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WIREs Nanomed Nanobiotechnol
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Nanomedicine and drug delivery systems in cancer and regenerative medicine

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Abstract Nanomedicine and drug delivery technologies play a prominent role in modern medicine, facilitating better treatments than conventional drugs. Nanomedicine is being increasingly used to develop new methods of cancer diagnosis and treatment, since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Regenerative medicine provides another area where innovative drug delivery technology is being studied for improved tissue regeneration. Drug delivery systems can protect therapeutic proteins and peptides against degradation in biological environments and deliver them in a controlled manner. Similarly, the combination of drug delivery systems and stem cells can improve their survival, differentiation, and engraftment. The present review summarizes the most important steps carried‐out by the group of Prof Blanco‐Prieto in nanomedicine and drug delivery technologies. Throughout her scientific career, she has contributed to the area of nanomedicine to improve anticancer therapy. In particular, nanoparticles loaded with edelfosine, doxorubicin, or methotrexate have demonstrated great anticancer activity in preclinical settings of lymphoma, glioma, and pediatric osteosarcoma. In regenerative medicine, a major focus has been the development of drug delivery systems for brain and cardiac repair. In this context, several microparticle‐based technologies loaded with biologics have demonstrated efficacy in clinically relevant animal models such as monkeys and pigs. The latest research by this group has shown that drug delivery systems combined with cell therapy can achieve a more complete and potent regenerative response. Cutting‐edge areas such as noninvasive intravenous delivery of cardioprotective nanomedicines or extracellular vesicle‐based therapies are also being explored. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Transmission electron microscopy of SQ‐gem/EF NAs (a–c). High angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) of SQ‐gem/EF NAs (d, e) (the signal corresponding to the organic material is inverted in comparison with TEM). Supramolecular organization diagram, Fourier transform image spectrum analysis and mean lattice spacing measurement of SQ‐gem/EF NAs (f). Reprinted with permission from Rodríguez‐Nogales, Sebastián, et al. (2019). Copyright 2019 Elsevier
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Edelfosine (ET) and edelfosine lipid nanoparticles (ET‐LN) exhibited an antitumor effect in a 143 B‐osteosarcoma induced model. 143 B‐osteosarcoma cells were inoculated in intratibial site of nude mice. Six days after cell injection, mice were treated with ET (peroral, 30 mg/kg, three times/week), ET‐LN (peroral, 30 mg/kg, three times/week), DOX (doxorubicin, intravenous, 2 mg/kg × 3 consecutive days every 21 days), their combination and PBS as control. (a) Effect of edelfosine (ET) and edelfosine‐lipid nanoparticles (ET‐LN) in primary OS tumor growth induced by 143 B cells. (b) After 26 days of treatment with ET and E‐LN compared to the control group, macroscopic lung metastases were enumerated. ***p ≤ .001 (n = 9, mean + SEM). Reprinted with permission from González‐Fernández et al. (2018). Copyright 2018 Elsevier
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Tumor growth evolution in the C6 glioma model in mice, expressed as fold‐increase ratio compared to tumor initial size, after treatment with edelfosine‐loaded LN (30 mg/kg) and free edelfosine (30 mg/kg) every 3 days. *p < .05; **p < .01; ***p < .001 levels by Student's t test compared to the control. Reprinted with permission from Estella‐Hermoso de Mendoza et al. (2011). Copyright 2011 Elsevier
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Timeline representing key contributions performed by the group of Prof Blanco‐Prieto in the field of nanomedicine and drug delivery
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(a) Bright field and fluorescence images of GFP‐ADSCs in combination with rhodamine‐labeled NRG‐MPs. (b) Retention of rhodamine‐MPs in the ischemic myocardium after 14 days (asterisks) and GFP‐ADSCs survival at 7 days and 3 months after their administration adhered to NRG‐MPs in the heart (green). (c) Quantification of infarct size, left ventricular (LV) wall thickness and number of capillaries at 3 months showing that ADSC‐NRG‐MPs prevented adverse cardiac remodeling and induced angiogenesis. (d) Quantification of proliferative cardiomyocytes (cTnT+ ki67+) and representative fluorescence image reflecting the enhanced proliferation of cardiac muscle cells (arrows) after treatment with ADSC‐NRG‐MPs. (e) Cardiac function improvement at 2 months after treatment with CMs adhered to MPs (hiPSC‐CM‐MPs) and integration of transplanted cells (h‐MITO, green) with other native/transplanted cardiomyocytes (arrows) reflected in the expression of connexin‐43 (red). Data are mean ± SEM. *p < .05, **p < .01 and ***p < .001. Reprinted with permission from Díaz‐Herráez et al. (2013). Copyright 2013 Elsevier; Díaz‐Herráez et al. (2017). Copyright 2017 Elsevier; Saludas et al. (2019). Copyright 2019 Aspet
