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The current spotlight of cancer therapeutics is shifting towards personalized medicine with the widespread use of monoclonal antibodies (mAbs). Despite their increasing potential, mAbs have an intrinsic limitation related to their inability to cross cell membranes and reach intracellular targets. Nanotechnology offers promising solutions to overcome this limitation, however, formulation challenges remain. These challenges are the limited loading capacity (often insufficient to achieve clinical dosing), the complex formulation methods, and the insufficient characterization of mAb-loaded nanocarriers. Here, we present a new nanocarrier consisting of hyaluronic acid-based nanoassemblies (HANAs) specifically designed to entrap mAbs with a high efficiency and an outstanding loading capacity (50%, w/w). HANAs composed by an mAb, modified HA and phosphatidylcholine (PC) resulted in sizes of ~ 100 nm and neutral surface charge. Computational modeling identified the principal factors governing the high affinity of mAbs with the amphiphilic HA and PC. HANAs composition and structural configuration were analyzed using the orthogonal techniques cryogenic transmission electron microscopy (cryo-TEM), asymmetrical flow field-flow fractionation (AF4), and small-angle X-ray scattering (SAXS). These techniques provided evidence of the formation of core-shell nanostructures comprising an aqueous core surrounded by a bilayer consisting of phospholipids and amphiphilic HA. In vitro experiments in cancer cell lines and macrophages confirmed HANAs’ low toxicity and ability to transport mAbs to the intracellular space. The reproducibility of this assembling process at industrial-scale batch sizes and the long-term stability was assessed. In conclusion, these results underscore the suitability of HANAs technology to load and deliver biologicals, which holds promise for future clinical translation.
Crescioli, S.; Kaplon, H.; Chenoweth, A.; Wang, L.; Visweswaraiah, J.; Reichert, J. M. Antibodies to watch in 2024. mAbs 2024, 16, 2297450.
Cruz, E.; Kayser, V. Monoclonal antibody therapy of solid tumors: Clinical limitations and novel strategies to enhance treatment efficacy. Biologics 2019, 13, 33–51.
Mosch, R.; Guchelaar, H. J. Immunogenicity of monoclonal antibodies and the potential use of HLA haplotypes to predict vulnerable patients. Front. Immunol. 2022, 13, 885672.
Carter, P. J.; Lazar, G. A. Next generation antibody drugs: Pursuit of the 'high-hanging fruit'. Nat. Rev. Drug Discov. 2018, 17, 197–223.
Estévez, A. M.; Lapuhs, P.; Pineiro-Alonso, L.; Alonso, M. J. Personalized cancer nanomedicine: Overcoming biological barriers for intracellular delivery of biopharmaceuticals. Adv. Mater. 2024, 36, 2309355
Durán-Lobato, M.; López-Estévez, A. M.; Cordeiro, A. S.; Dacoba, T. G.; Crecente-Campo, J.; Torres, D.; Alonso, M. J. Nanotechnologies for the delivery of biologicals: Historical perspective and current landscape. Adv. Drug Deliv. Rev. 2021, 176, 113899.
Anselmo, A. C.; Gokarn, Y.; Mitragotri, S. Non-invasive delivery strategies for biologics. Nat. Rev. Drug Discov. 2019, 18, 19–40.
Shi, J. J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2017, 17, 20–37.
Yu, M.; Wu, J.; Shi, J. J.; Farokhzad, O. C. Nanotechnology for protein delivery: Overview and perspectives. J. Control. Release 2016, 240, 24–37.
Perrault, S. D.; Walkey, C.; Jennings, T.; Fischer, H. C.; Chan, W. C. W. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 2009, 9, 1909–1915.
Schädlich, A.; Caysa, H.; Mueller, T.; Tenambergen, F.; Rose, C.; Göpferich, A.; Kuntsche, J.; Mäder, K. Tumor accumulation of NIR fluorescent PEG-PLA nanoparticles: Impact of particle size and human xenograft tumor model. ACS Nano 2011, 5, 8710–8720.
Sykes, E. A.; Chen, J.; Zheng, G.; Chan, W. C. W. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano 2014, 8, 5696–5706.
