Therapeutic Nanoreactors:  Combining Chemistry and Biology in a Novel Triblock Copolymer Drug Delivery System

Abstract

Triblock copolymeric nanoreactors are introduced as an alternative for liposomes as encapsulating carrier for prodrug activating enzymes. Inosine-adenosine-guanosine preferring nucleoside hydrolase of Trypanosoma vivax, a potential prodrug activating enzyme, was encapsulated in nanometer-sized vesicles constructed of poly(2-methyloxazoline)-block-poly(dimethylsiloxane)-block-(2-methyloxazoline) triblock copolymers. The nanoreactor is functionalized by incorporation of bacterial porins, OmpF or Tsx, in the reactor wall. Efficient cleavage of three natural substrates and one prodrug, 2-fluoroadenosine, by the nanoreactors was demonstrated.

Self‐Assembled Block Copolymer Aggregates: From Micelles to Vesicles and their Biological Applications

“…[135][136][137] Several pioneering reports based on PMOXA-PDMS-PMOXA triblock copolymer vesicles have demonstrated a wide variety of potential biological applications. [137][138][139][140] Significant reduction in the cytotoxicity of anti-cancer drugs has been reported by encapsulating prodrugs within the vesicular interior, whereby the active (hence cytotoxic) compound is only generated when exposed to the specific conditions found within tumourous tissues. [138] Functionalization of these vesicles with membrane channel proteins coupled with encapsulation of prodrug-activating enzymes also show some promise for cancer treatment.…”

Bio-Decorated Polymer Membranes: A New Approach in Diagnostics and Therapeutics

“…Increasing the amount of protein added to block copolymers increased the permeability of the membrane as measured by enzymatic conversion inside polymeric vesicles, for example due to reconstituted OmpF channel protein. A ratio of 1:10, OmpF to PMOXA-PDMS-PMOXA block copolymer, resulted in a higher activity of the nanoreactors as compared to a 1:100 ratio [34]. Different behavior was seen in the case of AqpZ insertion in polymeric membranes.…”

“…Meier and coworkers developed various methods to prepare nanovesicles of triblock copolymers poly(2-methyl-2-oxazoline)-blockpoly(dimethyl siloxane)-block-poly(2-methyl-2-oxazoline) (PMOXA-PDMS-PMOXA), and were able to reconstitute membrane proteins [32] such as OmpF (outer membrane protein F) [34] and FhuA [35]. Another approach is to consider enzymes as hydrophilic blocks and, together with a hydrophobic polymer domain, these generate a bilayer [39].…”

“…The PMOXA-PDMS-PMOXA membrane is impermeable to small molecules, including water [36], and its permeability was increased by reconstituting channel proteins, allowing the transport of various molecules through the polymeric membrane (Figure 7). Similarly, other membrane proteins have been successfully reconstituted in PMOXA-PDMS-PMOXA membranes: LamB, FhuA, Tsx, AqpZ, Complex I [34,36,37,59], as shown by the movement of different molecules (water, NADH, nucleotides, DNA, enzyme substrates) through the polymeric membrane. F0F1-ATP synthase and bacteriorhodopsin reconstituted in poly(2-ethyl-2-oxazoline)-bpoly(dimethylsiloxane)-b-poly(2-ethyl-2-oxazoline) (PEtOz-PDMS-PEtOz) polymeric vesicles are further examples of transmembrane proteins that retained their activity after reconstitution in polymer membranes [38].…”

“…Polymer vesicles with engineered membrane proteins for controlled transport advance the optimal use of polymeric vesicles, especially for applications related to sensitive biological entities as, for example, sRNA, or enzymes. Despite numerous examples of polymersomes in use for drug delivery [64][65][66], only a few of them are bio-decorated [34,67,69]. All of them, presented here, were designed in the context of developing nanoreactors, or synthetic organelles, which serve to provide protected enzymes/proteins in the desired biological compartment.…”