Cancer Nanomedicine: Addressing the Dark Side of the Enhanced Permeability and Retention Effect
2015; Future Medicine; Volume: 10; Issue: 13 Linguagem: Inglês
10.2217/nnm.15.86
ISSN1748-6963
Autores Tópico(s)Graphene and Nanomaterials Applications
ResumoNanomedicineVol. 10, No. 13 EditorialFree AccessCancer nanomedicine: addressing the dark side of the enhanced permeability and retention effectElizabeth Huynh & Gang ZhengElizabeth HuynhPrincess Margaret Cancer Center & Techna Institute, University Health Network, Toronto, ONT M5G 2M9, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ONT M5G 1L7, Canada & Gang Zheng*Author for correspondence: E-mail Address: gang.zheng@uhnresearch.utoronto.caPrincess Margaret Cancer Center & Techna Institute, University Health Network, Toronto, ONT M5G 2M9, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ONT M5G 1L7, CanadaPublished Online:22 Jun 2015https://doi.org/10.2217/nnm.15.86AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: cancer therapydrug deliveryEPR effectimagingmicrobubblesnanoparticlestumor microenvironmentThe field of nanomedicine has been rapidly gaining attention for its use in diagnosis and therapy of disease, in particular, for the treatment of cancer. The promise of nanomedicine lies in the tumor microenvironment in which solid tumors are characterized by a leaky vasculature and poor lymphatic drainage. This microenvironment enables the permeation of nano-sized particles from blood vessels to the tumor interstitial space and the retention of the particles within the tumor. This phenomenon, termed 'the enhanced permeability and retention (EPR) effect' [1], is used to deliver high payloads of drugs or imaging agents with tumor specificity, better than small molecules.While the distinctive tumor microenvironment enabling the EPR effect is hailed as the cornerstone of cancer nanomedicine, the tumor microenvironment is also one of its greatest barriers. The tumor microenvironment has abnormal vasculature, elevated interstitial fluid pressure and deregulated extracellular matrix components, which disfavor the EPR effect. These characteristics limit the ability to effectively deliver nanomedicines in sufficient quantities and homogenously throughout the tumor, thus impacting imaging sensitivity and specificity, and therapeutic efficacy [2].To address this issue, there has been a movement in the field to improve the delivery of nanoparticles to tumors. A number of strategies have been reported and can be organized into two categories: improving the EPR effect and bypassing the EPR effect. Improving the EPR effect involves modifying biological conditions, whether through altering the overall physiological condition or specifically the tumor microenvironment. Alternatively, bypassing the EPR effect refers to strategies that do not heavily rely on the leaky vasculature and poor lymphatic drainage of tumors for delivery. By developing these new methods, researchers hope to increase accumulation and improve the intratumoral distribution of nanoparticles.Improving the EPR effectTumor vasculature is not only leaky but also irregular in diameter, shape and density, and contains discontinuous vessels. This results in poor and heterogeneous perfusion in the tumor, elevated interstitial fluid pressure from the extravasation of fluid, and can also create hypoxic and acidic conditions. This environment prevents the penetration of nanoparticles and also contributes to tumor progression, metastasis and drug resistance [3].To improve perfusion in the tumor, the overall physiological condition of the patient can be altered. For example, Nagamitsu et al. induced systemic hypertension in patients with solid tumors using angiotensin II during infusion of nanoparticles [4]. They found that this strategy increased the accumulation of nanoparticles and resulted in improved therapeutic response, less toxicity and a shorter time to achieve tumor regression [5].While inducing hypertension has shown to be a promising approach clinically, augmenting the EPR effect through a strategy that alters the physiological condition of the patient has challenges since it may have a whole body effect. In the case of inducing hypertension, the patient population that may undergo this treatment is limited to those who are not already on antihypertensive medication. While in some countries hypertension is not prevalent, such as Japan where the current study was conducted, in other countries such as the USA, where approximately a third of the population have hypertension [6], fewer patients may be eligible for this treatment. Therefore, strategies augmenting the EPR effect that may have a whole body effect will have to take into consideration the demographic of the population in its eligibility to alter the standard of care for cancer treatment.Another strategy to improve the EPR effect is to target the tumor microenvironment. It has been shown that repairing the abnormal vasculature in tumors can increase the accumulation of small nanoparticles by reducing the interstitial fluid pressure in the tumor [7]. Furthermore, other approaches utilize external stimuli to promote the vascular supply, increase perfusion and permeability of nanoparticles using methods such as hyperthermia [8] and radiation therapy [9]. Combination therapies have also been explored with nanomedicine in which a therapy primes the tumor region for nanoparticles by targeting cancer cells in the perivascular region which are a