Diseño y desarrollo de materiales poliméricos anfifílicos sensibles a estímulos y su evaluación como vehículos selectivos para el transporte de fármacos hacia células cancerígenas

Pese a que durante los últimos años se han llevado a cabo múltiples investigaciones orientadas hacia el desarrollo de nuevos agentes quimioterapéuticos, muchos de los compuestos que presentan actividad no pueden ser trasladados a pruebas clínicas o finalmente comercializados debido a problemas de selectividad, estabilidad, biodisponibilidad, solubilidad, toxicidad, entre otros. ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nrd4609","ISSN":"1474-1784","abstract":"This Analysis article describes the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer.The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality.Safety and toxicology are the largest sources of failure within the data set.The link between calculated physicochemical properties and frequent causes of attrition (preclinical toxicology, clinical safety and human pharmacokinetics) is assessed.Analysis of this data set shows that none of the physicochemical descriptors we examined correlates with preclinical toxicology outcomes.This work is the first to indicate a link between lipophilicity and clinical failure owing to safety issues. The utility of this finding in a prospective sense is discussed.Although control of physicochemical properties is clearly important, this analysis suggests that further stringency in this respect is unlikely to have a significant effect on attrition in development and that additional work is required to address safety-related failures.","author":[{"dropping-particle":"","family":"Waring","given":"Michael J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arrowsmith","given":"John","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leach","given":"Andrew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leeson","given":"Paul D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mandrell","given":"Sam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Owen","given":"Robert M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pairaudeau","given":"Garry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pennie","given":"William D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pickett","given":"Stephen D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Jibo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallace","given":"Owen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weir","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Drug Discovery","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2015"]]},"page":"475-486","title":"An analysis of the attrition of drug candidates from four major pharmaceutical companies","type":"article-journal","volume":"14"},"uris":["http://www.mendeley.com/documents/?uuid=02a332a5-7716-4369-a5a0-1290b1dddbd6"]}],"mendeley":{"formattedCitation":"1","plainTextFormattedCitation":"1","previouslyFormattedCitation":"1"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}1 Por ejemplo, la camptotecina (CMT) ha sido empleada en pruebas clínicas fase I y II para el tratamiento del cáncer de estómago y leucemia, sin embargo, bajo condiciones fisiológicas sufre la apertura del anillo lactónico generando un carboxilato que posee menos actividad que su estructura original; además de esto, la CMT posee baja solubilidad, bajas velocidades de respuesta y alta toxicidad (inmunosupresión, toxicidad gastrointestinal, cistitis hemorrágica, entre otros).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"2156-6976","abstract":"Camptothecin (CPT) was discovered from plant extracts more than 60 years ago. Since then, only two CPT analogues (irinotecan and topotecan) have been approved for cancer treatment, although several thousand CPT derivatives have been synthesized and many of them were actively studied in our research community over the past 6+ decades. In this review article, we briefly summarize: (1) the discovery and early development of CPTs, (2) the recognized CPT mechanism of action (MOA), (3) the synthesis of CPT and CPT analogues, and (4) the structure-activity relationship (SAR) of CPT and its analogues. Next, we provide evidence that certain CPT analogues can exert improved efficacy with low toxicity independently of topoisomerase I (Top1) inhibition; instead, these CPT analogues use novel MOAs by targeting important cancer survival-associated oncogenic proteins and/or by bypassing various treatment-resistant mechanisms. We then present a comprehensive review of the most advanced CPT analogues in clinical development, with the goal of resolving why no new CPTs have been FDA approved for cancer treatment, beyond irinotecan and topotecan. We argue that new CPT Top1 inhibitor drugs are unlikely being found to be significantly better than irinotecan and/or topotecan in terms of the overall antitumor activity and toxicity. The significance of CPT analogues that possess novel MOAs has not been sufficiently recognized so far. In our opinion, this is a research area with great potential to make a breakthrough for