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Current Trends in Cancer Nanotheranostics: Metallic, Polymeric, and Lipid-Based Systems

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Current Trends in Cancer Nanotheranostics: Metallic, Polymeric, and Lipid-Based Systems pharmaceutics Review Current Trends in Cancer Nanotheranostics: Metallic, Polymeric, and Lipid-Based Systems Catarina Oliveira Silva 1,† , Jacinta Oliveira Pinho 1,†, Joana Margarida Lopes 2, António J. Almeida 1, Maria Manuela Gaspar 1,* and Catarina Reis 1,3,* 1 iMedUlisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; [email protected] (C.O.S.); [email protected] (J.O.P.); [email protected] (A.J.A.) 2 Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; [email protected] 3 IBEB, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal * Correspondence: [email protected] (M.M.G.); [email protected] (C.R.); Tel.: +351-217-946-400 (ext. 14774 or 14244) (M.M.G. & C.R.); Fax: +351-217-946-470 (M.M.G. & C.R.) † Equal Contributors. Received: 2 December 2018; Accepted: 1 January 2019; Published: 8 January 2019 Abstract: Theranostics has emerged in recent years to provide an efficient and safer alternative in cancer management. This review presents an updated description of nanotheranostic formulations under development for skin cancer (including melanoma), head and neck, thyroid, breast, gynecologic, prostate, and colon cancers, brain-related cancer, and hepatocellular carcinoma. With this focus, we appraised the clinical advantages and drawbacks of metallic, polymeric, and lipid-based nanosystems, such as low invasiveness, low toxicity to the surrounding healthy tissues, high precision, deeper tissue penetration, and dosage adjustment in a real-time setting. Particularly recognizing the increased complexity and multimodality in this area, multifunctional hybrid nanoparticles, comprising different nanomaterials and functionalized with targeting moieties and/or anticancer drugs, present the best characteristics for theranostics. Several examples, focusing on their design, composition, imaging and treatment modalities, and in vitro and in vivo characterization, are detailed herein. Briefly, all studies followed a common trend in the design of these theranostics modalities, such as the use of materials and/or drugs that share both inherent imaging (e.g., contrast agents) and therapeutic properties (e.g., heating or production reactive oxygen species). This rationale allows one to apparently overcome the heterogeneity, complexity, and harsh conditions of tumor microenvironments, leading to the development of successful targeted therapies. Keywords: nanotheranostics; gold nanoparticles; polymeric nanoparticles; lipid-based nanosystems; cancer treatment; cancer imaging 1. Introduction Cancer, a complex, heterogeneous, and aggressive disease, is globally recognized as overwhelmingly challenging in terms of clinical management. Recent worldwide data from GLOBOCAN estimate 18.1 million new cases and 9.6 million deaths due to cancer in 2018 [1]. Therefore, a precise diagnosis combined with effective treatments are vital for improved clinical outcomes. In this context, the recent advancements in nanotechnology and combined biomaterials have been providing novel nanosystems with increased complexity and multiple properties to respond to the distinct mechanisms involved in cancer development. Hybrid nanotheranostic systems are multicomponent individual particles, made of organic and inorganic materials, capable of both diagnostic and therapeutic actions, such as for drug/gene delivery, Pharmaceutics 2019, 11, 22; doi:10.3390/pharmaceutics11010022 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, x 2 of 45 PharmaceuticsHybrid2019 nanotheranostic, 11, 22 systems are multicomponent individual particles, made of organic2 ofand 40 inorganic materials, capable of both diagnostic and therapeutic actions, such as for drug/gene delivery, laser-assisted therapy (e.g., photodynamic therapy (PDT) and photothermal therapy (PTT)), laser-assisted therapy (e.g., photodynamic therapy (PDT) and photothermal therapy (PTT)), and/or and/or imaging modalities (e.g., magnetic resonance imaging (MRI) and positron emission imaging modalities (e.g., magnetic resonance imaging (MRI) and positron emission tomography tomography (PET) [2]. The association of these individual agents to a nanocarrier system expanded (PET) [2]. The association of these individual agents to a nanocarrier system expanded and enhanced and enhanced the available nanotheranostics tools, offering the possibility of integrating both tumor the available nanotheranostics tools, offering the possibility of integrating both tumor accumulation, accumulation, drug release, and multiple imaging modalities for optimal treatment outcomes [3]. drug release, and multiple imaging modalities for