Alexis, F.; Pridgen, E.; Molnar, L. K.; Farokhzad, O. C. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 2008, 5, 505–515.
He, C. B.; Hu, Y. P.; Yin, L. C.; Tang, C.; Yin, C. H. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 2010, 31, 3657–3666.
Bewersdorff, T.; Gruber, A.; Eravci, M.; Dumbani, M.; Klinger, D.; Haase, A. Amphiphilic nanogels: Influence of surface hydrophobicity on protein corona, biocompatibility and cellular uptake. Int. J. Nanomedicine 2019, 14, 7861–7878.
Harris, J. M.; Chess, R. B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2003, 2, 214–221.
Shi, L. W.; Zhang, J. Q.; Zhao, M.; Tang, S. K.; Cheng, X.; Zhang, W. Y.; Li, W. H.; Liu, X. Y.; Peng, H. S.; Wang, Q. Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery. Nanoscale 2021, 13, 10748–10764.
Corbo, C.; Molinaro, R.; Tabatabaei, M.; Farokhzad, O. C.; Mahmoudi, M. Personalized protein corona on nanoparticles and its clinical implications. Biomater. Sci. 2017, 5, 378–387.
Anselmo, A. C.; Mitragotri, S. Nanoparticles in the clinic: An update. Bioeng. Transl. Med. 2019, 4, e10143.
Tangutoori, S.; Spring, B. Q.; Mai, Z.; Palanisami, A.; Mensah, L. B.; Hasan, T. Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer. Nanomedicine 2016, 12, 223–234.
Deng, H. Z.; Song, K.; Zhao, X. F.; Li, Y. N.; Wang, F.; Zhang, J. H.; Dong, A. J.; Qin, Z. H. Tumor microenvironment activated membrane fusogenic liposome with speedy antibody and doxorubicin delivery for synergistic treatment of metastatic tumors. ACS Appl. Mater. Interfaces 2017, 9, 9315–9326.
Wang, S. J.; Hüttmann, G.; Zhang, Z. X.; Vogel, A.; Birngruber, R.; Tangutoori, S.; Hasan, T.; Rahmanzadeh, R. Light-controlled delivery of monoclonal antibodies for targeted photoinactivation of Ki-67. Mol. Pharm. 2015, 12, 3272–3281.
Tang, Y.; Soroush, F.; Tong, Z. H.; Kiani, M. F.; Wang, B. Targeted multidrug delivery system to overcome chemoresistance in breast cancer. Int. J. Nanomedicine 2017, 12, 671–681.
Chen, P. W.; Yang, W. Q.; Hong, T.; Miyazaki, T.; Dirisala, A.; Kataoka, K.; Cabral, H. Nanocarriers escaping from hyperacidified endo/lysosomes in cancer cells allow tumor-targeted intracellular delivery of antibodies to therapeutically inhibit c-MYC. Biomaterials 2022, 288, 121748.
Rafael, D.; Montero, S.; Carcavilla, P.; Andrade, F.; German-Cortés, J.; Diaz-Riascos, Z. V.; Seras-Franzoso, J.; Llaguno, M.; Fernández, B.; Pereira, A. et al. Intracellular delivery of anti-Kirsten rat sarcoma antibodies mediated by polymeric micelles exerts strong in vitro and in vivo anti-tumorigenic activity in Kirsten rat sarcoma-mutated cancers. ACS Appl. Mater. Interfaces 2023, 15, 10398–10413.
Srinivasan, A. R.; Lakshmikuttyamma, A.; Shoyele, S. A. Investigation of the stability and cellular uptake of self-associated monoclonal antibody (MAb) nanoparticles by non-small lung cancer cells. Mol. Pharm. 2013, 10, 3275–3284.
Jiang, G. Y.; Huang, Z. L.; Yuan, Y.; Tao, K.; Feng, W. L. Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells. J. Hematol. Oncol. 2021, 14, 139.