development of the next generation of CPT analogues that possess high efficacy (due to novel targets) and low toxicity (due to low inhibition of Top1 activity/function) for effective treatment of human disease, including cancer.","author":[{"dropping-particle":"","family":"Li","given":"Fengzhi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Tao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Qingyong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ling","given":"Xiang","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American journal of cancer research","id":"ITEM-1","issue":"12","issued":{"date-parts":[["2017","12","1"]]},"language":"eng","page":"2350-2394","publisher":"e-Century Publishing Corporation","title":"Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?","type":"article-journal","volume":"7"},"uris":["http://www.mendeley.com/documents/?uuid=8d3c8cb4-7b07-4eaa-b186-c82aea159392"]}],"mendeley":{"formattedCitation":"2","plainTextFormattedCitation":"2","previouslyFormattedCitation":"2"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}2 Por otra parte, es bien conocido que los quimioterapéuticos disponibles en el mercado de administración intravenosa causan efectos secundarios indeseados, y, debido a que se distribuyen en el organismo de acuerdo con su afinidad con los tejidos, pocas moléculas del agente quimioterapéutico alcanzan el blanco sobre el cual se espera que actúen. Por ejemplo, el cisplatino (CPT) una de las sustancias más utilizadas en el tratamiento de diversos tipos de cáncer, presenta efectos secundarios como nefrotoxicidad causada por bioacumulación, hepatotoxicidad por estrés oxidativo, ototoxicidad debido a la alta generación de especies reactivas de oxígeno (EROs), entre otros.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.bioorg.2019.102925","ISSN":"10902120","PMID":"31003078","abstract":"Cisplatin or (SP-4-2)-diamminedichloridoplatinum(II) is one of the most potential and widely used drugs for the treatment of various solid cancers such as testicular, ovarian, head and neck, bladder, lung, cervical cancer, melanoma, lymphomas and several others. Cisplatin exerts anticancer activity via multiple mechanisms but its most acceptable mechanism involves generation of DNA lesions by interacting with purine bases on DNA followed by activation of several signal transduction pathways which finally lead to apoptosis. However, side effects and drug resistance are the two inherent challenges of cisplatin which limit its application and effectiveness. Reduction of drug accumulation inside cancer cells, inactivation of drug by reacting with glutathione and metallothioneins and faster repairing of DNA lesions are responsible for cisplatin resistance. To minimize cisplatin side effects and resistance, combination therapies are used and have proven more effective to defect cancers. This article highlights a systematic description on cisplatin which includes a brief history, synthesis, action mechanism, resistance, uses, side effects and modulation of side effects. It also briefly describes development of platinum drugs from very small cisplatin complex to very large next generation nanocarriers conjugated platinum complexes.","author":[{"dropping-particle":"","family":"Ghosh","given":"Sumit","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bioorganic Chemistry","id":"ITEM-1","issue":"March","issued":{"date-parts":[["2019"]]},"page":"102925","publisher":"Elsevier","title":"Cisplatin: The first metal based anticancer drug","type":"article-journal","volume":"88"},"uris":["http://www.mendeley.com/documents/?uuid=586bfe75-856e-45d6-a4ef-b553e666e7bd"]}],"mendeley":{"formattedCitation":"3","plainTextFormattedCitation":"3","previouslyFormattedCitation":"3"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}3 Como alternativa para mitigar las desventajas que limitan el uso clínico de sustancias con actividad farmacológica frente al cáncer, el empleo de vehículos nanoestructurados tales como nanopartículas poliméricas (NP) ha permitido la utilización de nuevos agentes terapéuticos, disminuido los efectos tóxicos de fármacos convencionales utilizados en quimioterapia y ha aumentado la selectividad en la entrega de estos.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1039/C8PY01160E","ISSN":"1759-9954","abstract":"This review summarizes the current state of prodrugs and elaborates the logical design and future development of the prodrug platform.","author":[{"dropping-particle":"","family":"Meng","given":"Qingye","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhou","given":"Liping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Yixin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Bing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Youqing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cong","given":"Hailin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Polymer Chemistry","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"306-324","publisher":"Royal Society of Chemistry","title":"Logical design and application of prodrug