title: 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.
authors: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering Chinese Academy of Sciences, Beijing, 100190, P.R. China.|University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
authors: Dezhi
authors: D
authors: Ni
authors: University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
authors: Hui
authors: H
authors: Ding
authors: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering Chinese Academy of Sciences, Beijing, 100190, P.R. China.|University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
authors: Shan
authors: S
authors: Liu
authors: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering Chinese Academy of Sciences, Beijing, 100190, P.R. China.
authors: Hua
authors: H
authors: Yue
authors: Department of Ophthalmology, The First Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010110, P.R. China.
authors: Yali
authors: Y
authors: Bao
authors: Department of Ophthalmology, The First Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010110, P.R. China.
authors: Zhenhua
authors: Z
authors: Wang
authors: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering Chinese Academy of Sciences, Beijing, 100190, P.R. China.
authors: Zhiguo
authors: Z
authors: Su
authors: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering Chinese Academy of Sciences, Beijing, 100190, P.R. China.
authors: Wei
authors: W
authors: Wei
authors: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering Chinese Academy of Sciences, Beijing, 100190, P.R. China.|Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300072, P.R. China.
authors: Guanghui
authors: G
authors: Ma
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D009842:Oligopeptides; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D010316:Particle Size; D020442:Poloxamer; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D020442:Poloxamer; D017239:Paclitaxel
keywords: cancer metastasis; drug delivery; intratumoral infiltration; medicine; nanodots