Designing sub-20&nbsp;nm self-assembled nanocarriers for small molecule delivery: Interplay among structural geometry, assembly energetics, and cargo release kinetics

Jung, Benson T.; Lim, Marc; Jung, Katherine; Li, Michael; Dong, He; Dube, Nikhil; Xu, Ting

doi:10.1016/j.jconrel.2020.09.037

Designing sub-20 nm self-assembled nanocarriers for small molecule delivery: Interplay among structural geometry, assembly energetics, and cargo release kinetics

Journal Article · Tue Sep 22 04:00:00 EDT 2020 · Journal of Controlled Release

DOI:https://doi.org/10.1016/j.jconrel.2020.09.037· OSTI ID:1840938

Jung, Benson T. ^[1]; ^[1]; Jung, Katherine ^[1]; Li, Michael ^[1]; Dong, He ^[2]; Dube, Nikhil ^[1]; ^[3]

Univ. of California, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States); Univ. of Texas, Arlington, TX (United States)
Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Biological constraints in diseased tissues have motivated the need for small nanocarriers (10–30 nm) to achieve sufficient vascular extravasation and pervasive tumor penetration. Here, this particle size limit is only an order of magnitude larger than small molecules, such that cargo loading is better described by co-assembly processes rather than simple encapsulation. Understanding the structural, kinetic, and energetic contributions of carrier-cargo co-assembly is thus critical to achieve molecular-level control towards predictable in vivo behavior. These interconnected set of properties were systematically examined using sub-20 nm self-assembled nanocarriers known as three-helix micelles (3HM). Both hydrophobicity and the “geometric packing parameter” dictate small molecule compatibility with 3HM's alkyl tail core. Planar obelisk-like apomorphine and doxorubicin (DOX) molecules intercalated well within the 3HM core and near the core-shell interface, forming an integral component to the co-assembly, as corroborated by small-angle X-ray and neutron-scattering structural studies. DOX promoted crystalline alkyl tail ordering, which significantly increased (+63%) the activation energy of 3HM subunit exchange. Subsequently, 3HM-DOX displayed slow-release kinetics (t_1/2 = 40 h) at physiological temperatures, with ~50× greater cargo preference for the micelle core as described by two drug partitioning coefficients (micellar core/shell K_p1 ~ 24, and shell/bulk solvent K_p2 ~ 2). The geometric and energetic insights between nanocarrier and their small molecule cargos developed here will aid in broader efforts to deconvolute the interconnected properties of carrier-drug co-assemblies. Adding this knowledge to pharmacological and immunological explorations will expand our understanding of nanomedicine behavior throughout all the physical and in vivo processes they are intended to encounter.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1840938

Alternate ID(s):: OSTI ID: 1785001

Journal Information:: Journal of Controlled Release, Journal Name: Journal of Controlled Release Vol. 329; ISSN 0168-3659

Publisher:: Controlled Release SocietyCopyright Statement

Country of Publication:: United States

Language:: English

References (62)