platforms","type":"article-journal","volume":"10"},"uris":["http://www.mendeley.com/documents/?uuid=5d021e7e-531e-4532-8b4a-bf4726b96a58"]},{"id":"ITEM-2","itemData":{"DOI":"10.1038/nrd.2018.183","ISSN":"14741784","abstract":"Biologics now constitute a significant element of available medical treatments. Owing to their clinical and commercial success, biologics are a rapidly growing class and have become a dominant therapeutic modality. Although most of the successful biologics to date are drugs that bear a peptidic backbone, ranging from small peptides to monoclonal antibodies (~500 residues; 150 kDa), new biologic modalities, such as nucleotide-based therapeutics and viral gene therapies, are rapidly maturing towards widespread clinical use. Given the rise of peptides and proteins in the pharmaceutical landscape, tremendous research and development interest exists in developing less-invasive or non-invasive routes for the systemic delivery of biologics, including subcutaneous, transdermal, oral, inhalation, nasal and buccal routes. This Review summarizes the current status, latest updates and future prospects for such delivery of peptides, proteins and other biologics.","author":[{"dropping-particle":"","family":"Anselmo","given":"Aaron C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gokarn","given":"Yatin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mitragotri","given":"Samir","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Drug Discovery","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2018"]]},"page":"19-40","publisher":"Nature Publishing Group","title":"Non-invasive delivery strategies for biologics","type":"article-journal","volume":"18"},"uris":["http://www.mendeley.com/documents/?uuid=c3bb26a2-0d58-43c8-a75e-ce7f71676913"]}],"mendeley":{"formattedCitation":"4,5","plainTextFormattedCitation":"4,5","previouslyFormattedCitation":"4,5"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}4,5 Estos materiales poliméricos presentan baja toxicidad, alta biocompatibilidad y son capaces de autoensamblarse en medio acuoso, lo cual les confiere la capacidad de encapsular fármacos, favoreciendo su solubilización e incrementado su estabilidad química. ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1039/C8PY01160E","ISSN":"1759-9954","abstract":"This review summarizes the current state of prodrugs and elaborates the logical design and future development of the prodrug platform.","author":[{"dropping-particle":"","family":"Meng","given":"Qingye","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhou","given":"Liping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Yixin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Bing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Youqing","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cong","given":"Hailin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Polymer Chemistry","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"306-324","publisher":"Royal Society of Chemistry","title":"Logical design and application of prodrug platforms","type":"article-journal","volume":"10"},"uris":["http://www.mendeley.com/documents/?uuid=5d021e7e-531e-4532-8b4a-bf4726b96a58"]}],"mendeley":{"formattedCitation":"4","plainTextFormattedCitation":"4","previouslyFormattedCitation":"4"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}4,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1039/c6py01872f","ISBN":"1759-9954","ISSN":"17599962","abstract":"This review summarizes pH-responsive monomers, polymers and their derivative nano- and micro-structures including micelles, cross-linked micelles, microgels and hydrogels.","author":[{"dropping-particle":"","family":"Kocak","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tuncer","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bütün","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Polymer Chemistry","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017"]]},"page":"144-176","publisher":"Royal Society of Chemistry","title":"PH-Responsive polymers","type":"article-journal","volume":"8"},"uris":["http://www.mendeley.com/documents/?uuid=8fb6ceae-26d9-4eae-98eb-3044dcc2c9a6"]}],"mendeley":{"formattedCitation":"6","plainTextFormattedCitation":"6","previouslyFormattedCitation":"6"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}6 Además de lo mencionado anteriormente, las particularidades de las células cancerígenas permiten diseñar nanoestructuras sensibles a estímulos químicos, pues su metabolismo acelerado conduce a la generación de microambientes extra e intracelulares diferentes a los de una célula normal. Estos microambientes se caracterizan por tener un pH menor, un aumento en la concentración de EROs y glutatión (GSH), los cuales desencadenan cambios estructurales como ruptura de enlaces tipo acetal (RO-CR2-OR), tioacetal (RS-CR2-SR) y disulfuro (RS-SR) de la nanoestructura, controlando así la liberación del fármaco cambiando su farmacocinética y farmacodinamia.