Macromolecular HPMA-based nanoparticles with cholesterol for solid-tumor targeting: detailed study of the inner structure of a highly efficient drug delivery system.
We report a rigorous investigation into the detailed structure of nanoparticles already shown to be successful drug delivery nanocarriers. The basic structure of the drug conjugates consists of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer bearing the anticancer drug doxorubicin (Dox) bound via a pH-sensitive hydrazone bond and a defined amount of cholesterol moieties that vary in hydrophobicity. The results show that size, anisotropy, and aggregation number N(aggr) of the nanoparticles grows with increasing cholesterol content. From ab initio calculations, we conclude that the most probable structure of HPMA copolymer-cholesterol nanoparticles is a pearl necklace structure, where ellipsoidal pearls mainly composed of cholesterol are covered by a HPMA shell; pearls are connected by bridges composed of hydrophilic HPMA copolymer chains. Using a combination of techniques, we unambiguously show that the Dox moieties are not impregnated inside a cholesterol core but are instead uniformly distributed across the whole nanoparticle, including the hydrophilic HPMA shell surface.
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v v i, Prague 6, Czech Republic. sfill225@gmail.com
Sergey K
SK
Filippov
Petr
P
Chytil
Petr V
PV
Konarev
Margarita
M
Dyakonova
Christinem
C
Papadakis
Alexander
A
Zhigunov
Josef
J
Plestil
Petr
P
Stepanek
Tomas
T
Etrych
Karel
K
Ulbrich
Dmitri I
DI
Svergun
D000178:Acrylamides / Q000737:chemistry*; D000465:Algorithms; D016880:Anisotropy; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002784:Cholesterol; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008027:Light; D046911:Macromolecular Substances / Q000737:chemistry; D008823:Micelles; D008958:Models, Molecular; D008968:Molecular Conformation; D053769:Nanocapsules / Q000737:chemistry*; D033363:Neutron Diffraction; D010316:Particle Size; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D046911:Macromolecular Substances; D008823:Micelles; D053769:Nanocapsules; D004317:Doxorubicin; D002784:Cholesterol; C032976:N-(2-hydroxypropyl)methacrylamide