Preparation and characterization of intelligent core-shell nanoparticles based on poly(D,L-lactide)-g-poly(N-isopropyl acrylamide-co-methacrylic acid).

New thermo-responsive, pH-responsive, and biodegradable nanoparticles comprised of poly(D,L-lactide)-graft-poly(N-isopropyl acrylamide-co-methacrylic acid) (PLA-g-P(NIPAm-co-MAA)) were developed by grafting biodegradable poly(D,L-lactide) onto N-isopropyl acrylamide and methacrylic acid. A core-shell type nano-structure was formed with a hydrophilic outer shell and a hydrophobic inner core, which exhibited a phase transition temperature above 37 degrees C suitable for biomedical application. Upon heating above the phase transition temperature, PLA-g-P(NIPAm-co-MAA) nanoparticle showed a polarity increase of pyrene in either buffer solution or intra-hepato-carcinoma cells as determined by fluorescence measurement, indicating that the structure of nanoparticles caused leakages from outer shell copolymers aggregation and collapsed. The drug loading level of 5-fluorouracil (5-FU) encapsulated in the PLA-g-P(NIPAm-co-MAA) nanoparticles can be as high as 20%. The release of 5-FU from nanoparticles was strongly controlled by the pH in the aqueous solution. Based on these results, PLA-g-P(NIPAm-co-MAA) nanoparticles can be used as a drug carrier for intracellular delivery of anti-cancer drug.

[1]  T. Park,et al.  A new antisense oligonucleotide delivery system based on self-assembled ODN-PEG hybrid conjugate micelles. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[2]  Shen‐guo Wang,et al.  Enzymatic biodegradation of poly(ethylene oxide-b-∈-caprolactone) diblock copolymer and its potential biomedical applications , 1999 .

[3]  M. Winnik,et al.  Fluorescence probe techniques used to study micelle formation in water-soluble block copolymers , 1990 .

[4]  T. Okano,et al.  Comb-type grafted hydrogels with rapid deswelling response to temperature changes , 1995, Nature.

[5]  M. Akashi,et al.  Design of nanoparticles composed of graft copolymers for oral peptide delivery. , 2001, Advanced drug delivery reviews.

[6]  P. Couvreur,et al.  Nanoparticles in cancer therapy and diagnosis. , 2002, Advanced drug delivery reviews.

[7]  Jan Feijen,et al.  Thermosensitive Micelle-Forming Block Copolymers of Poly(ethylene glycol) and Poly(N-isopropylacrylamide) , 1997 .

[8]  Allan S. Huffman,et al.  Thermally reversible hydrogels: II. Delivery and selective removal of substances from aqueous solutions , 1986 .

[9]  Nikolaos A. Peppas,et al.  Pulsatile local delivery of thrombolytic and antithrombotic agents using poly(N-isopropylacrylamide-co-methacrylic acid) hydrogels , 1996 .

[10]  A S Hoffman,et al.  An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[11]  Teruo Okano,et al.  Physical Entrapment of Adriamycin in AB Block Copolymer Micelles , 1995, Pharmaceutical Research.

[12]  K. Sakamoto,et al.  Transcatheter arterial chemoembolization therapy for hepatocellular carcinoma using polylactic acid microspheres containing aclarubicin hydrochloride. , 1989, Cancer research.

[13]  Atsushi Harada,et al.  Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. , 2003, Angewandte Chemie.

[14]  T. Okano,et al.  Reversibly thermo-responsive alkyl-terminated poly(N-isopropylacrylamide) core-shell micellar structures , 1997 .

[15]  R. Jain,et al.  Intracellular magnetic labeling of lymphocytes for in vivo trafficking studies. , 1998, BioTechniques.

[16]  Ging-Ho Hsiue,et al.  New amphiphilic poly(2-ethyl-2-oxazoline)/ poly(L-lactide) triblock copolymers. , 2003, Biomacromolecules.

[17]  T. Okano,et al.  A novel recovery system for cultured cells using plasma-treated polystyrene dishes grafted with poly(N-isopropylacrylamide). , 1993, Journal of biomedical materials research.

[18]  L. Bromberg,et al.  Release of Hydrophobic Compounds from Micellar Solutions of Hydrophobically Modified Polyelectrolytes , 1999 .

[19]  H. Tenhu,et al.  Characterisation of thermally controlled chain association in aqueous solutions of poly(N-isopropyl acrylamide)-g-poly(ethylene oxide): Dynamic light scattering , 2003 .

[20]  Y. L. Feng,et al.  Permanent hepatic artery embolization with dextran microspheres in 131 patients with unresectable hepatocellular carcinoma. , 1993, Chinese medical journal.

[21]  Y. Tu,et al.  Self-Assembled Nanostructures of Rod-Coil Diblock Copolymers with Different Rod Lengths , 2003 .

[22]  T. Park,et al.  Doxorubicin-conjugated biodegradable polymeric micelles having acid-cleavable linkages. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[23]  T. Okano,et al.  Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[24]  C. Pouton,et al.  Macromolecular Systems for Chemotherapy and Magnetic Resonance Imaging. , 1996 .

[25]  Allan S. Hoffman,et al.  Temperature-induced phase transition behaviors of random vs. graft copolymers of N-isopropylacrylamide and acrylic acid , 1995 .

[26]  T. Okano,et al.  Inner core segment design for drug delivery control of thermo-responsive polymeric micelles. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[27]  T. Okano,et al.  Thermo‐responsive polymeric surfaces; control of attachment and detachment of cultured cells , 1990 .

[28]  A. Müller,et al.  Characterization of Micelles of Polyisobutylene-block-poly(methacrylic acid) in Aqueous Medium , 2000 .

[29]  T. Okano,et al.  A new thermo-sensitive hydrogel: Interpenetrating polymer networks from N-acryloylpyrrolidine and poly(oxyethylene) , 1988 .

[30]  A. Hoffman,et al.  Graft copolymers that exhibit temperature-induced phase transitions over a wide range of pH , 1995, Nature.

[31]  J. K. Thomas,et al.  Environmental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar systems , 1977 .