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jsps.2020.01.004","ISSN":"13190164","abstract":"In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.","author":[{"dropping-particle":"","family":"Alsehli","given":"Mosa","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Saudi Pharmaceutical Journal","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2020"]]},"page":"255-265","publisher":"The Author(s)","title":"Polymeric nanocarriers as stimuli-responsive systems for targeted tumor (cancer) therapy: Recent advances in drug delivery","type":"article-journal","volume":"28"},"uris":["http://www.mendeley.com/documents/?uuid=c2648e29-191d-4394-9d2b-e736d7ebb100"]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/marc.201900038","ISSN":"15213927","PMID":"30977952","abstract":"Dynamic bonds have achieved significant attention for their ability to impart fascinating properties to polymeric materials, such as high mechanical strength, self-healing, shape memory, 3D printability, and conductivity. Incorporating multiple dynamic bonds into polymer systems affords an attractive and efficient approach to endow multiple functionalities. This mini-review focuses on the use of complementary dynamic interactions to control the properties of soft materials. Owing to the diversity in dynamic chemistries that can be explored, the scope of this article is restricted to polymers and does not include colloids, amphiphiles, liquid crystals, or biological soft matter.","author":[{"dropping-particle":"","family":"Jiang","given":"Zhen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhaskaran","given":"Ayana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aitken","given":"Heather M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shackleford","given":"India C.G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Connal","given":"Luke A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Macromolecular Rapid Communications","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2019"]]},"page":"1-10","title":"Using Synergistic Multiple Dynamic Bonds to Construct Polymers with Engineered Properties","type":"article-journal","volume":"40"},"uris":["http://www.mendeley.com/documents/?uuid=d8b5e39f-588f-42f1-bb59-35658d3d446f"]}],"mendeley":{"formattedCitation":"7,8","plainTextFormattedCitation":"7,8","previouslyFormattedCitation":"7,8"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}7,8 Adicionalmente, la encapsulación y estabilidad del fármaco en las NP se puede incrementar realizando funcionalizaciones con moléculas “nodrizas” como las ciclodextrinas (CD), capaces de generar complejos de inclusión con moléculas orgánicasADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/978-3-319-76159-6","ISBN":"9783540228608","abstract":"Cyclodextrins are natural oligosaccharides obtained from starch. They were discovered in 1891 by Villiers, and attracted major scientific and industrial interests from the late 1970s. Actually, cyclodextrins are among the most remark- able macrocyclic molecules with major theoretical and practical interest for chem- istry and biology. Cyclodextrins belong to the family of cage molecules due to their structure, which is composed of a hydrophobic cavity that can encapsulate other molecules. Indeed, the most characteristic feature of cyclodextrins is their ability to form inclusion complexes with various molecules through host-guest interactions. Cyclodextrins and their derivatives have a wide variety of practical applications including pharmacy, medicine, foods, cosmetics, toiletries, catalysis, chromatogra- phy, biotechnology, nanotechnology, and textile production. Cyclodextrins are also the object of numerous fundamental studies. Between 2011 and 2015, 18,430 cyclodextrin- related publications have been published. In this chapter, after a brief description of cyclodextrin basics, we highlight selected works on cyclodextrins published over the last 5 years by various research groups","author":[{"dropping-particle":"","family":"Crini","given":"Gregorio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fourmentinn","given":"Sophie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lichtfouse","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2018"]]},"number-of-pages":"262","title":"Cyclodextrin Fundamentals, Reactivity and Analysis","type":"book"},"uris":["http://www.mendeley.com/documents/?uuid=76a4cc17-90cb-4e2e-ac57-9f156b9f5155"]}],"mendeley":{"formattedCitation":"9","plainTextFormattedCitation":"9","previouslyFormattedCitation":"9"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}9 e inorgánicas,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"18278620","abstract":"Solubility and the dissolution rates of poorly water soluble drugs is an important aspect of formulation and development. Cisplatin is a drug with small molecular weight (Mol. Wt. 300.05) and is inherently associated with lack of tumor selectivity and short blood circulation time, which cause various toxic side effects. The purpose of the present study was to prepare a physically and chemically stable Cisplatin conjugate to increase the drug solubility, to improve its dissolution rate and to examine the possibility for reduced toxicity. Therefore, we prepared Cisplatin/HP-β-CD complexes and investigated