Baião, A.; Sousa, F.; Oliveira, A. V.; Oliveira, C.; Sarmento, B. Effective intracellular delivery of bevacizumab via PEGylated polymeric nanoparticles targeting the CD44v6 receptor in colon cancer cells. Biomater. Sci. 2020, 8, 3720–3729.
Sousa, F.; Dhaliwal, H. K.; Gattacceca, F.; Sarmento, B.; Amiji, M. M. Enhanced anti-angiogenic effects of bevacizumab in glioblastoma treatment upon intranasal administration in polymeric nanoparticles. J. Control. Release 2019, 309, 37–47.
Abbadessa, A.; Nuñez Bernal, P.; Buttitta, G.; Ronca, A.; D’Amora, U.; Zihlmann, C.; Stiefel, N.; Ambrosio, L.; Malda, J.; Levato, R. et al. Biofunctionalization of 3D printed collagen with bevacizumab-loaded microparticles targeting pathological angiogenesis. J. Control. Release 2023, 360, 747–758.
Pang, J. T.; Xing, H. X.; Sun, Y. G.; Feng, S.; Wang, S. Z. Non-small cell lung cancer combination therapy: Hyaluronic acid modified, epidermal growth factor receptor targeted, pH sensitive lipid-polymer hybrid nanoparticles for the delivery of erlotinib plus bevacizumab. Biomed. Pharmacother. 2020, 125, 109861.
Date, T.; Nimbalkar, V.; Kamat, J.; Mittal, A.; Mahato, R. I.; Chitkara, D. Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics. J. Control. Release 2018, 271, 60–73.
Jia, Y. F.; Chen, S. W.; Wang, C. Y.; Sun, T.; Yang, L. Q. Hyaluronic acid-based nano drug delivery systems for breast cancer treatment: Recent advances. Front. Bioeng. Biotechnol. 2022, 10, 990145.
Hurt, E. M.; Kawasaki, B. T.; Klarmann, G. J.; Thomas, S. B.; Farrar, W. L. CD44+CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br. J. Cancer 2008, 98, 756–765.
Idowu, M. O.; Kmieciak, M.; Dumur, C.; Burton, R. S.; Grimes, M. M.; Powers, C. N.; Manjili, M. H. CD44+/CD24−/low cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum. Pathol. 2012, 43, 364–373.
Payne, W. M.; Svechkarev, D.; Kyrychenko, A.; Mohs, A. M. The role of hydrophobic modification on hyaluronic acid dynamics and self-assembly. Carbohydr. Polym. 2018, 182, 132–141.
Kelkar, S. S.; Hill, T. K.; Marini, F. C.; Mohs, A. M. Near infrared fluorescent nanoparticles based on hyaluronic acid: Self-assembly, optical properties, and cell interaction. Acta Biomater. 2016, 36, 112–121.
Choi, K. Y.; Chung, H.; Min, K. H.; Yoon, H. Y.; Kim, K.; Park, J. H.; Kwon, I. C.; Jeong, S. Y. Self-assembled hyaluronic acid nanoparticles for active tumor targeting. Biomaterials 2010, 31, 106–114.
Deng, C. F.; Xu, X. H.; Tashi, D.; Wu, Y. M.; Su, B. Y.; Zhang, Q. Co-administration of biocompatible self-assembled polylactic acid-hyaluronic acid block copolymer nanoparticles with tumor-penetrating peptide-iRGD for metastatic breast cancer therapy. J. Mater. Chem. B 2018, 6, 3163–3180.
Le, N. T. T.; Cao, V. D.; Nguyen, T. N. Q.; Le, T. T. H.; Tran, T. T.; Thi, T. T. H. Soy lecithin-derived liposomal delivery systems: Surface modification and current applications. Int. J. Mol. Sci. 2019, 20, 4706.
Sharifi, S.; Mahmoud, N. N.; Voke, E.; Landry, M. P.; Mahmoudi, M. Importance of standardizing analytical characterization methodology for improved reliability of the nanomedicine literature. Nanomicro Lett. 2022, 14, 172.
Leong, H. S.; Butler, K. S.; Brinker, C. J.; Azzawi, M.; Conlan, S.; Dufés, C.; Owen, A.; Rannard, S.; Scott, C.; Chen, C. Y. et al. On the issue of transparency and reproducibility in nanomedicine. Nat. Nanotechnol. 2019, 14, 629–635.
