Ciencia Puerto Rico

Fundamental contributions to understanding the fluid mechanics of magnetic nanoparticle suspensions in time-varying magnetic fields: Ferrofluids, semi-dilute suspensions of magnetic nanoparticles, are fascinating practically relevant examples of fluids that can be manipulated by magnetic fields. Although ferrofluids have been known since the 1960s, we still lack a complete, experimentally validated formulation of their governing equations, limiting our ability engineer novel applications of ferrofluids. Rinaldi has made fundamental contributions to this field through a combination of complementary experimental, theoretical, and simulation approaches. This work led to the demonstration that the description of ferrofluid flows in rotating magnetic fields requires consideration of transport of angular momentum through the so-called couple stress and spin viscosity. Rinaldi’s group was the first to experimentally demonstrate the existence of the spin viscosity and to measure its value for ferrofluids. Rinaldi’s group has also developed simulation methods to test continuum-level phenomenological models in ways that are currently not possible through experiments.

• Arlex Chaves and Carlos Rinaldi, “Interfacial Stress Balances in Structured Continua and Free Surface Flows in Ferrofluids.” Physics of Fluids, 26:042101, 2014.
• Isaac Torres-Diaz, Angelica Cortes, Yarilyn Cedeño-Mattei, Oscar Perales-Perez, and Carlos Rinaldi, “Flows and torques in Brownian ferrofluids subjected to rotating uniform magnetic fields in a cylindrical and annular geometry.” Physics of Fluids, 26:012004, 2014.
• Denisse Soto-Aquino and Carlos Rinaldi, “Magnetoviscosity in dilute ferrofluids from rotational Brownian dynamics simulations.” Physical Review E, 82(4):046310, 2010.
• Arlex Chaves, Markus Zahn, and Carlos Rinaldi, “Spin-up flow of ferrofluids: Asymptotic theory and experimental measurements.” Physics of Fluids, 20:053102, 2008.

Synthesis and modification of magnetic nanoparticles for biomedical applications: Although magnetic nanoparticles have been synthesized since the 1960’s, most methods to obtain them yield particles with sub-optimal magnetic properties. Furthermore, many formulations intended for use in aqueous-phase result in rapid aggregation and precipitation in biological environments and in cell culture media. These limitations seriously hinder the rational design of magnetic nanoparticles for biomedical applications. Rinaldi’s group has made fundamental contributions to synthesis and modification of magnetic nanoparticles for biomedical applications by developing methods to synthesize nearly defect free particles with optimal magnetic properties and inexpensive and scalable methods to coat magnetic nanoparticles with covalently grafted layers of polysaccharides and polymers. These particles have demonstrated superior colloidal stability in biological environments and possess predictable physicochemical properties, facilitating rational design and interpretation of studies of their interactions with cells and tissues.

• Mythreyi Unni, Amanda Uhl, Shehaab Savliwala, Benjamin Savitzky, Rohan Dhavalikar, Nicolas Garraud, David Arnold, Lena Kourkoutis, Jennifer Andrew, and Carlos Rinaldi, “Thermal decomposition synthesis of iron oxide nanoparticles with diminished magnetic dead layer by controlled addition of oxygen.” ACS Nano, 11(2):2284-2303, 2017. (PMID: 28178419)
• Carola Barrera, Adriana P. Herrera, Nayla Bezares, Esteban Fachini, Juan P. Hinestroza, and Carlos Rinaldi, “Effect of poly(ethylene oxide) graft molecular weight on the colloidal properties of iron oxide nanoparticles for biomedical pplications.” Journal of Colloid and Interface Science, 377:40-50, 2012. (PMID: 22513169)
• Mar Creixell, Adriana P. Herrera, Magda Latorre-Esteves, Vanessa Ayala, Madeline Torres-Lugo, and Carlos Rinaldi, “The effect of graft method on the stability and cytotoxicity of carboxymethyl dextran coated magnetic nanoparticles.” Journal of Materials Chemistry, 20:8539-8547, 2010.
• Carola Barrera, Adriana P. Herrera, and Carlos Rinaldi, “Colloidal dispersions of monodisperse magnetite nanoparticles modified with poly(ethylene glycol).” Journal of Colloid and Interface Science, 329:107-113, 2009. (PMID: 18930466)