the stabilizing effect of HP-β-CD on Cisplatin. Solid inclusion complexes of Cisplatin/ HP-β-CD were prepared in 1:1 and 1:2 molar ratios by freeze-drying method. Complex formation was evaluated by comparing the infrared (FT-IR) spectra of the solid complexes with a simple physical mixture containing the same amount of Cisplatin. FT-IR experiments provided data indicating that the amino groups of Cisplatin was involved in the inclusion process. Differential scanning calorimetry (DSC) indicated stronger drug amorphization and entrapment in HP-β-CD. Phase solubility study was used to evaluate the complexation in solution at 25 °C. The phase solubility studies indicated the formation of Cisplatin/HP-β-CD inclusion complexes at a 1:1M ratio in solution. The solubility and dissolution rate of Cisplatin were significantly improved by complexation with HP-β-CD. The complexes formed were quite stable.","author":[{"dropping-particle":"","family":"Balaji","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pandey","given":"V. P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Srinath","given":"M. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Manavalan","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pharmacologyonline","id":"ITEM-1","issued":{"date-parts":[["2009"]]},"page":"1135-1143","title":"Synthesis and characterization studies of cisplatin/hydroxypropyl-β-cyclodextrin complex","type":"article-journal","volume":"1"},"uris":["http://www.mendeley.com/documents/?uuid=829007dd-e92d-476d-abd1-bce16cd10136"]}],"mendeley":{"formattedCitation":"10","plainTextFormattedCitation":"10","previouslyFormattedCitation":"10"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}10 lo cual conduce a una variación en sus propiedades físicas, químicas y la manera en la cual las sustancias interactúan con sistemas biológicos. Las CD son capaces de incrementar la solubilidad en medios acuosos de fármacos hidrófobos y alterar sus propiedades farmacocinéticas,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/b978-0-12-813663-8.00015-4","ISBN":"9780128136638","abstract":"Cyclodextrins (CyDs) are bioavailable, water soluble molecules with a typical structure, able to form inclusion complexes with a large range of polar and apolar guests. These features determine their applicability in different fields. In recent years, nanosystems based on CyDs have been explored for pharmacological applications. This chapter will focus in particular on the nanoparticles based on CyD polymers. Some successful examples for their application in vivo will be discussed. Among these, the most relevant systems are based on the Cyclosert delivery platform, designed specifically to overcome some limitations in the systemic transport of drugs, and the Rondel platform, engineered to deliver genes. Both these systems are currently in Phase II clinical development.","author":[{"dropping-particle":"","family":"Oliveri","given":"Valentina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vecchio","given":"Graziella","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Organic Materials as Smart Nanocarriers for Drug Delivery","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"number-of-pages":"619-658","publisher":"Elsevier Inc.","title":"Cyclodextrin-based nanoparticles * *Dedicated to the memory of Dr. Carmela Spatafora.","type":"book"},"uris":["http://www.mendeley.com/documents/?uuid=cef9a4fb-65bb-4fe5-b42d-b00e50d065d5"]}],"mendeley":{"formattedCitation":"11","plainTextFormattedCitation":"11","previouslyFormattedCitation":"11"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}11 con lo cual se puede incrementar el tiempo de circulación del fármaco, reducir su acumulación en tejidos y proteger del metabolismo de primer paso. Con base en lo expuesto anteriormente, el presente proyecto comprende el diseño, síntesis y evaluación de compuestos poliméricos anfifílicos conjugados con CD, con la capacidad de agregarse para generar nano-vehículos que permitan la encapsulación de camptotecina y cisplatino mediante interacciones anfitrión-huésped. Además, estas moléculas contarán con enlaces escindibles en presencia de ambientes con pH ácidos y elevadas concentraciones de especies redox (EROs y GSH), lo que permitirá una desintegración del nano-vehículo y la liberación controlada del fármaco en ambientes cercanos a las células cancerígenas de cérvix HeLa (CCL2) y colon HT-29 (HTB-38). La selectividad de la liberación del fármaco por parte de estos sistemas será determinada mediante comparación con la citotoxicidad sobre fibroblastos sanos de ratón L929, y se estudiará el proceso de internalización celular de los sistemas más promisorios (Esquema 1). Esquema 1. Como se observa en el esquema 1, los copolímeros estarán compuestos por un bloque de monometil éter polietilenglicol (mPEG), el cual facilitará que las nanoestructuras se dispersen en medios fisiológicos y asegure su paso a través diversas barreras biológicas;ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1126/scitranslmed.3003594","ISSN":"19466234","abstract":"Prevailing opinion suggests that only substances up