barrier to nanoparticle penetration [10]. Sano et al. used photoimmunotherapy targeted to destroy perivascular cancer cells prior to injection of nanoparticles and observed an enhanced uptake of nanoparticles in the tumor and distribution of the nanoparticle throughout the tumor [11]. Another study used radiation therapy targeted to the perivascular cells prior to administration of nanoparticles and also observed enhanced uptake of nanoparticles and improved therapeutic responses [12]. Combined therapies have shown to be effective in improving the uptake and distribution of nanoparticles in tumors. These are promising approaches, although since the enhancement effect is temporary, the optimal time frame for nanoparticle administration needs to be identified. Furthermore, many of these therapies target the perivascular cells in tumors in which overtreatment may result in vascular shut down and limited delivery of nanoparticles.While the field of cancer nanomedicine has been working vigorously toward improving the EPR effect, more recently, attention has been drawn to whether or not the EPR effect is actually clinically relevant or predominantly observed in animal models. This controversy stems from the lack of data from patients showing improved therapeutic efficacy, despite the successes observed in animal models [13]. This has led to some research groups working toward delivering nanomedicines without relying on the EPR phenomenon, which we refer to as bypassing the EPR effect.Bypassing the EPR effectStrategies have been developed to deliver nanoparticles without reliance on the permeability of the tumor vasculature. Ye et al. developed a fluorescent peptide that could form nanoparticles in situ in tumors. They proposed this strategy for imaging the detection of treatment response. The fluorescent peptide would penetrate tumors due to its small size and then would be activated to form nanoparticles by cleavage of the peptide by enzymes present in the apoptotic cells [14]. Perrault and Chan also used a similar approach in which gold nanoparticles and a fluorescent contrast agent were assembled in vivo for the detection of tumors [15]. In situ assembly of the nanoparticle components harnesses the advantages of small molecules (rapid influx) and nanoparticles (prolonged retention).Microbubbles have been developed for drug delivery as well as the delivery of nanoparticles by either encapsulating or tethering nanoparticles to the surface of the microbubbles. Microbubbles have been shown to induce transient vascular permeability when they are burst by ultrasound which allows the delivery of these particles from the blood stream into the tumor [16]. In a work reported in Nature Nanotechnology in 2015, Huynh et al. discovered that porphyrin-based microbubbles could be converted into nanoparticles in situ by ultrasound [17,18]. After systemic injection, bursting the microbubbles with ultrasound would increase the permeability of the vasculature, while forming and delivering porphyrin nanoparticles to the tumor, then used for imaging or therapy. The porphyrin microbubble not only serves the role of carrying the components to form the nanoparticle but is also the instrument by which the nanoparticle is able to enter the tumor. Therefore, using this micro-to-nano strategy, there is no dependence on the tumor microenvironment to deliver the nanoparticle. The emergence of these strategies that do not rely on the permeability of the EPR effect may have great clinical impact due to the ability to deliver high payloads of imaging agent or drug, while minimizing the reliance on aspects of the tumor microenvironment for delivery.The challenges & needsThe development of nanomedicines rely heavily on the preclinical models on which they are tested. It is well established that these models, especially tumor xenografts, display the EPR effect regardless of tumor subtypes [19], which has led to nanomedicines demonstrating exciting leaps forward in cancer imaging and therapy. Unfortunately, the successes preclinically are not observed, or to the same extent, clinically in patients. It is unknown, and requiring further studies, to determine whether preclinical models accurately represent all aspects of the EPR effect and if they are also present in patients with various cancer types and stages. A better clinical understanding of the EPR effect is needed to determine why certain nanomedicines have failed clinically, and how these issues can be addressed. Furthermore, how the EPR effect changes with tumor heterogeneity intratumorally and between different tumor types and stages is also necessary to develop clinically relevant animal models and nanomedicines for those particular scenarios.There will not be one universal strategy for all tumors or even for the same tumor type. The heterogeneity experienced in each tumor identifies a need for personalized treatment plans. This could include a method of identifying or characterizing patient tumors that will respond to certain nanomedicine therapeutic strategies prior to treatment. Therefore, the field of nanomedicine extends far beyond the chemists who create the nanoparticles. It requires biologists who will investigate the effects of nanomedicine and develop preclinical models that will translate into patient tumor scenarios. 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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.PDF download
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