Understanding nanoparticle transport in complex fluids and biological environments: The intracellular environment can be described as crowded, complex, and confined, where biomacromolecules with characteristic dimensions of 1-10’s of nm are present at high concentration, and where membranes, organelles, and filamentous matrices restrict motion. Although important in designing nanoparticles for biomedical applications, understanding of the transport of nanoparticles in such environments remains limited. Rinaldi’s group has developed methods based on magnetic measurements that can assess nanoparticle stability and mobility in complex fluid environments, including biological fluids. This approach requires small sample volumes (~20 μl), low concentrations of nanoparticles (~0.02% v/v), and does not require optic access to the sample. Work has demonstrated that this technique is quantitatively accurate, can provide insight into novel nanoscale phenomena, and can be used to assess the interaction of nanoparticles and proteins in situ at physiologically-relevant concentrations. These findings pave the way towards improved understanding of nanoparticle transport in complex fluid environments relevant to biomedical applications.

• Ana C. Bohorquez, Mythreyi Unni, Sayali Belsare, Andreina Chiu Lam, Lori Rice, Christine Pampo, Dietmar Siemann, and Carlos Rinaldi, “.” Bioconjugate Chemistry, 29(8):2793-2805, 2018.
• Lorena P. Maldonado-Camargo^G, Chuncheng Yang, and Carlos Rinaldi, “Scale-dependent rotational diffusion of nanoparticles in polymer solutions.” Nanoscale, 9(33):12039-12050, 2017.
• Ana C. Bohorquez, Chuncheng Yang, Donald Bejleri, and Carlos Rinaldi, “Rotational diffusion of magnetic nanoparticles in protein solutions.” Journal of Colloid and Interface Science, 506:393-402, 2017.
• Lorena P. Maldonado-Camargo and Carlos Rinaldi, “Breakdown of the Stokes-Einstein relation for the rotational diffusivity of polymer grafted nanoparticles in polymer melts.” Nano Letters, 16:6767-6773, 2016.

Harnessing Localized Nanoscale Heating in Nanoparticle Thermal Cancer Therapy: Although initially researchers had imagined that nanoscale heating effects in the vicinity of nanoparticles might be sufficient to damage and kill cells in the absence of a tissue-level temperature rise to the hyperthermia range (43-47°C), the paradigm in the field of nanoparticle thermal cancer therapy since the late 1990s had been that it was impossible to kill cancer cells in this way. Through a combination of magnetic nanoparticle engineering and judicious experimentation, Rinaldi’s research has demonstrated that this paradigm was incorrect and that nanoscale heating phenomena in the vicinity of receptor-targeted magnetic nanoparticles can lead to significant (>99%) reductions in cancer cell clonogenic survival without any macroscopic temperature rise. Furthermore, work has demonstrated that one mechanism responsible for cell death is disruption of nanoparticle-loaded lysosomes, activating lysosomal death pathways that are upregulated in many cancer cells. Furthermore, Rinaldi’s group recently demonstrated the potential of magnetic particle imaging guided magnetic hyperthermia for precise and spatially selective cancer thermal therapy. These findings are transforming the field of magnetic nanoparticle thermal therapy.

• Zhi Wei Tay, Prashant Chandrasekharan, Andreina Chiu-Lam, Daniel Hensley, Rohan Dhavalikar, Xinyi Zhou, Elaine Yu, Patrick Goodwill, Bo Zheng, Carlos Rinaldi, Steven M. Conolly, “Magnetic Particle Imaging Guided Heating In Vivo using Gradient Fields For Arbitrary Localization of Thermal Therapy.” ACS Nano, 12(4):3699-3713, 2018.
• Maribella Domenech, Ileana Marrero-Berrios, Madeline Torres-Lugo, and Carlos Rinaldi, “Lysosomal Membrane Permeabilization by Targeted Magnetic Nanoparticles in Alternating Magnetic Fields.” ACS Nano, 7(6):5091-5101, 2013.
• Liliana Polo-Corrales and Carlos Rinaldi, “Monitoring iron oxide nanoparticle surface temperature in an alternating magnetic field using thermoresponsive-fluorescent polymers.” Journal of Applied Physics, 111:07B334, 2012.
• Mar Creixell, Ana C. Bohorquez, Madeline Torres-Lugo, and Carlos Rinaldi, “EGFR-targeted magnetic nanoparticle heaters can kill cancer cells without a perceptible temperature rise.” ACS Nano, 5(9), 7124-7129, 2011.