Faria, M.; Björnmalm, M.; Thurecht, K. J.; Kent, S. J.; Parton, R. G.; Kavallaris, M.; Johnston, A. P. R.; Gooding, J. J.; Corrie, S. R.; Boyd, B. J. et al. Minimum information reporting in bio-nano experimental literature. Nat. Nanotechnol. 2018, 13, 777–785.
Courtois, F.; Agrawal, N. J.; Lauer, T. M.; Trout, B. L. Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab. mAbs 2016, 8, 99–112.
Goyon, A.; Excoffier, M.; Janin-Bussat, M. C.; Bobaly, B.; Fekete, S.; Guillarme, D.; Beck, A. Determination of isoelectric points and relative charge variants of 23 therapeutic monoclonal antibodies. J. Chromatogr. B 2017, 1065–1066, 119–128.
Filipe, V.; Hawe, A.; Jiskoot, W. Critical evaluation of nanoparticle tracking analysis (NTA) by nanosight for the measurement of nanoparticles and protein aggregates. Pharm. Res. 2010, 27, 796–810.
Brewer, A. K.; Striegel, A. M. Particle size characterization by quadruple-detector hydrodynamic chromatography. Anal. Bioanal. Chem. 2009, 393, 295–302.
Pedersen, J. S. Analysis of small-angle scattering data from colloids and polymer solutions: Modeling and least-squares fitting. Adv. Colloid Interface Sci. 1997, 70, 171–210.
Hammouda, B. A new Guinier-Porod model. J. Appl. Crystallogr. 2010, 43, 716–719.
Paula, S.; Volkov, A. G.; Van Hoek, A. N.; Haines, T. H.; Deamer, D. W. Permeation of protons, potassium ions, and small polar molecules through phospholipid bilayers as a function of membrane thickness. Biophys. J. 1996, 70, 339–348.
Kenworthy, A. K.; Hristova, K.; Needham, D.; McIntosh, T. J. Range and magnitude of the steric pressure between bilayers containing phospholipids with covalently attached poly(ethylene glycol). Biophys. J. 1995, 68, 1921–1936.
Liu, L. Y.; Zhou, C. P.; Xia, X. J.; Liu, Y. L. Self-assembled lecithin/chitosan nanoparticles for oral insulin delivery: Preparation and functional evaluation. Int. J. Nanomedicine 2016, 11, 761–769.
Gerelli, Y.; Di Bari, M. T.; Deriu, A.; Cantù, L.; Colombo, P.; Como, C.; Motta, S.; Sonvico, F.; May, R. Structure and organization of phospholipid/polysaccharide nanoparticles. J. Phys. Condens. Matter 2008, 20, 104211.
Mahdavi, M.; Rahmani, F.; Nouranian, S. Molecular simulation of pH-dependent diffusion, loading, and release of doxorubicin in graphene and graphene oxide drug delivery systems. J. Mater. Chem. B 2016, 4, 7441–7451.
Zhao, Q. Q.; Gao, H. S.; Su, Y.; Huang, T. H.; Lu, J. H.; Yu, H.; Ouyang, D. F. Experimental characterization and molecular dynamic simulation of ketoprofen-cyclodextrin complexes. Chem. Phys. Lett. 2019, 736, 136802.
Pozzi, D.; Caracciolo, G.; Digiacomo, L.; Colapicchioni, V.; Palchetti, S.; Capriotti, A. L.; Cavaliere, C.; Zenezini Chiozzi, R.; Puglisi, A.; Laganà, A. The biomolecular corona of nanoparticles in circulating biological media. Nanoscale 2015, 7, 13958–13966.
Mumtaz Virk, M.; Reimhult, E. Phospholipase A2-induced degradation and release from lipid-containing polymersomes. Langmuir 2018, 34, 395–405.
Harada, H.; Takahashi, M. CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and -2. J. Biol. Chem. 2007, 282, 5597–5607.
