Brain cancer diagnosis and therapy with nanoplatforms☆
Introduction
Brain tumors constitute a profound and unsolved clinical problem although significant strides have been made in the treatment of many other cancer types. The incidence of primary brain tumors in the United States has been estimated at approximately 43,800 per year [1], [2], [3] and 18,500 of these are expected to be malignant. Currently brain tumors account for at least 12,690 deaths in the United States yearly and are the most common cause of cancer-related death for children 0–14 years of age [1], [2], [3].
The earliest stages of intracranial cancer remain difficult to detect and treat. This problem is confounded by the location of several brain tumors that lie adjacent to or within anatomical structures critical for basic motor, cognitive, reflexive and other functions. As with most other tumors, early detection and remediation correlates with a positive prognosis. Currently an invasive biopsy is the preferred method to confirm the diagnosis of cancer as it can provide information about histological type, classification, grade, potential aggressiveness and other information that may help determine the best treatment. Modern imaging techniques such as CT, PET, ultrasound and MRI are rapidly emerging as standards in the detection of tumors and cancers. These imaging scans of malignant human brain tumors, however, do not readily allow quantitation of the actual tumor volume since a lot of extracellular water (edema) can build up around the tumor site, making exact discrimination of tumor margins difficult. Moreover, the delivery of contrast agents is inefficient, due to the blood–brain barrier (BBB). The BBB is a very specialized system of endothelial cells that separates the blood from the underlying brain cells, providing protection to brain cells and preserving brain homeostasis. The use of contrast agents often allows estimates of tumor domains from the largest cross-sectional area of contrast enhancement, indicating a compromised BBB. However, the contrast agents tend to diffuse away from the vessel, making precise measurements of the location of the disrupted BBB somewhat displaced. Finally, even in a tumor surrounded by an extensive zone of edema, there are most likely regions of infiltrating tumor cells which are not apparent. Therefore imaging is typically used to locate and stage neoplasm and visualize a tumor before biopsy or at the time of surgery [4].
The current practice of waiting for altered neurological function, neurological exam and pathological/microscopic evaluation/confirmation of the malignancy usually requires that the tumor (benign or malignant) develops either a significant mass or potential formigration in the neuraxis before invasive surgical or non-invasive neuroradiological therapies are invoked.
Treatment of brain tumors, therefore, has historically consisted of surgery followed by adjuvant therapy such as radiation therapy, chemotherapy and photodynamic therapy (PDT). Despite recent improvements in surgical and adjuvant therapy for brain tumors, the multimodality approach currently used in the treatment of malignant brain tumors does not produce a meaningful improvement in patient outcome [5]. Each treatment modality has limiting factors, as stated below.
Surgery is invasive but currently the primary mode of treatment for the vast majority of brain tumors due to difficulties in finding a tumor at early stages [6]. One of the greatest challenges in brain tumor surgery is achieving a complete resection without damaging crucial structures near the tumor bed. Unfortunately, neoplastic tissue that is easily detected radiographically, is virtually indistinguishable from normal brain. While surgery is the recommended initial treatment for brain tumors, it is rarely capable of eradicating all tumor cells [7]. Furthermore, surgery is not an option when eloquent structures are likely to be damaged during a resection. To address the inability of current surgical techniques to reliably eradicate residual or unresectable tumor, adjuvant radiation and chemotherapy regimens have been developed.
Radiation therapy, chemotherapy and PDT are non-invasive and often used as adjuvant therapy after surgery but may also be effective for curing early-stage tumors. Radiation therapy usually results in a delayed, but well-documented, decline in cognitive function in adults, in addition to posing the risk of secondary malignancy in the irradiated area [8]. In children, radiation therapy is known to interfere with brain development [9]. The efficiency of radiation therapy is often hindered by diffusely invasive characteristics of brain tumors as well as the emergence of radiation-resistant populations.
Most chemotherapeutic agents have a low therapeutic index. They are toxic and can affect not only cancer cells but also healthy cells, which leads to severe systemic side effects, generally resulting in morbidity or mortality in the patient. The chemotherapeutic treatment of brain cancer is further restricted due to the ability of the BBB to exclude a wide range of anti-cancer agents. Another limiting factor is the development of multi-drug resistance (MDR) by the cancer cells. A combinational chemotherapy, i.e. the use of more than one drug, is a common practice in clinical oncology. However, cancer cells often develop resistance against a wide variety of chemotherapeutic drugs, due to the very effective drug efflux system P-glycoprotein or multi-drug resistance-associated protein (MDRP) [10], [11]. The P-glycoprotein is an ATP-dependent transporter responsible for the cellular extrusion of a number of drugs. It is expressed in many tissues, including the luminal membrane of the cerebral endothelium.
The combination of chemotherapy and radiation therapy has been implemented with variable success in adult brain tumors [12] but also carries significant treatment-related morbidity. Moreover, the improvements in outcome demonstrated with the use of combination therapy are minimal: a prospective randomized controlled study on temozolomide, the most effective and best tolerated agent for treating gliomas, demonstrated an increase in the median two-year survival of only 2.5 months in patients with newly diagnosed glioblastoma receiving radiation and temozolomide, compared to those receiving radiation therapy alone [13].
