Photo-crosslinked hyaluronic acid nanoparticles with improved stability for in vivo tumor-targeted drug delivery.

One of the major hurdles of the nanoparticles as drug carriers is the unintended burst release of loaded drugs during blood circulation. To surmount this issue, we developed photo-crosslinked hyaluronic acid nanoparticles (c-HANPs) with improved stability for tumor-targeted drug delivery. They were readily prepared via UV-triggered chemical crosslinking with the acrylate groups in the polymer backbone. The size of c-HANPs was not much different from that of uncrosslinked HANPs. However, c-HANPs exhibited significantly high stability in a physiological buffer and released the loaded drug, paclitaxel (PTX), in a sustained manner. It is noteworthy that the drug release rate from c-HANPs remarkably increased in the presence of hyaluronidase, an enzyme abundant at the intracellular compartments of the tumor cells. It was found from in vitro cellular uptake tests that c-HANPs were rapidly taken up by the tumor cells via the receptor (CD44)-mediated endocytosis, which was not inhibited by photo-crosslinking. In non-invasive animal imaging results, they showed higher tumor-targeting ability than uncrosslinked HANPs because high stability of c-HANPs enabled their long circulation in the body. Owing to the sustained release of the drug and enhanced tumor-targeting ability, c-HANPs showed higher therapeutic efficacy compared to free PTX and uncrosslinked HANPs. These data implied the promising potential of c-HANP as tumor-targeting drug carriers and demonstrated the remarkable effect of the improved stability upon the biodistribution and therapeutic efficacy of drug-loaded nanoparticles.

[1]  Kwangmeyung Kim,et al.  The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection. , 2012, Biomaterials.

[2]  K. M. Watts,et al.  Shell crosslinked nanoparticles carrying silver antimicrobials as therapeutics. , 2010, Chemical communications.

[3]  Fabian Kiessling,et al.  Theranostic nanomedicine. , 2020, Accounts of chemical research.

[4]  Ick Chan Kwon,et al.  Multifunctional nanoparticles for multimodal imaging and theragnosis. , 2012, Chemical Society reviews.

[5]  James F. Leary,et al.  Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapy. , 2012, Biomaterials.

[6]  Kwangmeyung Kim,et al.  Bioorthogonal copper-free click chemistry in vivo for tumor-targeted delivery of nanoparticles. , 2012, Angewandte Chemie.

[7]  Li Wang,et al.  A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer. , 2009, Biomaterials.

[8]  Lisa Brannon-Peppas,et al.  Active targeting schemes for nanoparticle systems in cancer therapeutics. , 2008, Advanced drug delivery reviews.

[9]  Y. Bae,et al.  pH-sensitivity and pH-dependent interior structural change of self-assembled hydrogel nanoparticles of pullulan acetate/oligo-sulfonamide conjugate. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[10]  Ick Chan Kwon,et al.  In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micelles. , 2010, Chemical communications.

[11]  Ick Chan Kwon,et al.  Tumor-homing photosensitizer-conjugated glycol chitosan nanoparticles for synchronous photodynamic imaging and therapy based on cellular on/off system. , 2011, Biomaterials.

[12]  S. Smedt,et al.  Hyaluronan: Preparation, Structure, Properties, and Applications , 1999 .

[13]  M. Soloway,et al.  Association of hyaluronic acid family members (HAS1, HAS2, and HYAL‐1) with bladder cancer diagnosis and prognosis , 2011, Cancer.

[14]  Vladimir Torchilin,et al.  Tumor delivery of macromolecular drugs based on the EPR effect. , 2011, Advanced drug delivery reviews.

[15]  Kwangmeyung Kim,et al.  Hyaluronidase-sensitive SPIONs for MR/optical dual imaging nanoprobes , 2011 .

[16]  Hua Ai,et al.  Surface-engineered magnetic nanoparticle platforms for cancer imaging and therapy. , 2011, Accounts of chemical research.

[17]  Kwangmeyung Kim,et al.  Early diagnosis of arthritis in mice with collagen-induced arthritis, using a fluorogenic matrix metalloproteinase 3-specific polymeric probe. , 2011, Arthritis and rheumatism.

[18]  Kwangmeyung Kim,et al.  PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo. , 2011, Biomaterials.

[19]  In‐San Kim,et al.  Mineralized hyaluronic acid nanoparticles as a robust drug carrier , 2011 .

[20]  Ick Chan Kwon,et al.  Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapy. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Kwangmeyung Kim,et al.  Smart nanocarrier based on PEGylated hyaluronic acid for cancer therapy. , 2011, ACS nano.

[22]  I. Kwon,et al.  Spatially mineralized self-assembled polymeric nanocarriers with enhanced robustness and controlled drug-releasing property. , 2010, Chemical communications.

[23]  Ick Chan Kwon,et al.  In vivo targeted delivery of nanoparticles for theranosis. , 2011, Accounts of chemical research.

[24]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[25]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[26]  Fabian Kiessling,et al.  Polymeric nanomedicines for image-guided drug delivery and tumor-targeted combination therapy , 2010 .

[27]  Kwangmeyung Kim,et al.  Nanoprobes for biomedical imaging in living systems , 2011 .

[28]  Y. Bae,et al.  Stability issues of polymeric micelles. , 2008, Journal of controlled release : official journal of the Controlled Release Society.