to 64 nm in diameter can move at appreciable rates through the brain extracellular space (ECS). This size range is large enough to allow diffusion of signaling molecules, nutrients, and metabolic waste products, but too small to allow efficient penetration of most particulate drug delivery systems and viruses carrying therapeutic genes, thereby limiting effectiveness of many potential therapies. We analyzed the movements of nanoparticles of various diameters and surface coatings within fresh human and rat brain tissue ex vivo and mouse brain in vivo. Nanoparticles as large as 114 nm in diameter diffused within the human and rat brain, but only if they were densely coated with poly(ethylene glycol) (PEG). Using these minimally adhesive PEG-coated particles, we estimated that human brain tissue ECS has some pores larger than 200 nm and that more than one-quarter of all pores are ?100 nm. These findings were confirmed in vivo in mice, where 40- and 100-nm, but not 200-nm, nanoparticles spread rapidly within brain tissue, only if densely coated with PEG. Similar results were observed in rat brain tissue with paclitaxel-loaded biodegradable nanoparticles of similar size (85 nm) and surface properties. The ability to achieve brain penetration with larger nanoparticles is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find use in the treatment of brain tumors, stroke, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible.","author":[{"dropping-particle":"","family":"Nance","given":"Elizabeth A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Woodworth","given":"Graeme F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sailor","given":"Kurt A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shih","given":"Ting Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xu","given":"Qingguo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swaminathan","given":"Ganesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xiang","given":"Dennis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eberhart","given":"Charles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hanes","given":"Justin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Science Translational Medicine","id":"ITEM-1","issue":"149","issued":{"date-parts":[["2012"]]},"title":"A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue","type":"article-journal","volume":"4"},"uris":["http://www.mendeley.com/documents/?uuid=78a222fa-e798-4a61-919c-74f9b8fba69f"]}],"mendeley":{"formattedCitation":"12","plainTextFormattedCitation":"12","previouslyFormattedCitation":"12"},"properties":{"noteIndex":0},"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}12 y una cadena hidrófoba compuesta por policaprolactona (PCL) y/o policarbonato (PC) que cuenta con la presencia de enlaces tipo acetal (RO-CR2-OR), tioacetal (RS-CR2-SR) y disulfuro (RS-SR), de tal modo que tras su fragmentación proceda la liberación del quimioterapéutico, haciendo este proceso más selectivo hacia ambientes cercanos al tumor y se reduzca el daño en otro tipo de tejidos. Adicionalmente, la presencia de CD incrementará la cantidad de fármaco encapsulado en la nanoestructura, el tiempo de vida del agente quimioterapéutico, la estabilidad de la estructura micelar debido al entrecruzamiento generado y la probabilidad que la nanoestructura llegue a la célula carcinogénica y el fármaco a su diana terapéutica. En aras de establecer relaciones entre la estructura de los materiales propuestos y su aplicación, se obtendrá un conjunto de copolímeros en los cuales se tendrá como variable: 1) Longitud del segmento de mPEG; 2) distintas relaciones molares de los segmentos hidrófilo (PEG) / hidrófobo; 3) composición del segmento hidrófobo PCL y PC; 4) enlaces de tipo RO-CR2-OR, RS-CR2-SR y RS-SR sensibles a estímulos de pH y condiciones redox; 5) número de moléculas de CD a injertar 1, 3 y 5. Por otro lado, con el fin de evaluar la encapsulación y liberación de los sistemas de manera expedita, se plantea inicialmente la obtención de polímeros con enlaces de tipo acetal y se variarán los pesos moleculares de mPEG (1 o 2KDa), PC (1.5, 2.5 y 3.5KDa) y las unidades CD (1, 3 o 5). De acuerdo con los resultados de encapsulación y liberación de estos sistemas se establecerán los mejores pesos moleculares de mPEG, PC y unidades de CD y se procederá con la síntesis de los sistemas de PCL y enlaces tioacetal y disulfuro. Estos sistemas serán cargados con el fármaco y se evaluará su citotoxicidad sobre las líneas celulares propuestas, el sistema que presente mejor actividad le será estudiada su internalización celular (Esquema 2). Esquema 2. Con el desarrollo de este proyecto se pretende la obtención de nano-vehiculos selectivos en la entrega de agentes quimioterapéuticos que presenten buena actividad en el tratamiento del cáncer pero con baja estabilidad en condiciones fisiológicas y alta toxicidad; y, debido a que este tipo de nanoestructuras mejora la permeabilidad y retención 13 se pueda disminuir la dosis efectiva de los tratamientos ya disponibles, constituyendo un punto de partida hacia el desarrollo de terapias más seguras.