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Superior intratumoral penetration of paclitaxel nanodots strengthens tumor restriction and metastasis prevention.

Abstract
Recently discovered intratumoral diffusion resistance, together with poor solubility and nontargeted distribution of chemotherapeutic drugs, has significantly impaired the performance of cancer treatments. By developing a well-designed droplet-confined/cryodesiccation-driven crystallization approach, we herein report the successful preparation of nanocrystallites of insoluble chemotherapeutic drug paclitaxel (PTX) in forms of nanodots (NDs, ≈10 nm) and nanoparticles (NPs, ≈70 nm) with considerably high drug loading capacity. Superficially coated Pluronic F127 is demonstrated to endow the both PTX nanocrystallites with excellent water solubility and prevent undesired phagocyte uptake. Further decoration with tumor-penetrating peptide iRGD, as expected, indiscriminatively facilitates tumor cell uptake in traditional monolayer cell culture model. On the contrary, distinctly enhanced performances in inward penetration and ensuing elimination of 3D multicellular tumor spheroids are achieved by iRGD-NDs rather than iRGD-NPs, revealing the significant influence of particle size variation in nanoscale. In vivo experiments verify that, although efficient tumor enrichment is achieved by all nanocrystallites, only the iRGD-grafted nanocrystallites of ultranano size realize thorough intratumoral delivery and reach cancer stem cells, which are concealed inside the tumor core. Consequently, much strengthened restriction on progress and metastasis of orthotopic 4T1 mammary adenocarcinoma is achieved in murine model, in sharp contrast to commercial PTX formulation Taxol.
AuthorsDezhi Ni, Hui Ding, Shan Liu, Hua Yue, Yali Bao, Zhenhua Wang, Zhiguo Su, Wei Wei, Guanghui Ma
JournalSmall (Weinheim an der Bergstrasse, Germany) (Small) Vol. 11 Issue 21 Pg. 2518-26 (Jun 03 2015) ISSN: 1613-6829 [Electronic] Germany
PMID25678130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • Antineoplastic Agents, Phytogenic
  • Drug Carriers
  • N-end cysteine peptide tumor-homing peptide
  • Oligopeptides
  • Poloxamer
  • Paclitaxel
Topics
  • Adenocarcinoma (drug therapy, metabolism, secondary)
  • Animals
  • Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects, pharmacokinetics)
  • Cell Line, Tumor
  • Drug Carriers (administration & dosage, chemistry)
  • Drug Delivery Systems
  • Female
  • Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Confocal
  • Nanoparticles (administration & dosage, chemistry, ultrastructure)
  • Oligopeptides
  • Paclitaxel (administration & dosage, adverse effects, pharmacokinetics)
  • Particle Size
  • Poloxamer
  • Spheroids, Cellular (drug effects, metabolism, pathology)
  • Tissue Distribution

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