Laye, J. P.; Gill, J. H. Phospholipase A2 expression in tumours: A target for therapeutic intervention. Drug Discov. Today 2003, 8, 710–716.
Crecente-Campo, J.; Guerra-Varela, J.; Peleteiro, M.; Gutiérrez-Lovera, C.; Fernández-Mariño, I.; Diéguez-Docampo, A.; González-Fernández, Á.; Sánchez, L.; Alonso, M. J. The size and composition of polymeric nanocapsules dictate their interaction with macrophages and biodistribution in zebrafish. J. Control. Release 2019, 308, 98–108.
Walkey, C. D.; Olsen, J. B.; Guo, H. B.; Emili, A.; Chan, W. C. W. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J. Am. Chem. Soc. 2012, 134, 2139–2147.
Snipstad, S.; Hak, S.; Baghirov, H.; Sulheim, E.; Mørch, Ý.; Lélu, S.; von Haartman, E.; Bäck, M.; Nilsson, K. P. R.; Klymchenko, A. S. et al. Labeling nanoparticles: Dye leakage and altered cellular uptake. Cytometry Part A 2017, 91, 760–766.
Neuwelt, A. J.; Kimball, A. K.; Johnson, A. M.; Arnold, B. W.; Bullock, B. L.; Kaspar, R. E.; Kleczko, E. K.; Kwak, J. W.; Wu, M. H.; Heasley, L. E. et al. Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms. J. Immunother. Cancer 2020, 8, e000441.
Marroquin, C. E.; Downey, L.; Guo, H. T.; Kuo, P. C. Osteopontin increases CD44 expression and cell adhesion in RAW 264.7 murine leukemia cells. Immunol. Lett. 2004, 95, 109–112.
Krejcova, D.; Pekarova, M.; Safrankova, B.; Kubala, L. The effect of different molecular weight hyaluronan on macrophage physiology. Neuro Endocrinol. Lett. 2009, 30 Suppl 1, 106–111.
Qhattal, H. S. S.; Liu, X. L. Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes. Mol. Pharm. 2011, 8, 1233–1246.
Li, W. H.; Yi, X. L.; Liu, X.; Zhang, Z. R.; Fu, Y.; Gong, T. Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy. J. Control. Release 2016, 225, 170–182.
Younis, M. A.; Tawfeek, H. M.; Abdellatif, A. A. H.; Abdel-Aleem, J. A.; Harashima, H. Clinical translation of nanomedicines: Challenges, opportunities, and keys. Adv. Drug Deliv. Rev. 2022, 181, 114083.
Dormont, F.; Rouquette, M.; Mahatsekake, C.; Gobeaux, F.; Peramo, A.; Brusini, R.; Calet, S.; Testard, F.; Lepetre-Mouelhi, S.; Desmaële, D. et al. Translation of nanomedicines from lab to industrial scale synthesis: The case of squalene-adenosine nanoparticles. J. Control. Release 2019, 307, 302–314.
Valencia, P. M.; Farokhzad, O. C.; Karnik, R.; Langer, R. Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat. Nanotechnol. 2012, 7, 623–629.
Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A. E.; Berendsen, H. J. C. GROMACS: Fast, flexible, and free. J. Comput. Chem. 2005, 26, 1701–1718.
Schmid, N.; Eichenberger, A. P.; Choutko, A.; Riniker, S.; Winger, M.; Mark, A. E.; van Gunsteren, W. F. Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur. Biophys. J. 2011, 40, 843–856.
Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J. Phys. Chem. 1994, 98, 11623–11627.
Lu, T.; Chen, F. W. Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33, 580–592.
O’Boyle, N. M.; Banck, M.; James, C. A.; Morley, C.; Vandermeersch, T.; Hutchison, G. R. Open babel: An open chemical toolbox. J. Cheminform. 2011, 3, 33.
Piaggi, P. M.; Parrinello, M. Predicting polymorphism in molecular crystals using orientational entropy. Proc. Natl. Acad. Sci. USA 2018, 115, 10251–10256.
Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007, 126, 014101.
Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N·log( N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98, 10089–10092.
Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 1996, 14, 33–38.
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