A new dimension in cancer treatment

A new dimension in cancer treatment

7:24 AM, 21st June 2018
Dr. Apoorv Shanker, post-doctoral associate at Prof. Paula T. Hammond Lab, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology.
Dr. Apoorv Shanker, post-doctoral associate, MIT.

In an interview, Dr. Apoorv Shanker with Chemical Today Magazine delves into the use of polymers and sift materials in his research on cancer immunotherapy.

Dr. Shanker is a post-doctoral associate at Prof. Paula T. Hammond Lab, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT).

Research insight.

With new cancer treatment regimens coming up, a lot of effort is being expended on developing spatiotemporally-controlled drug delivery systems. Polymers and soft materials are at the core of such systems.

In my current project, I am focusing on cancer immunotherapy. Immunotherapy refers to treatments which harness and enhance the innate immune system to fight cancer. Over the years, several different approaches such as stimulating the effector mechanisms and suppressing the inhibitory mechanisms of the immune system have been developed as effective anti-cancer treatments. This tweaking of the immune system is carried out through administration of certain antibodies and small molecule drugs that can be termed as “immune-modulators”. However, the optimal sequencing of immune-modulators is currently not known. I am investigating the effect of their dosage and sequencing on immune activity through layer-by-layer (LbL)-fabricated microparticle delivery vehicles. Such microparticles can deliver agents in both spatially- and temporally-controlled fashions. LbL structures on micro-particle vaccines will allow direct comparison of different sequences in a higher throughput than currently possible with conventional dosing.

Changing molecular structure of plastic.

Thermal conductivity in bulk amorphous polymers is generally inhibited by the following:

• highly coiled and entangled intrachain structure

• loose chain packing with voids that dampen the speed at which heat-carrying vibrations propagate, and

• weak nonbonding interchain interactions (for example, van der Waals and dipole-dipole).

In the new technique we developed, we formulated a way to simultaneously tackle these three bottlenecks. Ionization of the pendant acidic groups on a commercial polyelectrolyte (polyacrylic acid, PAA) led to coulombic repulsion between the negatively-charged groups resulting in “opening-up” of the coils or in other words, chain expansion. Furthermore, ionization also stiffened up the chains through ionic interactions in addition to hydrogen-bonding and van der Waals forces, and resulted in more compact packing of the chains. Together these three effects resulted in approximately 250 percent enhancement in thermal conductivity in chain-expanded PAA compared to the coiled-up polymer. It can be understood as the difference between a tightly stretched guitar string to a loosely coiled piece of twine - the guitar string vibrates when plucked, the twine doesn’t.

Challenges of adding metallic or ceramic fillers to plastics.

Achieving high thermal conductivity in composites usually requires high loading of metallic or ceramic fillers to create a continuous conducting or percolating network through which heat energy can transfer efficiently. This results in unwanted properties such as loss of processability and machinability, increased weight, color and cost (for eg, CNTs: $1000/kg, PMMA: $2/kg). Moreover, thermal transport in composites is limited by poor filler dispersion in the polymer matrix, and interfacial thermal resistance between fillers and the matrix. The achieved thermal conductivity is mostly far lower than the weighted average of those of the fillers and the polymer matrix. For example, thermal conductivity achieved in composites with spherical metal particles above the percolation threshold is on the order of 1 Wm-1K-1. In such composites, vibrational mismatch between the polymer matrix and the filler particles is the killer. A better understanding of thermal transport across the polymer-filler interface will aid in the development of composites with high thermal conductivities.

Chemical process used to change plastic’s molecular structure.

The molecular make-up of polymers can be classified at three levels:

• chemical structure including the chain backbone, side groups and chain length

• chain morphology and orientation, and

• inter-chain interactions.

Computer simulations have revealed important molecular parameters that affect thermal transport in polymers. Experimentally, covalent cross-linking has been widely investigated as a mean to enhance polymer’s thermal conductivity. However, only miniscule enhancement or, in some cases, even a decrease in the thermal conductivity has been observed. Clearly, it’s not an effective technique. “Physical” processes such as electro-spinning, mechanical stretching, ultra-drawing and template-assisted polymerization have yielded very high thermal conductivities in oriented polymers in the direction of chain alignment. These techniques basically change the morphology of the polymers from coiled-up chains to expanded or linearized, oriented ones.