PDT involves the delivery of photosensitizers (PS) such as Photofrin® to tumors, combined with local excitation by the appropriate wavelength of light, resulting in the production of singlet oxygen and other reactive oxygen species which initiate apoptosis and cytotoxicity in many types of tumors, with minimal systemic toxicity. PDT has emerged as a promising method for overcoming some of the problems inherent in classical cancer therapies [14], [15], [16], [17]. It is more selective and less toxic than chemotherapy because the drug is not activated until the light is delivered. PDT was initially applied clinically to cutaneous and bladder malignancies that can easily be exposed to light. However, PDT is also an interesting approach for the treatment of malignant gliomas, as it offers a localized treatment approach. Several investigations have been made on the application of PDT for the treatment of brain tumors [18], [19], [20], [21], [22], [23], [24], [25]. Recently it was reported that PDT of primary and recurrent gliomas resulted in an increase in patient median survival [26]. The efficacy of PDT for brain cancer is also limited by the BBB and MDR, just like chemotherapy, as it requires the delivery of the PS to the brain.
The therapeutic efficacy of chemotherapy and PDT can be greatly improved by efficient delivery of the drugs to the specific tumor location. The recent molecularly-targeting approach allows the medical intervention to affect only cancer cells but not the normal cells, based on molecular recognition processes (ligand–receptor or antibody–antigene interaction) [27], [28], [29], [30], [31]. This innovative approach is inherently different from classical modalities. It has the potential to improve the therapeutic efficacy or imaging contrast enhancement, by increasing the amount of therapeutic or contrast agents delivered to the specific site, and to minimize toxicity, or imaging background signal, by reducing systemic exposure. The promise of the molecularly targeted approach in imaging is that one may be able to obtain dramatic contrast enhancement so as to detect the tumor at an earlier stage than possible by current methods, with sensitivity good enough to avoid an invasive biopsy. Since the specific molecular signature of one brain tumor may be different from that of another, and can not be differentiated based upon traditional anatomical imaging, the ability to diagnose brain tumors based on their genetic presentation, in a targeted manner, would be of great value. By the same notion, the approach of delivering a therapeutic agent in a targeted manner should give clinicians the ability to treat cancer or to manage it as a chronic disease, thus preventing it from progressing to its later, more virulent stages. Towards more efficient chemotherapeutic treatment of brain cancer, there have been continuous efforts to develop special delivery methods designed to overcome the BBB. Proper combination of these methods and the molecular-targeting approach should be a key factor for achieving an improved therapeutic efficacy.
Section snippets
Drug delivery methods for the brain
In contrast to the open endothelium of the peripheral circulation, the tightly fused junctions of the cerebral capillary endothelium, the anatomic basis for the BBB, essentially form a continuous lipid layer that effectively restricts free diffusional movement of molecules into and out of the brain. Only small, electrically neutral, lipid-soluble molecules (molecular weight up to 500 Da) can penetrate the BBB by passive diffusion and most chemotherapeutic agents do not fall into this category.
Nanoparticle delivery system
The ability to deliver effective concentrations of contrast or therapeutic agents selectively to tumors is a key factor for the efficacy of cancer detection and therapy. The utilization of the nanoparticle as a potential vector for brain or other site-specific delivery has the following advantages, due to its excellent engineerability and non-toxicity:
- 1.
The loading/releasing of active agents (drugs/contrast agents) can be controlled. The drugs are loaded into nanoparticles by encapsulation,
Magnetic nanoparticles for MRI
MRI of the CNS is usually performed with short-lived gadolinium-based contrast agents, which gives rapid and transient imaging of brain and spinal permeability. Iron oxide nanoparticle-based MRI contrast agents also show excellent potential for imaging in the CNS. The iron oxide contrast agents are termed superparamagnetic iron oxide (SPIO) or ultrasmall superparamagnetic iron oxide (USPIO), depending on the size distribution of the nanoparticles. Two generic types of magnetic nanoparticles
Dual imaging nanoparticles (MRI and optical imaging)
Following earlier design [51], [52], two groups made a multi-functional nanoprobe detectable by both magnetic resonance imaging and fluorescence microscopy [65], [81]. This dual imaging nanoprobe could potentially be used for the determination of brain tumor margins both during the pre-surgical planning phase (MRI) and during surgical resection (optical imaging). Surgery has been limited in its effectiveness because it is difficult to distinguish visually between cancerous and normal brain
Nanoparticles for chemotherapy
Chemotherapy has shown a poor outcome due to the low permeability of most anti-cancer agents through the blood–brain barrier. The nanoparticle delivery system has emerged as a promising tool for chemotherapy of brain cancer due to the nanoparticle advantages and the evidence for their ability to cross the BBB (Section 3). Several types of nanoparticles have been adopted so far as anti-cancer drug delivery systems to the brain, as given below.
Targeted multi-functional PAA nanoparticles for PDT and MRI
Nanoparticles of various matrices have also been investigated for PDT, demonstrating that the nanoparticle-based PDT is a promising approach for killing tumor cells [55], [56], [57], [58], [98], [99], [100], [101]. The nanoparticle-based PDT of cancer shares the general advantages of the nanoparticle delivery system with the nanoparticle-based chemotherapy (Section 3). Moreover, it has additional advantages: 1) Unlike chemotherapy, the PDT efficacy does not depend on the drugs' release from the
Conclusions
Brain cancer is a life-threatening disease in which a minority of patients are likely to survive (only 5% for glioma after five years). Late diagnosis and the limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agents to brain tumors, due to the BBB and non-specificity of the agents, are major reasons for this unsolved clinical problem. There have been numerous investigations on special delivery strategies to overcome the BBB and
Acknowledgements
We thank Rodney Agayan for preparing Figures 1 and 2. This work was supported, in part, by NCI Contract N01-CO-37123, by NIH/NCI Grants R01-ES08854, P50CA93990, P01CA85878, and by NIH Grant R24CA83099.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Particulate Nanomedicines” Vol. 58/14, 2006.