A Nanoparticle Size Series for In Vivo Fluorescence Imaging Popović, Zoran; Liu, Wenhao; Chauhan, Vikash P. Angewandte Chemie, Vol. 122, Issue 46 https://doi.org/10.1002/ange.201003142	journal	September 2010
Nanoparticles in the clinic Anselmo, Aaron C.; Mitragotri, Samir Bioengineering & Translational Medicine, Vol. 1, Issue 1 https://doi.org/10.1002/btm2.10003	journal	March 2016
Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)‐block‐polycaprolactone diblock copolymer micelles: Theoretical and experimental data and correlations Letchford, Kevin; Liggins, Richard; Burt, Helen Journal of Pharmaceutical Sciences, Vol. 97, Issue 3 https://doi.org/10.1002/jps.21037	journal	March 2008
A method for estimating both the solubility parameters and molar volumes of liquids. Supplement Fedors, Robert F. Polymer Engineering and Science, Vol. 14, Issue 6 https://doi.org/10.1002/pen.760140611	journal	June 1974
X-Ray Interactions: Photoabsorption, Scattering, Transmission, and Reflection at E = 50-30,000 eV, Z = 1-92 Henke, B. L.; Gullikson, E. M.; Davis, J. C. Atomic Data and Nuclear Data Tables, Vol. 54, Issue 2, p. 181-342 https://doi.org/10.1006/adnd.1993.1013	journal	July 1993
Release, Partitioning, and Conjugation Stability of Doxorubicin in Polymer Micelles Determined by Mechanistic Modeling Ponta, Andrei; Fugit, Kyle D.; Anderson, Bradley D. Pharmaceutical Research, Vol. 32, Issue 5 https://doi.org/10.1007/s11095-014-1573-2	journal	November 2014
Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date Bobo, Daniel; Robinson, Kye J.; Islam, Jiaul Pharmaceutical Research, Vol. 33, Issue 10 https://doi.org/10.1007/s11095-016-1958-5	journal	June 2016
Mechanisms of solute release from porous hydrophilic polymers Korsmeyer, Richard W.; Gurny, Robert; Doelker, Eric International Journal of Pharmaceutics, Vol. 15, Issue 1 https://doi.org/10.1016/0378-5173(83)90064-9	journal	May 1983
A simple equation for the description of solute release. III. Coupling of diffusion and relaxation Peppas, Nikolaos A.; Sahlin, Jennifer J. International Journal of Pharmaceutics, Vol. 57, Issue 2 https://doi.org/10.1016/0378-5173(89)90306-2	journal	December 1989
The Enthalpy Change of Adenosine Triphosphate Hydrolysis Podolsky, Richard J.; Morales, Manuel F. Journal of Biological Chemistry, Vol. 218, Issue 2 https://doi.org/10.1016/S0021-9258(18)65857-0	journal	February 1956
Biodegradable poly(ε-caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen Chawla, Jugminder S.; Amiji, Mansoor M. International Journal of Pharmaceutics, Vol. 249, Issue 1-2 https://doi.org/10.1016/S0378-5173(02)00483-0	journal	December 2002
Cancer nanomedicines: So many papers and so few drugs! Venditto, Vincent J.; Szoka, Francis C. Advanced Drug Delivery Reviews, Vol. 65, Issue 1 https://doi.org/10.1016/j.addr.2012.09.038	journal	January 2013
Delivery of cancer therapeutics to extracellular and intracellular targets: Determinants, barriers, challenges and opportunities Au, Jessie L. -S.; Yeung, Bertrand Z.; Wientjes, Michael G. Advanced Drug Delivery Reviews, Vol. 97 https://doi.org/10.1016/j.addr.2015.12.002	journal	February 2016
Self-assembling peptide-based building blocks in medical applications Acar, Handan; Srivastava, Samanvaya; Chung, Eun Ji Advanced Drug Delivery Reviews, Vol. 110-111 https://doi.org/10.1016/j.addr.2016.08.006	journal	February 2017
Regulatory aspects on nanomedicines Sainz, Vanessa; Conniot, João; Matos, Ana I. Biochemical and Biophysical Research Communications, Vol. 468, Issue 3 https://doi.org/10.1016/j.bbrc.2015.08.023	journal	December 2015
A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas Li, Yan; He, Hai; Jia, Xinru Biomaterials, Vol. 33, Issue 15 https://doi.org/10.1016/j.biomaterials.2012.02.004	journal	May 2012
