Nano Today
ReviewOdyssey of a cancer nanoparticle: From injection site to site of action
Highlights
► No drug can be effective against cancer until it is successfully delivered from the administration site to its site of action within the tumor. ► There are barriers to drug delivery at every level of drug distribution including systemic, tissue and cellular levels. ► Current delivery strategies such as receptor–ligand targeting and EPR may not be effective in clinical tumors. ► New drug carrier designs should be educated by an appreciation of the full scope of drug delivery barriers.
Introduction
It has been more than 60 years since Sidney Farber conducted the first successful trial of a chemotherapeutic agent against a nonresectable cancer. Having discovered that acute leukemia was overly dependent on folate, he surmised that the folate antagonist aminopterin may inhibit white blood cell proliferation and stop the cancer's spread. Most patients responded to the treatment, but relapsed within 6 months to a year, bearing a more aggressive and resistant form of the cancer [1]. In spite of the disappointment from the relapse of the cancer, the trial was rightfully hailed as a tremendous success. For the first time, doctors had a weapon to wield against metastatic cancer. The ensuing decades brought many advancements to chemotherapeutic treatments. Acute leukemia, which was a sentence of certain death in 1947, held a 60 percent survival rate only 30 years later. The treatment of other cancers was similarly revolutionized in the same time period [2].
The introduction of chemotherapy as a revolutionary cancer treatment led to tremendous optimism regarding the prospects of finally finding a cure for cancer. In lobbying for the National Cancer Act, Farber himself advised in 1969 that, “[w]e are so close to a cure for cancer. We lack only the will and the kind of money and comprehensive planning that went into putting a man on the moon” [3]. The National Cancer Act became law in 1971, but the promised “cure for cancer” never materialized. After investing billions of dollars and tremendous research focus, only incremental gains, which are largely attributed to improved diagnostic techniques allowing earlier intervention, against cancer have been achieved (see Fig. 1) [4]. More than 60 years after Farber's initial trial, traditional chemotherapy is still our frontline treatment against cancer [5].
Though still our best tool against metastatic cancer, chemotherapy falls short as a cure for numerous reasons. Most prominent among them is the nonspecific toxicity associated with almost all chemotherapeutic treatments, which manifests itself through unwanted side effects including hair loss, nausea and vomiting, anemia, fatigue, increased bruising, immunodeficiency, loss of appetite, dyspepsia, irritation of the mucous membranes of the eye, nose and throat, rashes, urinary problems, and weight change (see Fig. 2) [6]. This toxicity may pose a genuine danger to the life of the patient and often limits the dose which can be administered [7]. Chemotherapy treatments are also vulnerable to the development of multidrug resistance (MDR) in the target tumor, which often occurs in relapsed tumors [8]. Any revolutionary technology to treat cancer would have to rectify these shortcomings and effectively kill cancer cells without damaging healthy cells while preventing or overcoming resistant relapses.
Nanotechnology is regarded as one of the most promising tools to surpass traditional chemotherapy as a front-line cancer treatment. Nano-sized drug carriers offer a versatile platform to which many useful functionalities can be added to improve the specificity and effectiveness of treatment (see Fig. 3). Drug carriers can be designed to overcome many of the mechanisms conferring drug resistance to MDR cancers [9]. They can also be modified to improve specificity to tumors, thus limiting the drug exposure of healthy tissue and reducing side effects. Simultaneous diagnostic capability can also be added to aid doctors in making informed decisions regarding treatment [10].
However, 20 years of intensive research into nanomedicine has failed to translate into clinically successful cancer treatments. With the exception of monoclonal antibodies, only a few FDA approved nanotherapies exist today, and all of these are very simple in concept and design, not reflecting the complexity commonly seen in literature [11]. The gap between the promise of nanomedicine and the results seen in the clinic indicate a flaw either in concept or in implementation. Research groups around the world have developed countless complex and innovative nanoparticles [10], [12]. These particles are often tailored to accomplish a few very specific functions, such as enhancing cellular uptake or prolonging blood circulation. Tests in petri dish or small animal models often show impressive results but correlate poorly with clinical tumors.
One explanation for the failures of drug delivery may be a gap in the prevailing conceptual framework guiding nanocarrier design. Before a drug can take action inside a cell it must complete an extensive journey [13]. The journey begins with the injection of the drug carrier into the bloodstream and continues through stages of circulation, extravasation, accumulation, distribution, endocytosis, endosomal escape, intracellular localization and action. Most nanoparticles specialize in one or two of these stages, but each is critical to the overall success of the therapy [14], [15]. Even targeted nanoparticles largely end up in organs other than the tumor. Twenty-four hours after injection the vast majority of nanoparticles are sequestered in the liver, spleen, kidneys and skin [16], [17]. Any drug localized away from the tumor can be considered to be a poison rather than a cure; this is due to the inevitable damage to healthy tissues.
Intratumoral drug accumulation and distribution may be the single most important challenge to future nanoparticle design. New nanocarriers must be designed with an understanding and due consideration of all stages of drug delivery. In some cases this may require a paradigm shift in the way we conceive the interactions between the drug carrier and the surrounding environment, opening new strategies such as the modification of the tumor microenvironment to make it more amenable to drug delivery [18], [19]. Successful new designs to improve drug distribution may relieve a major roadblock to bringing more nanotherapies to the market.
