapy requires the DNA carrying liposomes to remain a center of development [41] . Since they are nonbiological vectors, the GMP and safety concerns are smaller than with viral vectors. For example, utilization of liposomes in the intravenous delivery of the surviving promoter as a DNA– liposome complex shows high specification and ability to suppress cancer growth in vitro and in vivo. It is currently being evaluated in a Phase II clinical trial for melanoma 2. liposomes The viral therapies are hindered by the immune systems clearing of viruses before the virus can infect the tumor cells. A newly developed technique in the viral therapy of the tumors utilizes a liposome-conjugated virus to overcome the limitation of the humoral immune response against the virus when it appears in the blood stream before reaching the liver, thereby decreasing the level of infection. With this technique, the antibodies attenuate the virus alone but do not attenuate the liposome-conjugated virus. When the liposome conjugated virus reaches the targeted cells in the liver it can still be engulfed in the cell membrane, allowing the healthy virus to enter the cell. Oncolytic viruses are good candidates for this technique since they may overcome resistance mechanisms and additionally mount a strong immune response. Several oncolytic viruses have been used in cancer therapy [42] . In PDAC, for example adenoviruses [43] have been tested in preclinical models, but also clinical trials (Phase II study; NCT00998322). A major challenge for oncolytic viruses will be a pre-existing immune response that will eliminate the viruses before reaching the target, targeting, local versus systemic side effects, and possible interference with standard chemotherapies [44] . A potential method to overcome the problem of too early elimination of the viruses and the problems of targeting is to use liposome-encapsulation in combination with an adenoviral prodrug strategy [45] . Shielding of a virus temporarily from the immune system immediately after injection may gain even more impact if combined with efficient and selective targeting mechanisms. Strictly localizing a virus (and possibly a drug) to the tumor site or organ of action would lead to a reduction of the required drug dose and systemic toxicity, as well as increased treatment efficacy. This has been

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complexes Cationic liposomes are positively charged liposomes that bind to negative charged DNA and allow for passive and receptor-mediated endocytosis-based delivery strategies. DNA and RNA strands are negatively charged and, thus, bind naturally to the surface of the positively charged liposomes. Cationic liposomes are efficient gene-delivery agents that bind strongly to negatively charged cell membrane and facilitate transfection in vitro. DNA–liposome complexes can protect the delivered DNA from its surroundings during the delivery and increase the delivery efficiency [38] through targeting of a specific cell type and tissue through EPR. Nevertheless, they exhibit some toxicity in vivo [39,40] and are subject to the extremely rapid clearance from the blood by macrophages. However, the need for efficient

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However, the correct mixture of different lipid species is crucial for controlled release to enable sufficient permeability during regional hyperthermia and avoid leakage at normal body temperature. Besides balancing lipid mixtures, the release rate of TSL can be further adjusted by additional components such as Au-nanorods that can be heated easily with a near-infrared laser [24,31] . Ultrasound, MRI, implanted devices or external heat can be used for application of thermal energy [32–34] . As for nontemperature-sensitive liposomes, ligands can be conjugated to the surface of TSL for active targeting [35] . Additionally, TSL can be combined with optical and/or MRI contrast moieties for tracking purposes in vivo. The magnitude of signal changes that MRI contrast agents exhibit depends strongly on the nano-environment of the contrast moieties. Therefore, a combination of drug-loaded TSL with iron oxide nanoparticles or gadolinium chelates facilitates additional monitoring of the release of the payload [36,37] . There are current clinical attempts to utilize thermosensitive liposomal formulations of doxorubicin, ThermoDox ® (Celsion Corporation). This formulation has been used for treatment of primary and metastatic tumors of the liver (Phase I; clinicalTrials. gov identifier: NCT00441376), breast cancer recurrence at the chest wall (DIGNITY, Phase I/II; NCT00826085) and locally recurrent breast cancer (Phase I; NCT00346229) as well as hepatocellular carcinoma (Phase III; NCT00617981).

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Inorganic NPs nanoparticles There have been promising clinically relevant attempts to modify an inherently nontoxic and biocompatible material, amorphous silica, for targeted diagnostics and/or therapeutics. Although it has been reported that silica is an essential nutrient for humans in small doses, it has been shown that steady exposure to non-PEGylated silica nanoparticles after 48 h is toxic in the concentrations above 50 mg/l in vitro. In addition, there are contradicting reports of skin eruptions in human dialysis patients with plasma silicon levels higher than 2 mg/l [47–51] . This has offered an attractive strategy for achieving a favorable toxicological profile in vivo. To realize such a platform, Cy5 dye-encapsulating core–shell silica nanoparticles (emission maxima >650 nm), coated with methoxy-terminated PEG chains (PEG ~0.5 kDa), were prepared according to previously published protocols [36] . The neutral PEG coating prevented uptake by other cells (opsonization). The use of bifunctional PEGs enables the attachment of small numbers (~6–7 per particle) of aub3 integrin-targeting cyclic arginine-glycine-aspartic acid (cRGDY) peptide ligands in order to maintain a small hydrodynamic size facilitating efficient renal clearance [52] . Labeling the peptide ligands with the radionuclide 124 I using a tyrosine linker enables radiolabel PET imaging and quantitation of the subject in real time and in 3D. An important practical advantage of relatively long-lived 124I (physical half-life: 4.2 d) is that sufficient signal persists long enough to allow radiodetection up to at least several days post-administration. The relative brightness of the cRGDY-PEGdots was determined to be approximately 200% greater than that of the free dye [53] . The relatively rapid clearance of the particle together with the rather nontoxic nature of the particle has allowed the particle to be used in early human trials.