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Schematic illustration of benefits and advantages of cell therapy and microparticle‐based protein delivery as well as therapeutic outcomes obtained when both are combined in a single strategy for cardiac repair
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Efficacy of microencapsulated GDNF in parkinsonian monkeys. (a) GDNF‐MPs were administered into the left putamen using stereotaxic surgery. (b) Motor function improvement was observed 9 months after treatment in GDNF‐MP‐treated monkeys (blue) compared to control (red) (***p < .001 vs. GDNF‐MP pretreatment and *p < .05 vs. blank‐MP pretreatment). (c) Therapeutic effect of GDNF‐MPs in the striatum. Representative bipolar tyrosine hydroxylase‐immunoreactive (TH‐ir) neuron found in the striatum after treatment with GDNF‐MPs. GDNF‐MPs induced a significant increase in dopaminergic neuron density in the precommissural striatum 9 months after administration (*p < .05 vs. blank‐MP treated and nontreated side). (d) Therapeutic efficacy of GDNF‐MPs in the substantia nigra. Representative dopaminergic neuron found in the substantia nigra after treatment with GDNF‐MPs. GDNF‐MPs induced a significant bilateral increase in the total number of dopaminergic neurons in both hemispheres 9 months after treatment (*p < .05 vs. blank‐MP treated and nontreated side). Reprinted with permission from Garbayo, Ansorena, et al. (2016). Copyright 2016 Elsevier; Torres‐Ortega, Saludas, Hanafy, Garbayo, and Blanco‐Prieto (2019). Copyright 2019 Elsevier
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Functional comparison between PLGA and PEGylated PLGA MPs in the cardiac tissue. (a) Confocal fluorescent images representing the phagocytosis of PLGA and PEGylated PLGA MPs in the heart. Both MPs (in red) can be observed inside macrophages (in green) since red signal and green signal colocalize in consecutive z‐stacks (5 μm length between consecutive stacks). (b) Cardiac function measured by ejection fraction showing that NRG1 or FGF1 loaded PLGA or PEGylated PLGA MPs improve heart function in rats 3 months after treatment administration. (c) NRG1 or FGF1 loaded PLGA or PEGylated PLGA MPs significantly increase the number of small caliber vessels in the cardiac tissue compared to controls 3 months after treatment. (d) NRG1 or FGF1 loaded PLGA or PEGylated PLGA MPs significantly induce the maturation of blood vessels (big caliber vessels) in the cardiac tissue compared to controls 3 months after treatment. (e) NRG1 PLGA MPs promote macrophage polarization toward a reparative phenotype in vitro and in vivo. Their effect on polarization is similar to that of IL‐4. White arrows indicate CD206+ macrophages in the cardiac tissue located close to the injection track. Scale bar 30 μm. Reprinted with permission from Pascual‐Gil et al. (2019). Copyright 2019 Taylor Francis; Pascual‐Gil, Simón‐Yarza, Garbayo, Prósper, and Blanco‐Prieto (2017). Copyright 2017 Elsevier
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PLGA MPs as vehicles for the delivery of therapeutics to the cardiac tissue. (a) Scanning electron microscope imaging of PLGA MPs. (b) Representative images showing the in vivo release of NRG1 from PLGA MPs. NRG1 (brown precipitate) can be observed for up to 12 weeks after MP administration. Scale bar 50 μm. (c) Activated biological receptor for NRG1, called ErbB4, could be detected in its phosphorylated from during at least 3 months after NRG1 PLGA MPs administration. The activated receptor was not detected when non loaded MPs were administered. Scale bar 50 μm. Scale bar of magnification inserts 8 μm. (d) NRG1 PLGA MPs significantly increase blood vessel number in the cardiac tissue compared to non‐loaded MPs. (e) Representative bipolar area NOGA maps taken at time of injection and 3 months after treatment administration in pigs. (f) Cardiac function measured by fraction shortening showing that both NRG1 and FGF1 PLGA MPs improve heart function 3 months after treatment administration in pigs. Reprinted with permission from Garbayo, Gavira, et al. (2016). Copyright 2016 Springer Nature; Pascual‐Gil, Simón‐Yarza, et al. (2015). Copyright 2015 Elsevier
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Advantages of TROMS® versus conventional multiple emulsion‐solvent evaporation method for the encapsulation of therapeutics. (a) Diagram representing TROMS technology. First a simple emulsion is formed by mixing W1 and O phases. Then a multiple emulsion is created by mixing the simple emulsion with W2. Neither shear stress nor aggressive conditions are need for drug encapsulation. * indicates where the needles used to mix the phases of the multiple emulsion are located. (b) Conventional multiple emulsion solvent‐evaporation method. Simple emulsion is formed by mixing W1 and O phases. Then a multiple emulsion is created by mixing the simple emulsion with W2. Emulsification requires external mechanical forces such as agitators or pressure. Aggressive conditions are also normally needed for homogenization
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