In vitro release kinetics model fitting of liposomes: An insight Jain, Ankit; Jain, Sanjay K. Chemistry and Physics of Lipids, Vol. 201 https://doi.org/10.1016/j.chemphyslip.2016.10.005	journal	December 2016
Isn't self-assembly a misnomer? Multi-disciplinary arguments in favor of co-assembly Uskoković, Vuk Advances in Colloid and Interface Science, Vol. 141, Issue 1-2 https://doi.org/10.1016/j.cis.2008.02.004	journal	September 2008
Encapsulation of dexamethasone into biodegradable polymeric nanoparticles Gomezgaete, C.; Tsapis, N.; Besnard, M. International Journal of Pharmaceutics, Vol. 331, Issue 2 https://doi.org/10.1016/j.ijpharm.2006.11.028	journal	March 2007
Preparation of rapamycin-loaded chitosan/PLA nanoparticles for immunosuppression in corneal transplantation Yuan, Xu-Bo; Yuan, Yan-Bo; Jiang, Wei International Journal of Pharmaceutics, Vol. 349, Issue 1-2 https://doi.org/10.1016/j.ijpharm.2007.07.045	journal	February 2008
Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis Roger, E.; Lagarce, F.; Garcion, E. Journal of Controlled Release, Vol. 140, Issue 2 https://doi.org/10.1016/j.jconrel.2009.08.010	journal	December 2009
Tuning core vs. shell dimensions to adjust the performance of nanoscopic containers for the loading and release of doxorubicin Lin, Lily Yun; Lee, Nam S.; Zhu, Jiahua Journal of Controlled Release, Vol. 152, Issue 1 https://doi.org/10.1016/j.jconrel.2011.01.009	journal	May 2011
Doxil® — The first FDA-approved nano-drug: Lessons learned Barenholz, Yechezkel (Chezy) Journal of Controlled Release, Vol. 160, Issue 2 https://doi.org/10.1016/j.jconrel.2012.03.020	journal	June 2012
Analysis on the current status of targeted drug delivery to tumors Kwon, Il Keun; Lee, Sang Cheon; Han, Bumsoo Journal of Controlled Release, Vol. 164, Issue 2 https://doi.org/10.1016/j.jconrel.2012.07.010	journal	December 2012
Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications Wicki, Andreas; Witzigmann, Dominik; Balasubramanian, Vimalkumar Journal of Controlled Release, Vol. 200 https://doi.org/10.1016/j.jconrel.2014.12.030	journal	February 2015
Self-assembled 20-nm 64Cu-micelles enhance accumulation in rat glioblastoma Seo, Jai Woong; Ang, JooChuan; Mahakian, Lisa M. Journal of Controlled Release, Vol. 220 https://doi.org/10.1016/j.jconrel.2015.09.057	journal	December 2015
Advances in polymeric micelles for drug delivery and tumor targeting Kedar, Uttam; Phutane, Prasanna; Shidhaye, Supriya Nanomedicine: Nanotechnology, Biology and Medicine, Vol. 6, Issue 6 https://doi.org/10.1016/j.nano.2010.05.005	journal	December 2010
Reaction Kinetics in Differential Thermal Analysis Kissinger, H. E. Analytical Chemistry, Vol. 29, Issue 11 https://doi.org/10.1021/ac60131a045	journal	November 1957
Survey of Clinical Translation of Cancer Nanomedicines—Lessons Learned from Successes and Failures He, Hongliang; Liu, Lisha; Morin, Emily E. Accounts of Chemical Research, Vol. 52, Issue 9 https://doi.org/10.1021/acs.accounts.9b00228	journal	August 2019
Internal Structure of 15 nm 3-Helix Micelle Revealed by Small-Angle Neutron Scattering and Coarse-Grained MD Simulation Ang, JooChuan; Ma, Dan; Lund, Reidar Biomacromolecules, Vol. 17, Issue 10 https://doi.org/10.1021/acs.biomac.6b00986	journal	September 2016
Kinetic Pathway of 3-Helix Micelle Formation Ang, JooChuan; Jung, Benson T.; Dong, He Biomacromolecules, Vol. 18, Issue 3 https://doi.org/10.1021/acs.biomac.6b01831	journal	February 2017
Sub-20 nm Stable Micelles Based on a Mixture of Coiled-Coils: A Platform for Controlled Ligand Presentation Ang, JooChuan; Ma, Dan; Jung, Benson T. Biomacromolecules, Vol. 18, Issue 11 https://doi.org/10.1021/acs.biomac.7b00917	journal	September 2017