Iron

oxide nanoparticles Superparamagnetic nanoparticles serve as contrast agents in MRI. They consist of maghemite (Fe 2O3 ) and magnetite (Fe 3O 4 ), embedded in or coated by a stabilizing matrix such as dextran [57] , and result in negative contrast on MRI scans. They have been conjugated to antibodies and peptides for active targeting of, for example, apoptosis [58] , inflammation [59,60] and angiogenesis [61,62] . Iron oxide nanoparticles are largely phagocytosed by macrophages. This feature has been used to track macrophages in the context of disease. Macrophages are an important element in the composition of lymph nodes. Invasion of tumor cells during lymphatic metastatic spread disturbs this normal architecture. It is known from histologic examination that lymphatic metastases contain less macrophage than normal lymph nodes. Since macrophages internalize iron oxide nanoparticles, and iron oxide lowers the signal in T2 weighted MRI scans, lymphatic metastases appear as bright spots in dark lymph nodes on MRI scans after application of ultrasmall iron oxide nanoparticles USPIO [63–64] . The same strategy has been applied for the detection of liver tumors, since a significantly lower number of Kupffer cells are present in tumors than in healthy liver parenchyma [65,66] . For the latter application, two iron oxide based nanoparticles were approved for clinical use, ferucarbotran (Resovist ®, Schering) and Feridex ® (AMAG Pharmaceuticals). However, both contrast agents have been discontinued in the meantime due to economical reasons (AMAG Pharmaceuticals Inc. Q4 2008 Earnings Call Transcript). Iron oxide nanoparticles have also been used for therapeutic applications [44] including

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It has been shown that 5.5 nm nanoparticles are rapidly cleared from the blood by the kidneys, thus lowering toxicity [54] . For optical nanoparticles an attractive field is intraoperative surgery where nanoparticles can help the surgeon to detect areas of interest such as metastatic lymph nodes [55,56] . Furthermore, there are reports that the rapidly clearing quantum dot nanoparticles could be used for inhalation applications. Small nanoparticles less than 34 nm in diameter will travel from the lungs to the lymph nodes, and particles less than 6.5 nm in diameter will be rapidly cleared by the kidney [72] .

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demonstrated with a herpes simplex virus in the treatment of multible liver metastases [46] .

Quantum dot nanoparticles Using a similar strategy, quantum dot nano particles have been used for optical imaging. The basic problem of quantum dots is that they are highly toxic. A method to reduce the toxicity is to use small renally cleared nanoparticles. 8




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Conclusion The number of nanoparticles used in clinical drug delivery and imaging is constantly increasing. Lipid-based nanoparticles are frontrunners of the technology but other innovative applications, especially small inorganic nanoparticles are also entering the field, in particular in imaging applications. Despite this emerging field, the pace of the development has been moderate. The nanoparticle delivery and imaging systems will not come to the forefront until they have considerable advancement compared with direct parenteral drug delivery. Stringent controls in the development phase have to be applied so that the real benefits of the controlled release or targeted release systems are thoroughly evaluated. The combination of DDS development and imaging can speed up the development and translation of drug delivery and imaging systems to the clinic in the future. This is especially true in the field of nonsoluble drug delivery, ultrafast clearance drug delivery, such as peptide delivery, and DNA delivery. In these applications the carriers will either be totally biodegradable medium-size carriers with diameters of 80–800 nm or small nonbiodegradable particles with diameters under 10 nm that are suited mostly for imaging.

