Apoptin, a protein derived from chicken anemia virus, is known to translocate to the nucleus of tumor cells where it accumulates, activating an apoptotic cascade (otherwise known as cell death). The protein selectively accumulates in tumor cells, leaving normal tissue unharmed- an obvious advantage over techniques currently used in cancer therapy such as small molecule chemotherapeutics. (It should be noted here that to date the mechanism for this selectivity is not well understood). To benefit from the possibly therapeutic properties of apoptin, the protein has to find its way into cancerous cells. And here comes the challenge of drug delivery. Earlier this year, Muxun Zhao and coworkers encapsulated a protein with similar properites to apoptin, which the authors refer to as MBP-APO, with a positively charged polymer nanocapsule. The encapsulation of MBP-APO is achieved through electrostatic deposition of two monomers and a crosslinker onto the protein, and in situ polymerization initiated by free radicals. The cross-linker chosen has disulfide bonds that degrade in the presence of a reducing environment like that found in the cytoplasm of eukaryotic cells. The monomers chosen create a slightly positively charged polymer shell that protects MBP-APO and is of optimized charge to enable cellular uptake.
By performing in situ and in vivo tests, the authors demonstrate the necessity of the degradable polymer shell for shuttling MBP-APO into cells and for releasing the protein cargo once in the cytoplasm. Cell specificity studies showed an accumulation of MBP-APO in tumor nuclei, while in healthy cells MBP-APO remained in the cytoplasm, as seen by confocal microscopy. When the protein was encapsulated by a non-degradable polymer shell it was unable to enter the nucleus of either cell because the protein remained trapped within the nanocapsule. When MBP-APO was not encapsulated it was unable to enter the cells at all. Cell viabilities studies also confirmed the effectiveness of the polymer nanocapsules and of MBP-APO. All cancer cells treated with the degradable nanocapsules had no viable cells remaining, while 75% of the healthy cells survived. When the nanocapsules were non-degradable, or if the protein was not encapsulated, both tumor cells and healthy cells survived. Similar results were obtained for in vivo studies. Mice that were subcutaneously grafted with breast cancer cells were randomly separated into four groups and treated with an intratumoral injection. Tumors that were injected with serum, pristine MBP-APO (with no nanocapsule), and degradable nanocapsules full of serum expanded rapidly. Conversely, tumor growth was significantly suppressed in mice treated with degradable-polymer-encapsulated MBP-APO.
Biodegradable polymers are particularly attractive for biomedical applications because they often exhibit excellent biocompatibility. Their degradability can be can be tuned such that the polymers decompose under the desired conditions for applications such as drug delivery or scaffolding. When used for scaffolds, it was shown that if the degradable polymer can be made electrically conductive, similarly to the polymers used for electronic applications such as LEDs and photovoltaics, electrical stimulation could promote cell adhesion and proliferation. A review article published in Progress in Polymer Science details advancements and challenges in the synthesis of conductive and degradable polymers. Some of the methods outlined include blends and composites of degradable polymers with small amounts of conductive polymers, multiblock copolymers with degradable and conductive oligomers, and the synthesis of star-shaped and hyperbranched degradable polymers with conductive segments. Among the challenges degradable conducting polymers still face are the control of conductivity and their processability. Most conducting polymers are only soluble in organic solvents that are toxic to the environment and to biological organisms. Research is underway towards synthesizing semiconducting polymers that can be processed from environmentally-friendlier solvents also for applications of organic electronics. As the authors conclude they suggest that efforts could develop the use of degradable electrically conductive polymers for the use of drug delivery, with similar advantages to what was shown by the degradable nanocapsules, with particular application for neural drugs.
References:
Muxun Zhao, Biliang Hu, Zhen Gu, Kye-Il Joo, Pin Wang, Yi Tang, Degradable polymeric nanocapsule for efficient intracellular delivery of a high molecular weight tumor-selective protein complex, Nano Today, Volume 8, Issue 1, February 2013, Pages 11-20.
(http://www.sciencedirect.com/science/article/pii/S1748013212001405)
Baolin Guo, Lidija Glavas, Ann-Christine Albertsson, Biodegradable and electrically conducting polymers for biomedical applications, Progress in Polymer Science, Volume 38, Issue 9, September 2013, Pages 1263-1286.
(http://www.sciencedirect.com/science/article/pii/S0079670013000671)