optimal treatment outcomes [3]. Often, these Often, these nanosystems are functionalized with biocompatible polymeric layers and/or targeting nanosystems are functionalized with biocompatible polymeric layers and/or targeting moieties, moieties, including contrast agents. Additionally, drug release is frequently controlled by an external including contrast agents. Additionally, drug release is frequently controlled by an external stimulus, stimulus, such as ultrasound, light, thermal, or chemical triggers (e.g., pH alterations), allowing for such as ultrasound, light, thermal, or chemical triggers (e.g., pH alterations), allowing for the the succeeding interaction between the imaging and the therapeutic part of nanoparticles [3]. succeeding interaction between the imaging and the therapeutic part of nanoparticles [3]. In light of the fast developments in the field of nanotheranostics and the need for regular updates In light of the fast developments in the field of nanotheranostics and the need for regular updates on products’ advances, this review focuses on polymeric, metallic, and lipid-based nanosystems for on products’ advances, this review focuses on polymeric, metallic, and lipid-based nanosystems for application on solid tumors (Figure 1). application on solid tumors (Figure1). FigureFigure 1.1. Nanotheranostics:Nanotheranostics: polymeric, metallic, and lipid-basedlipid-based nanosystems for cancer management. Hence,Hence, forfor thethe appraisalappraisal ofof currentcurrent literature,literature, aa non-systematicnon-systematic reviewreview waswas conductedconducted betweenbetween SeptemberSeptember and and October October 2018. 2018. We have We have identified identified both original both original research research and review and articles, review reporting articles, reportingrecent techniques recent techniques for the development for the development of nanother ofanostics, nanotheranostics, based on polymeric, based on polymeric, metallic, and metallic, lipid- andbased lipid-based nanoparticles nanoparticles for cancers at for early cancers or metastatic at early stage. or metastatic Only the stage.most recent Only and the representative most recent andpublications representative indexed publications in PubMed/MEDLINE indexed in or PubMed/MEDLINE Scopus, written in English or Scopus, and/or written Portuguese in English were and/orconsidered. Portuguese Otherwise, were research considered. articles Otherwise, were manually research obtained articles from were previous manually publications. obtained from previous publications. 2. Theranostic Nanosystems: From Single to Multimodality 2.1. The Evolution of the Design and Composition of Nanotheranostic Systems In terms of design, it is generally accepted that nanosystems with a size between 5 and 200 nm (and around 100 nm) are adequate for tumor targeting; nevertheless, this assumption is dependent on the type of tumor and its specificities (e.g., blood flow) [4]. For instance, clusters of nanoparticles with a size of ~100 nm, but with an individual size of 5 nm, were shown to be released when reaching the acidic media of the tumor [3]. Moreover, Dreifuss and co-workers have found different responses concerning the applications foreseeable by the size of the gold nanoparticles, ranging between 20 and 120 nm [5]. Pharmaceutics 2019, 11, x 3 of 45 2. Theranostic Nanosystems: From Single to Multimodality 2.1. The Evolution of the Design and Composition of Nanotheranostic Systems In terms of design, it is generally accepted that nanosystems with a size between 5 and 200 nm (and around 100 nm) are adequate for tumor targeting; nevertheless, this assumption is dependent on the type of tumor and its specificities (e.g., blood flow) [4]. For instance, clusters of nanoparticles Pharmaceuticswith a size2019 of, 11 ~100, 22 nm, but with an individual size of 5 nm, were shown to be released when reaching3 of 40 the acidic media of the tumor [3]. Moreover, Dreifuss and co-workers have found different responses concerning the applications foreseeable by the size of the gold nanoparticles, ranging between 20 and In their120 nm study, [5]. theIn their authors study, verified the authors that a size verified that allowed that a size the that highest allowed tumor the uptake highest (i.e., tumor optimal uptake drug (i.e., delivery)optimal was drug not delivery) equal to was that not capable equal of to achieving that capa theble highestof achieving contrast the highest enhancement contrast (i.e., enhancement optimal tumor(i.e., image) optimal [5]. tumor In the image) case of [5]. liposomes, In the case it is of well-known liposomes, that it is size well-known influences that loading size capacity,influences as loading well as stability,capacity, interaction as well as with stability, biosurface, interaction
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