Tuning core vs. shell dimensions to adjust the performance of nanoscopic containers for the loading and release of doxorubicin.
Detailed studies were performed to probe the effects of the core and shell dimensions of amphiphilic, shell crosslinked, knedel-like polymer nanoparticles (SCKs) on the loading and release of doxorubicin (DOX), a widely-used chemotherapy agent, in aqueous buffer, as a function of the solution pH. Effects of the nanoparticle composition were held constant, by employing SCKs constructed from a single type of amphiphilic diblock copolymer, poly(acrylic acid)-b-polystyrene (PAA-b-PS). A series of four SCK nanoparticle samples, ranging in number-average hydrodynamic diameter from 14-30 nm, was prepared from four block copolymers having different relative block lengths and absolute degrees of polymerization. The ratios of acrylic acid to styrene block lengths ranged from 0.65 to 3.0, giving SCKs with ratios of shell to core volumes ranging from 0.44 to 2.1. Although the shell thicknesses were calculated to be similar (1.5-3.1 nm by transmission electron microscopy (TEM) calculations and 3.5-4.9 nm by small angle neutron scattering (SANS) analyses), two of the SCK nanoparticles had relatively large core diameters (19±2 and 20±2 nm by TEM; 17.4 and 15.3 nm by SANS), while two had similar, smaller core diameters (11±2 and 13±2 nm by TEM; 9.0 and 8.9 nm by SANS). The SCKs were capable of being loaded with 1500-9700 DOX molecules per each particle, with larger numbers of DOX molecules packaged within the larger core SCKs. Their shell-to-core volume ratio showed impact on the rates and extents of release of DOX, with the volume occupied by the poly(acrylic acid) shell relative to the volume occupied by the polystyrene core correlating inversely with the diffusion-based release of DOX. Given that the same amount of polymer was used to construct each SCK sample, SCKs having smaller cores and higher acrylic acid vs. styrene volume ratios were present at higher concentrations than were the larger core SCKs, and gave lower final extents of release., Higher final extents of release and faster rates of release were observed for all DOX-loaded particle samples at pH 5.0 vs. pH 7.4, respectively, ca. 60% vs. 40% at 60 h, suggesting promise for enhanced delivery within tumors and cells. By fitting the data to the Higuchi model, quantitative determination of the kinetics of release was made, giving rate constants ranging from 0.0431 to 0.0540 h⁻¹/² at pH 7.4 and 0.106 to 0.136 h⁻¹/² at pH 5.0. In comparison, the non-crosslinked polymer micelle analogs exhibited rate constants for release of DOX of 0.245 and 0.278 h⁻¹/² at pH 7.4 and 5.0, respectively. These studies point to future directions to craft sophisticated devices for controlled drug release.
Departments of Chemistry and Chemical Engineering, Texas A&M University, College Station, TX 77842-3012, USA.
Lily Yun
LY
Lin
Nam S
NS
Lee
Jiahua
J
Zhu
Andreas M
AM
Nyström
Darrin J
DJ
Pochan
Richard B
RB
Dorshow
Karen L
KL
Wooley
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility
D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D011108:Polymers; D004317:Doxorubicin
Adv Drug Deliv Rev. 2002 Sep 13;54(5):759-79
12204601
Chem Commun (Camb). 2008 Nov 14;(42):5339-41
18985203
Biomacromolecules. 2008 Jul;9(7):1997-2006
18510359
J Control Release. 2010 Sep 1;146(2):201-6
20381555
Chem Commun (Camb). 2008 Mar 14;(10):1205-7
18309418
PLoS Pathog. 2009 May;5(5):e1000417
19412526
Soft Matter. 2008 Mar 20;4(4):849-858
32907191
Analyst. 2010 Jan;135(1):21-7
20024176
Pharm Res. 1994 Nov;11(11):1568-74
7870673
Chem Soc Rev. 2006 Nov;35(11):1068-83
17057836
Biomaterials. 2000 Dec;21(23):2475-90
11055295
Clin Cancer Res. 2008 Mar 1;14(5):1310-6
18316549
Chem Biol. 2007 Oct;14(10):1152-62
17961827
J Am Chem Soc. 2005 Mar 23;127(11):3718-23
15771505
J Pharm Sci. 2003 Jul;92(7):1343-55
12820139
Curr Top Microbiol Immunol. 2009;327:1-21
19198568
Science. 1990 Sep 28;249(4976):1527-33
2218494
Int J Pharm. 2004 Sep 10;282(1-2):1-18
15336378
Bioconjug Chem. 2005 Mar-Apr;16(2):361-8
15769090
J Control Release. 2007 Aug 28;121(3):137-45
17630011
Pharmacol Rev. 2001 Jun;53(2):283-318
11356986
Chem Commun (Camb). 2008 Aug 14;(30):3579-81
18654719
Chem Soc Rev. 2010 Apr;39(4):1233-9
20309483
J Pharm Sci. 1977 Jul;66(7):958-61
18593
Langmuir. 2005 Sep 27;21(20):9308-13
16171366
Chem Rev. 2009 Nov;109(11):5620-86
19905010
J Control Release. 2002 Aug 21;82(2-3):189-212
12175737
Methods Enzymol. 1985;112:422-36
3930918
Biomaterials. 2006 Nov;27(31):5440-51
16828864
J Control Release. 2003 Apr 29;89(2):199-212
12711444
Science. 1994 Mar 18;263(5153):1600-3
8128245
Biophys J. 1998 Nov;75(5):2574-6
9788953
Crit Rev Ther Drug Carrier Syst. 2002;19(4-5):385-423
12661698
Drug Dev Ind Pharm. 1998 Aug;24(8):703-27
9876519
J Biomed Mater Res B Appl Biomater. 2003 Aug 15;66(2):559-66
12861608
J Am Chem Soc. 2004 Mar 31;126(12):3718-9
15038717
J Pharm Sci. 1963 Dec;52:1145-9
14088963
Int J Hyperthermia. 1995 Mar-Apr;11(2):211-6
7790735
Adv Drug Deliv Rev. 2001 Mar 23;47(1):113-31
11251249