circulation time in the blood. The delivery of the drugs to the tumor site is not enough, the molecules have to reach their receptors and the receptor occupancy should be documented over a time course. At the moment the EPR effect or heat-activated targeting delivery systems do not fulfill all of these needs. Large particles (100 nm diameter) do not penetrate deep into the tumor tissue and simple targeting of nanoparticles with antibodies is not successful in most cases. In the future, more complicated and smarter drug-delivery strategies will be required that can simultaneously manipulate several active sites in the same receptor, or several different receptors, and these interactions have to be verified by imaging. In addition, systems that can detect even the smallest differences between similar proteins and that can change their response according to their environment and report their state and location should be developed [73] . Delivery technologies and nanotechnologies together with biotechnology-derived drugs will bridge the gap in the future. The nanoparticles allow for versatile platforms that can be used for multifunctional DDS. At the moment, there are targeted nano particles and control release systems, which if improved and combined would offer a truly superior way of intervention with the target tissues. On the other hand, this new complexity caused by multiple functions and components would make the testing of the new generation activated delivery systems more difficult and expensive. It would also introduce the problem of the long term toxicity of the carriers. In parallel, old-generation nanotechnology will likely see more use as part of the mainstream drug development and drug delivery. Liposomes, micelles and PEG polymers are already in the toolboxes of large pharmaceutical companies, and their usage will continue to grow. An additional category gaining popularity is the intraoperative and endoscopic nanoparticle formulations, with optic and optic plus some other modality applications such as PET, single-photon emission computed tomography or MRI. The knowledge of the use of nanotechnology is increasing, which provides the ability to seek out approaches that are applicable and safe. At the same time the expectations of nanotechnology are high and a large amount of work is required to bring this technology into the clinical setting. Increasing the solubility, targeting the immune system or relying solely on the

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magnetic hyperthermia [59,60] and controlled release of drugs [67,68] . Additionally, attempts are made to develop drug carrier systems that are attached to USPIOs, which can be directed to the site of action by an external magnet [69,71] .

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Future perspective For efficient delivery, drug molecules should be water-soluble and stable. However, it is highly likely that there will continue to be difficulties to find enough new small molecules that are water-soluble and stable that can be used as drug molecules. This is primarily due to the fact that receptors that respond to an effect of a small water-soluble drug molecule alone are almost fully utilized. However, there are still large numbers of hydrophobic molecules that have the potential to be potent if solubilized and assisted in reaching their molecular target. On the other hand, after development of phage display and other high-throughput screening systems, there are new classes of biomolecules that have high specificity to the targets but have problems of stability and short future science group


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of the previous DDS development. The generation of large amounts of niche nanodrugs for personal medicine can be costly; however, by adding imaging as an essential part of the nanodrug-development process these costs can be reduced. Furthermore, combining these techniques with imaging will help in selection of the right models for the therapy trials and better patient selection. Microdosing studies before Phase II studies would allow researchers to determine whether the cure reaches the site of the disease and if there is a favorable response in molecular level prior to undertaking large trials. Because of the vast and complex needs for future drugs and DDS, it is perhaps not surprising that nanotechnology has progressed only in relatively small steps at this stage. However, a change in the paradigm of treatment protocols can take several decades rather than months or years and in the end nanotechnology combined with imaging techniques, based on the evidence shown so far, will revolutionize the medicine.

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passive EPR based targeting are all approaches that have the potential to bring more delivery systems to the market. When the biology of the disease is well known, nanotechnology has the ability to combine different functions in a single location to provide new treatment mechanisms for patients. There are several current nanotechnology projects that are entering the clinic (S upplemetary Table 1) but they have not been able to fully grasp the potential of nanotechnology and to give a watershed impact to the industry. There are currently pH-sensing, heatsensing, ultrasound-sensing, enzyme-triggered, ligand-targeted, cell-permeable, blood–brain barrier-permeable, light- and MRI-triggered delivery systems available. Together, these can bring more tools and alternatives to the clinicians when the theranostic approach can be accomplished by imaging a DDS or by transforming an imaging nanoparticle into DDS. There is a clear tendency that the drug and medical development will be more fragmented in the future. Illnesses such as cancer are now recognized to be composed of several different diseases. This together with the concept of personalized medicine means that there needs to be more sophisticated solutions to the specific problems of a patient that a niche product can solve. Nanoparticles allow a platform that is flexible and versatile enough to allow variations from patient to patient. This together with the imaging techniques will allow us in the future to diagnose the patients at a level that is personally detecting expression patterns of target proteins on patients. Combining this with the data of real expression occupancy will determine exactly what kind of drug with what kind of delivery profile should be used with each individual patient in each stage of the disease. This may sound like a tall order but should be achievable based on the track record

Supplementary data To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/ doi/suppl/10.4155/TDE.12.38/suppl_file/suppl_table_1. xls.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary

Nanoparticles are already in the clinic as drug-delivery systems.

They have improved the drugs from those used previously by decreasing toxicity and improved solubility.

There is a great need for nanoparticle-based drug-delivery systems.

On the side of the classical lipid-based nanoparticles, new small nonlipid nanoparticles are emerging.

The first-generation nanoparticles have been followed by second-generation nanoparticles (particles with multiple functions).

Further generation nanoparticles can bring new methods for clinical therapy strategies.

The development of nanoparticle and nanoparticle treatment strategies is slow but could speed up in the future as experience in this field grows.

The theranostic approach, where imaging is coupled with the therapy, in particular during drug development, is essential in the future rapid development of nanoparticle imaging systems.

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Liposomes & inorganic nanoparticles for drug delivery & cancer imaging experience and lessons learnt. Adv. Drug Deliv. Rev. 61(13), 1131–1148 (2009).

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