Understanding of Nano-scale Interactions between Polymers and Cells

In order to develop effective delivery vectors, fundamental understating of the biological properties of materials is essential. Part of Dr. Hong's dissertation work was focused on the biological interactions of polymers with cell membranes.  In this research, it was found for the first time that positively charged polyamidoamine (PAMAM) dendrimers and other polycationic polymers induce transient nano-scale hole formation in supported lipid bilayers and cellular membranes (Figure 1). The nano-scale hole formation mechanism plays a key role in cell entry of certain nanoparticles that have been applied for non-viral cell transfection or gene delivery.  However, it is obvious that the published data regarding this phenomenon does not indicate that the proposed mechanism should be considered as a replacement of endocytosis.  Rather, the results suggest a competitive process in which both mechanisms are operative.  Many inconclusive and contradictory experiments in this regard can be found in the literature and the details of the internalization mechanisms still remain elusive.

Related Publications: Bioconjugate Chem., 2004, 15(4), 774-82; 2006, 17(3), 728-34; J. Chem. Health Safety, 2006, 13(3), 16-20; Acc. Chem. Res. 2007, 40(5), 335-42.

Multivalent Targeting for Cancer Cells using Polymeric Delivery Vectors

Multivalent interaction, the simultaneous binding event of multiple ligands to multiple receptors in biological systems, has been investigated to promote targeting of specific cell types.  The recent development of nanotechnology has demonstrated many breakthroughs in a range of biomedical applications particularly for cancer treatment.  In the design of effective targeted drug delivery/imaging vectors based on nanotechnology, multivalent effects are desirable since it dramatically enhances active targeting efficacy.  The material properties of nanovectors required for maximal multivalent effects include: 1) flexibility for conformational deformation to increase interacting surface area at a low cost of entropy and 2) localized reactive groups for targeting agents to utilize receptor clustering effect.  Indeed, a series of experiments to quantitatively measure the multivalent targeting has been conducted using polyamidoamine (PAMAM) dendrimers that satisfy the two pre-requisite properties, yielding a substantial enhancement in binding avidity as high as ~170,000 folds compared to the analogous monovalent binding.  An optimum number of targeting molecules appeared to be ~5 where the dendrimers showed an exponential increase in binding avidity and sustained their monodispersed properties.  Engineered dendritic anti-cancer nanodevices utilizing the multivalency have exhibited great efficacy in targeting and killing cancer cells both in vitro and in vivo without apparent harmful side effects.  This study supports the idea that nanoparticle based drug delivery systems can be significantly improved in targeting efficacy if the optimization process is conducted to maximize the multivalent effect without compromising the materials properties.

Related Publications: Chem. Biol., 2007, 14(1), 107-15; Nature Nanotech., 2007, 2, 751-60; Nano Today, 2007, 2(3), 14-21; ACS Nano, 2008, 2(4), 773-83.

Cell Specific Capturing

Metastatic cancer colonies are initiated with an adhesion mechanism hijacked from the inflammation response.  The first step in this process involves transient, reversible, adhesive interactions between selectin molecules expressed on the endothelial venules and glycoprotein receptors on the leukocyte/invasive cancer cell, resulting in cell rolling.  By exploiting this natural process, circulating tumor cells (CTCs) may be selectively captured on devices containing selectins and other cancer cell specific ligands.  To translate this technique to realistic devices, capturing surfaces need to be non-fouling, stable, and controllable with minimum batch-by-batch variations, which are major drawbacks of current immobilization methods of the ligands, i.e. physisorption.  Covalent immobilization of P-selectin using non-toxic chemical reactions can enhance these properties as compared to physisorbed surfaces both in model and in vitro studies.  The results suggest that cancer cell specific capturing devices based on cell rolling can be achieved if specific ligands are covalently immobilized in a controlled way and present high specificity against their targets.  An optimized, polymer-based nanovector will be employed for this application in order to enhance the specific capturing capacity of the devices via multivalent effects.

Related Publications: Langmuir, 2007, 23(24), 12261-8; Nano Lett., 2008, 8(4), 1153-8.

 

 

Figure 1. Schematic diagram of polymer induced transient nanoscale hole formation.

 

Figure 2. Simulated sequential images of multivalent targeting of a PAMAM dendrimer-based targeted drug delivery platform onto receptors on virtual cell surface (courtesy of Dr. Mecke of MNiMBS).  Note that all 5 targeting molecules (yellow balls) simultaneously bind to 5 receptors (purple pairs).

 

Figure 3. A potential microfluidic device for selective capturing of target cells using multivalent nanovectors immobilized on microfluidic channels.