Förster Resonance Energy Transfer-Based Stability Assessment of PLGA Nanoparticles in Vitro and in Vivo Swider, Edyta; Maharjan, Sanish; Houkes, Karlijne ACS Applied Bio Materials, Vol. 2, Issue 3 https://doi.org/10.1021/acsabm.8b00754	journal	January 2019
Estimating Tumor Vascular Permeability of Nanoparticles Using an Accessible Diffusive Flux Model Lim, Marc; Dharmaraj, Vishnu; Gong, Boying ACS Biomaterials Science & Engineering, Vol. 6, Issue 5 https://doi.org/10.1021/acsbiomaterials.9b01590	journal	March 2020
Effect of Core Crystallization and Conformational Entropy on the Molecular Exchange Kinetics of Polymeric Micelles Zinn, Thomas; Willner, Lutz; Pipich, Vitaliy ACS Macro Letters, Vol. 4, Issue 6 https://doi.org/10.1021/acsmacrolett.5b00197	journal	May 2015
Mechanisms of Peptide Amphiphile Internalization by SJSA-1 Cells in Vitro ^† Missirlis, Dimitris; Khant, Htet; Tirrell, Matthew Biochemistry, Vol. 48, Issue 15 https://doi.org/10.1021/bi802356k	journal	April 2009
Evaluation of Doxorubicin-Loaded 3-Helix Micelles as Nanocarriers Dube, Nikhil; Shu, Jessica Y.; Dong, He Biomacromolecules, Vol. 14, Issue 10 https://doi.org/10.1021/bm4010518	journal	September 2013
Effect of Alkyl Length of Peptide–Polymer Amphiphile on Cargo Encapsulation Stability and Pharmacokinetics of 3-Helix Micelles Dube, Nikhil; Seo, Jai W.; Dong, He Biomacromolecules, Vol. 15, Issue 8 https://doi.org/10.1021/bm5005788	journal	July 2014
Micelle Stabilization via Entropic Repulsion: Balance of Force Directionality and Geometric Packing of Subunit Dong, He; Lund, Reidar; Xu, Ting Biomacromolecules, Vol. 16, Issue 3 https://doi.org/10.1021/bm501659w	journal	January 2015
Bulk Synthesis of Two-Dimensional Polymers: The Molecular Recognition Approach Stupp, S. I.; Son, S.; Li, L. S. Journal of the American Chemical Society, Vol. 117, Issue 19 https://doi.org/10.1021/ja00124a005	journal	May 1995
Conformational analysis. 130. MM2. A hydrocarbon force field utilizing V1 and V2 torsional terms Allinger, Norman L. Journal of the American Chemical Society, Vol. 99, Issue 25 https://doi.org/10.1021/ja00467a001	journal	December 1977
3-Helix Micelles Stabilized by Polymer Springs Dong, He; Shu, Jessica Y.; Dube, Nikhil Journal of the American Chemical Society, Vol. 134, Issue 28 https://doi.org/10.1021/ja3048128	journal	July 2012
Diffusion of Drug Delivery Nanoparticles into Biogels Using Time-Resolved MicroMRI Wang, Xiaoling; Chen, Ying; Xue, Lian The Journal of Physical Chemistry Letters, Vol. 5, Issue 21 https://doi.org/10.1021/jz501929u	journal	October 2014
Fast Release of Lipophilic Agents from Circulating PEG-PDLLA Micelles Revealed by in Vivo Förster Resonance Energy Transfer Imaging Chen, Hongtao; Kim, Sungwon; He, Wei Langmuir, Vol. 24, Issue 10 https://doi.org/10.1021/la703570m	journal	May 2008
Long-Circulating 15 nm Micelles Based on Amphiphilic 3-Helix Peptide–PEG Conjugates Dong, He; Dube, Nikhil; Shu, Jessica Y. ACS Nano, Vol. 6, Issue 6, p. 5320-5329 https://doi.org/10.1021/nn301142r	journal	May 2012
Self-assembling chimeric polypeptide–doxorubicin conjugate nanoparticles that abolish tumours after a single injection Andrew MacKay, J.; Chen, Mingnan; McDaniel, Jonathan R. Nature Materials, Vol. 8, Issue 12 https://doi.org/10.1038/nmat2569	journal	November 2009
Strategies for advancing cancer nanomedicine Chauhan, Vikash P.; Jain, Rakesh K. Nature Materials, Vol. 12, Issue 11 https://doi.org/10.1038/nmat3792	journal	October 2013
Sulfated glycopeptide nanostructures for multipotent protein activation Lee, Sungsoo S.; Fyrner, Timmy; Chen, Feng Nature Nanotechnology, Vol. 12, Issue 8 https://doi.org/10.1038/nnano.2017.109	journal	June 2017
