Fluorescent Nanorods and Nanospheres for Real-Time In Vivo Probing of Nanoparticle Shape-Dependent Tumor Penetration

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Authors: Vikash P. Chauhan, Zoran Popovic, Ou Chen, Jian Cui, Dai Fukumura, Moungi G. Bawendi, and Rakesh K. Jain

Entry by: Pichet Adstamongkonkul

Motivation and Hypothesis

Nanomedicine has been shown advantageous over conventional chemotherapy, in that it can greatly reduce systemic toxicity and lengthen circulation time. The major problem hindering the effectiveness of the treatment of cancer is the nonuniformly leaky vasculature and dense interstitial environment. These factors cause heterogeneous transvascular transport and limit penetration.

Many studies have reported that decreasing the size of nanoparticles partially improve delivery, lengthen the circulation time, and transport more rapidly within tumor mass. However, some shortcomings include lower drug payloads and loading efficiencies. The surface charges also affect the mode of delivery, as the cationic particles optimize the transvascular transport, while the neutral ones have long circulation time and interstitial transport in tumors. Modulating the charges are thus not attractive. Particle aspect ratio can affect diffusion rates through pores and porous media, but the effects on tumor penetration is unknown.

The main hypothesis of this study is that the nanorods will penetrate tumors more efficiently than nanospheres of the same hydrodynamic size.

Results and Discussion

Quantum dots were used as core in order to track the nanoparticles in vivo and at real time, with the use of multiphoton microscopy. Nanospheres and nanorods were designed to have the same diffusive transport rates in water, different rates in porous media and tumors. The biostable colloidal NPs have tunable size but identical surface charge and chemistry. The NPs used in the study are equal in hydrodynamic size.

ไฟล์:Nanospheres nanorods.jpg

  • Nanospheres:
    • Polyethylene glycol-modified CdSe/CdS quantum-dot cores
    • Spherical silica shells
    • 35 nm in diameter
    • 33-35 nm hydrodynamic diameter
  • Nanorods:
    • CdSe quantum-dot cores
    • Seed-grown elongated CdS shells
    • Capped with PEG layer
    • Aqueous solutions of stable and uniform CdSe/CdS nanorods are difficult to obtain (only longer PEG chains; PEG5k yield solutions that satisfy in vivo imaging criteria)
    • 14 (or 15) nm in diameter; 55 (or 54) nm in length
    • 33-35 nm hydrodynamic diameter
  • Thickness of PEG layer is measured, based on inter-rod packing distances with/without PEG (TEM) > approx. 5nm (confirmed by comparing difference between hydrodynamic and inorganic sizes for spherical NPs with the same PEG coating)
  • Stability checked in PBS; Serum adsorption tested in FBS (<math>37^oC</math>) - found formation of a small protein layer
  • Sizes (hydrodynamic diameter) measured by dynamic light scattering (DLS) and fluorescence correlation spectroscopy
  • Both cases diffuse through 5um pores at same rate
  • Nanorods pass through 100-400 nm pores (max pore size in tumor vascular walls) an order of magnitude faster than nanospheres
  • Also faster in tumor-mimetic collagen gels (5.3 times as fast)
  • How about tumor? - intravenously co-injected both in SCID mice with mammary tumors
    • Nanoparticle transvascular transport (effective permeability) = transvascualr mass flux per unit vascular surface area and transvascular concentration difference
    • Nanorods penetrated faster (4.1 times as fast)
  • Distribution (consequence of intersitital transport) at 1 hr - quantified as extravascular volume fraction of each tumor containing nanoparticles
    • Nanorods penetrated more (1.7 times the volume fraction of nanospheres)
  • No difference in plasma half-life in non-tumor bearing mice - indicate similar uptake and clearance rates by organs
  • Similar transport rate as 13nm PEG-coated CdSe/CdS QDs - short dimension determines the transport rates
  • (Alignment with bloodflow increases the probability of convective delivery: UNLIKELY) - tumors tend to have slow blood flow and low transvascular fluid flux
  • Reduced steric hindrance from vessel pore walls and reduced viscous drag near the walls may be responsible (seems to be the case for uniform pores in vitro)
  • Flexible nanorods may be advantageous
    • Reptation behavior - improves transport
    • Longer circulation time - likely through enhanced evasion of phagocytosis
  • Larger aspect ratio (surface area/volume) of nanorods may prove advantageous
    • Tagging ligands can further target cell via cell binding, involve in cell uptake

Application

  • Preventing matrix production in tumors (with losartan) improves probe diffusion rates and NP distribution in tumors - double the effectiveness of therapy
  • Degrading tumor collagen with collagenase also helps
  • Vascular normalization with anti-angiogenic agents improves probe penetration in tumors
  • NP shape is important: need to match size, charge, surface chemistry, drug loading, release kinetics

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