We took inspiration from these chain-oriented polymer systems and developed methods to translate the expanded chain conformations to amorphous polymer films. In the first work (published in Nature Materials, 2015), we utilized strong hydrogen bonds between two polymers – a long, loopy one and a short, rigid polymer – to stretch out the longer chains, resulting in an order of magnitude enhancement in thermal conductivity in the polymer blend at certain mixing ratios compared to the individual polymers. The hydrogen bonds further enhanced the inter-chain heat transfer in the blend films. In the second work described before, we utilized coulombic repulsion forces to the same effect.

Applying the technique to non-water soluble polymers by using organic solvents.

We employ chemical methods to change polymers’ molecular structure. This means that our methods rely on the chemical groups, either a pendant group or in the backbone itself, amenable to different chemistries. For example, we modified the carboxylic acid groups on polyacrylic acid chains via ionization in the work described above. Most of the commercial (and non-water soluble) polymers such as polyvinyl chloride, polystyrene and polymethyl methacrylate are not amenable to such chemical modifications. Alternate routes such as blending of different polymers are being probed. Some positive results have been obtained. However, I would like to add that it’s very challenging to work with non-water-soluble polymers.

Research projects for polymeric materials.

As far as purely polymeric materials are concerned, two methods have shown great promise. One, directional orientation of crystalline or semi-crystalline polymers through techniques such as shearing, mechanical stretching, gel-spinning, superdrawing, etc. has been developed to realize high thermal conductivities in polymer fibers along the direction of chain alignment. Thermal conductivity as high as 104 Wm-1K 1 has been achieved in polyethylene nanofibers with diameter of 50-500 nm. The second method involves nano-template assisted electropolymerization. Thermal conductivity up to 4.4 Wm-1K-1 along the direction of chain alignment has been achieved in amorphous systems.

These two methods achieve high thermal conductivities only along the orientation direction which is rather impractical as far as real applications are concerned. On the contrary, our method achieves high cross-plane thermal conductivity in thin films which are better suited for heat transfer applications. In the polymer/ method discussed above, we could achieve thermal conductivity up to 1.2 Wm-1K-1 in nanoscale amorphous thin films. It should be noted that the polyethylene nanofibers were crystalline (crystalline materials generally have higher thermal conductivity than amorphous materials). Furthermore, our method is amenable to coating of large areas through common industrial techniques such as spin- and contact-coating. For instance, we could achieve thermal conductivity greater than 0.6 Wm-1K-1 in micrometer-thick completely amorphous films made by the contact coating method. This value is 50 percent higher than that of semi-crystalline polyethylene in the bulk (ie, unstretched) form. Additionally, the method is cheaper and easier than the cumbersome chain orientation methods.

Sectors that will benefit from the research.

Developing a method to increase thermal conductivity of pure unmixed polymers without significantly impacting their other properties (eg, cost, weight, electrical conductivity) would enable them to displace more expensive materials in many thermal management applications and further improve the functionality of existing polymer products. For example, device performance and reliability can benefit from high thermal conductivities of plastic encapsulants used for LEDs, electronic chips and cellphones. Similarly, higher thermal conductivity in polymer-matrix composites can be achieved at lower filler loadings. The rapidly rising field of flexible electronics presents yet another severe challenge for thermal management. I believe polymers with high thermal conductivities can be greatly beneficial here.

As far as the material we have developed is concerned, it should be used in sealed environment because it is moisture-sensitive. Thermal interface materials used to link silicon die to the heat sink in electronic chips and underfill materials in 3D-stacked silicon dies, where generally elastomers such as silicone and epoxy (thermal conductivity ~0.2 Wm-1K-1) are used, are possible areas of application.

Solving issues such as characterization of polymer films.

The biggest challenge we faced in this work was the characterization of the polymer films. First, since we were using sodium hydroxide (NaOH) to ionize the polymer chains, we had to be perfectly sure that NaOH is not ending up as small particles in the film and acting as a filler. We carried out multiple tests and corroborated the results with theoretical calculations to rule out this possibility. Another challenge was that the films were moisture-sensitive. We had to take absorption of humidity by the polymer films into account during the thermal conductivity and elastic modulus measurements. Special arrangements had to be made to reduce errors induced by absorption of moisture.

Working on molecular designing of new materials for the future.

I am particularly interested in molecular designing of new materials to meet challenges in the fields of energy, sensing, and biomedicine. I would like to direct my own research lab in the future. The Koch Institute has provided me with excellent opportunity to learn about the rapidly evolving field of cancer immunotherapy and identify areas where I can contribute with my knowledge and expertise in soft materials.

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