Section snippets
Circulation and tumor targeting
Most cancer treatments require that the nanoparticles be administered intravascularly. Depending on the tumor type and degree of metastasis, the injection site can be quite far from the tumor, requiring the nanoparticle to travel through the circulatory system, perhaps many times, before it has the opportunity to see the tumor. Some of the particular dangers facing a nanoparticle in circulation include opsonization, uptake by the mononuclear phagocyte system (MPS), extravasation into
Extravasation determinants
Nanoparticles that encounter the tumor while in circulation must exit the tumor blood vessel and enter the tumor interstitial space to continue the journey to the site of action. A particle could theoretically transition out of a capillary in several ways. EPR suggests that the dominant mechanism is diffusion out of the large tumor fenestrae, possibly aided by pressure gradients across the capillary wall driving bulk flow into the tumor. Some particles may also be actively transported across
Intratumoral distribution
A treatment regime should ideally eradicate the tumor entirely, or at least sufficiently to allow natural processes and adjuvant therapy to finish what is left to prevent relapse. However, tumor vasculature is not evenly distributed through the entire tissue [61], necessitating that large portions of the tumor be accessed by diffusion, sometimes over very long distances. Aside from distance, diffusion to distal regions of the tumor is inhibited by densely packed cells, a dense extracellular
Cell uptake
For nanoparticles able to penetrate the tumor and reach a target tumor cell, the journey is not yet over. The nanoparticles must next deliver their cargo across the cell membrane and then safely deliver it to the drug's site of action, whether in the cytoplasm, the nucleus or some other organelle. A large portion of nanocarrier delivery strategies is designed specifically to promote cell uptake.
Intracellular localization
The final step in our journey is to bring the drug to its site of action within the cancer cell. The strategy for this step typically depends on the mechanism of the drug. Many drugs may begin to take effect immediately upon entering the cytoplasm. These include taxanes, which act on microtubules, and alkylating agents, which indiscriminately cross-link amino groups or nucleic acids. Some oligonucleotide therapies may also be effective in the cytoplasm such iRNA. Other drugs directly damage DNA
Conclusion: cost benefit analysis of nanotechnology-based therapies
After surveying the significant obstacles to nanoparticle delivery, it seems reasonable to question whether these nanotherapies work at all. Doxil® and Abraxane® are currently the most successful nanotechnology-based treatments on the market. While preclinical studies of both formulations showed tremendous gains in efficacy over free drug formulations [108], phase III clinical trials showed only marginal improvements over existing therapies. In the case of Doxil® the efficacy gains were not
Dr. You Han Bae worked at University of Utah as a research assistant/associate professor until 1994 when he joined the department of materials science and engineering at Gwangju Institute of Science and Technology (Korea) in 1994, and became a full professor in 1998. He re-joined the University of Utah as a full professor in 2002. His research interests include pH-sensitive micelles, multidrug resistance in tumors, tumor heterogeneity, intratumoral distribution, polymeric vectors for gene and
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N…Fe3+ sequence. It is an FDA-approved drug, intended for oral use at the acidic pH of the stomach and of most of the intestine track. However, based on FDA approval, a huge number of papers proposed the use of PB nanoparticles (PBnp) under “physiological conditions”, meaning pH buffered at 7.4 and high saline concentration. While most of these papers report that PBnp are stable at this pH, a small number of papers describes instead PBnp degradation at the same or similar pH values, i.e. in the 7–8 range. Here we give a definitively clear picture: PBnp are intrinsically unstable at pH ≥ 7, degrading with the fast disappearance of their 700 nm absorption band, due to the formation of OH- complexes from the labile Fe3+ centers. However, we show also that the presence of a polymeric coating (PVP) can protect PBnp at pH 7.4 for over 24 h. Moreover, we demonstrate that when “physiological conditions” include serum, a protein corona is rapidly formed on PBnp, efficiently avoiding degradation. We also show that the viability of PBnp-treated EA.hy926, NCI-H1299, and A549 cells is not affected in a wide range of conditions that either prevent or promote PBnp degradation.
Dr. You Han Bae worked at University of Utah as a research assistant/associate professor until 1994 when he joined the department of materials science and engineering at Gwangju Institute of Science and Technology (Korea) in 1994, and became a full professor in 1998. He re-joined the University of Utah as a full professor in 2002. His research interests include pH-sensitive micelles, multidrug resistance in tumors, tumor heterogeneity, intratumoral distribution, polymeric vectors for gene and protein delivery, and animal tumor models. He has published over 225 peer-reviewed scientific papers, book chapters and U.S. patents. He served the Controlled Release Society as a member of Board of Scientific Advisory, as chair of the Young Investigator Award committee, and as a program co-chair for the society's 34th annual meeting at Long Beach, CA (2007). He is a co-chair of International Symposium on Recent Advances in Drug Delivery System, and is currently an associate editor for the Journal of Controlled Release.
Joseph Nichols received his BS in chemical engineering from Brigham Young University, and is currently a PhD student in the bioengineering department at the University of Utah. His research interests include tissue-level pharmacokinetic models and intratumoral drug distribution.