Cancer nanomedicine: progress, challenges and opportunities Shi, Jinjun; Kantoff, Philip W.; Wooster, Richard Nature Reviews Cancer, Vol. 17, Issue 1 https://doi.org/10.1038/nrc.2016.108	journal	November 2016
Covalent-supramolecular hybrid polymers as muscle-inspired anisotropic actuators Chin, Stacey M.; Synatschke, Christopher V.; Liu, Shuangping Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-04800-w	journal	June 2018
The internal structure of self-assembled peptide amphiphiles nanofibers Jiang, Hongzhou; Guler, Mustafa O.; Stupp, Samuel I. Soft Matter, Vol. 3, Issue 4 https://doi.org/10.1039/b614426h	journal	January 2007
Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers Israelachvili, Jacob N.; Mitchell, D. John; Ninham, Barry W. Journal of the Chemical Society, Faraday Transactions 2, Vol. 72 https://doi.org/10.1039/f29767201525	journal	January 1976
Supramolecular design of self-assembling nanofibers for cartilage regeneration Shah, Ramille N.; Shah, Nirav A.; Del Rosario Lim, Marc M. Proceedings of the National Academy of Sciences, Vol. 107, Issue 8 https://doi.org/10.1073/pnas.0906501107	journal	February 2010
Reduction and analysis of SANS and USANS data using IGOR Pro Kline, Steven R. Journal of Applied Crystallography, Vol. 39, Issue 6, p. 895-900 https://doi.org/10.1107/S0021889806035059	journal	November 2006
The 30 m Small-Angle Neutron Scattering Instruments at the National Institute of Standards and Technology Glinka, C. J.; Barker, J. G.; Hammouda, B. Journal of Applied Crystallography, Vol. 31, Issue 3, p. 430-445 https://doi.org/10.1107/S0021889897017020	journal	June 1998
Self-Assembly and Mineralization of Peptide-Amphiphile Nanofibers Hartgerink, Jeffrey D.; Beniash, Elia; Stupp, Samuel I. Science, Vol. 294, Issue 5547, p. 1684-1688 https://doi.org/10.1126/science.1063187	journal	November 2001
Selective Differentiation of Neural Progenitor Cells by High-Epitope Density Nanofibers Silva, Gabriel A.; Czeisler, Catherine; Niece, Krista L. Science, Vol. 303, Issue 5662, p. 1352-1355 https://doi.org/10.1126/science.1093783	journal	February 2004
A Versatile Polymer Micelle Drug Delivery System for Encapsulation and In Vivo Stabilization of Hydrophobic Anticancer Drugs Rios-Doria, Jonathan; Carie, Adam; Costich, Tara Journal of Drug Delivery, Vol. 2012 https://doi.org/10.1155/2012/951741	journal	February 2012
Novel SN-38–Incorporating Polymeric Micelles, NK012, Eradicate Vascular Endothelial Growth Factor–Secreting Bulky Tumors Koizumi, Fumiaki; Kitagawa, Masayuki; Negishi, Takahito Cancer Research, Vol. 66, Issue 20 https://doi.org/10.1158/0008-5472.CAN-06-1605	journal	October 2006
Visible Drug Delivery by Supramolecular Nanocarriers Directing to Single-Platformed Diagnosis and Therapy of Pancreatic Tumor Model Kaida, Sachiko; Cabral, Horacio; Kumagai, Michiaki Cancer Research, Vol. 70, Issue 18 https://doi.org/10.1158/0008-5472.CAN-10-0303	journal	August 2010
Where Are the Nanodrugs? An Industry Perspective on Development of Drug Products Containing Nanomaterials Havel, Henry A. The AAPS Journal, Vol. 18, Issue 6 https://doi.org/10.1208/s12248-016-9970-6	journal	August 2016
Physicochemical characterization of drug nanocarriers Berbel Manaia, Eloísa; Paiva Abuçafy, Marina; Chiari-Andréo, Bruna Galdorfini International Journal of Nanomedicine, Vol. Volume 12 https://doi.org/10.2147/IJN.S133832	journal	January 2017

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Related Subjects

60 APPLIED LIFE SCIENCES
Drug delivery
Molecular geometry
Release kinetics
Small molecule encapsulation
Structural characterization
Sub-20 nm nanocarrier

Designing sub-20 nm self-assembled nanocarriers for small molecule delivery: Interplay among structural geometry, assembly energetics, and cargo release kinetics

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