Elucidating the Mechanisms Underlying Enhanced Synergy of Magnetic Nanoparticle Hyperthermia and Anti-Cancer Drugs: Hyperthermia (tissue temperature rise to 43-47°C) has been extensively explored in combination with radiotherapy and chemotherapy as a means to enhance treatment outcome, with positive results for some cancer types and treatment combinations. Rinaldi’s studies comparing traditional forms of hyperthermia with hyperthermia induced by magnetic nanoparticles led to hypothesize that localized nanoscale heating in the vicinity of the nanoparticles would cause additional physical damage, resulting in enhanced synergistic effects. Work has demonstrated that this is the case for platinum-based drugs and proteasome inhibitors, and that magnetic nanoparticle hyperthermia significantly re-sensitizes cancer cells with acquired drug resistance to these agents. Furthermore, it has been demonstrated that a variety of mechanisms underlie this enhancement/re-sensitization, including permeabilization/fluidization of the cell membrane, direct damage to microtubules, and increased proteotoxic stress.

• Angelie Rivera-Rodriguez, Andreina Chiu-Lam, Viacheslav Morozov, Alexander Ishov and Carlos Rinaldi, “Magnetic nanoparticle hyperthermia potentiates Paclitaxel activity in sensitive and resistant breast cancer cells.” International Journal of Nanomedicine, 2018(13):4771-4779, 2018.
• Merlis Alvarez-Berrios, Angel Castillo, Carlos Rinaldi, and Madeline Torres-Lugo, “Enhanced proteotoxic stress: one of the contributors for hyperthermic potentiation of the proteasome inhibitor bortezomib using magnetic nanoparticles,” Biomaterials Science, 3:391-400, 2015.
• Merlis Alvarez-Berrios, Angel Castillo, Jose Mendéz, Orlando Soto, Carlos Rinaldi, and Madeline Torres-Lugo, “Hyperthermic potentiation of cisplatin by magnetic nanoparticle heaters is correlated with an increase in cell membrane fluidity.” International Journal of Nanomedicine, 2013(8): 1003-1013, 2013. (PMCID: PMC3593770)
• Jason S. Lee, Hector L. Rodríguez-Luccioni, Anil K. Sood, Gabriel Lopez-Berestein, Carlos Rinaldi, and Madeline Torres-Lugo, “Hyperthermia induced by magnetic nanoparticles improves the effectiveness of the anticancer drug cis-diamminedichloroplatinum.” Journal of Nanoscience and Nanotechnology, 11:4153-4157, 2011.

Understanding the role of finite relaxation time of magnetic nanoparticles on their heating and magnetic particle imaging performance: The response of biocompatible magnetic nanoparticles to alternating magnetic fields forms the basis of exciting biomedical applications, such as nanoscale magnetic thermal therapy (magnetic hyperthermia), magnetic particle imaging, relaxometric sensing, and magnetically-triggered drug release. In all these applications, understanding the coupling between magnetic, hydrodynamic, thermal, and magnetocrystalline torques on the magnetic nanoparticle dipoles is vital to predict the performance of magnetic nanoparticles. Rinaldi’s group has made fundamental contributions to understanding these phenomena through a combination of theoretical/simulation and experimental approaches. Modeling of rotational Brownian relaxation and internal dipole rotation in the particles has led to understanding of the effect of non-linear magnetization on heat dissipation rates and understanding of the role of relaxation time and mechanism on magnetic particle imaging signal strength and resolution. This understanding is enabling realization of the theranostic potential of magnetic nanoparticles in magnetic particle imaging and hyperthermia applications.

• Zhiyuan Zhao and Carlos Rinaldi, “Magnetization dynamics and energy dissipation of interacting magnetic nanoparticles in alternating magnetic fields with and without a static bias field.” The Journal of Physical Chemistry C, 122(36):21018-21030, 2018.
• Rohan Dhavalikar and Carlos Rinaldi, “Theoretical Predictions for the Spatial Distribution of Magnetic Nanoparticle Heating in Magnetic Particle Imaging Field Gradients.” Journal of Magnetism and Magnetic Materials, 419:267-273, 2016.
• Denisse Soto-Aquino and Carlos Rinaldi, “Nonlinear energy dissipation in magnetic nanoparticle suspensions,” Journal of Magnetism and Magnetic Materials, 393:46-55, 2015.
• Rohan Dhavalikar and Carlos Rinaldi, “On the effect of finite magnetic relaxation on the magnetic particle imaging performance of magnetic nanoparticles.” Journal of Applied Physics, 115:074308, 2014.