Polymersomes: a new multi-functional tool for cancer diagnosis and therapy

Abstract

Nanoparticles are being developed as delivery vehicles for therapeutic pharmaceuticals and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties that make them ideal for these applications. Synthetic control over block copolymer chemistry enables tunable design of polymersome material properties. The polymersome architecture, with its large hydrophilic reservoir and its thick hydrophobic lamellar membrane, provides significant storage capacity for both water soluble and insoluble substances (such as drugs and imaging probes). Further, the brush-like architecture of the polymersome outer shell can potentially increase biocompatibility and blood circulation times. A further recent advance is the development of multi-functional polymersomes that carry pharmaceuticals and imaging agents simultaneously. The ability to conjugate biologically active ligands to the brush surface provides a further means for targeted therapy and imaging. Hence, polymersomes hold enormous potential as nanostructured biomaterials for future in vivo drug delivery and diagnostic imaging applications.

Fig. 1

Schematic representations of NIR-emissive polymersomes. (A) In aqueous solution, amphiphilic diblock copolymers of polyethyleneoxide-1,2 polybutadiene (PEO₃₀–PBD₄₆) self-assemble into polymer vesicles (polymersomes) with the hydrophobic PBD tails orienting end-to-end to form bilayer membranes. The depicted unilamellar polymersome displays an excised cross-sectional slice illustrating the bilayer PBD membrane (gray) containing the hydrophobic (porphinato)zinc(II) (PZn)-based near-IR fluorophores (NIRFs, red). (B) CAChe-generated sectional schematic of the NIR-emissive polymersome membrane indicating the molecular dimensions of: (i) the PBD component of the bilayer (9.6 nm); (ii) the large, dispersed PZn-based NIRFs (2.1–5.4 nm); and, (iii) a typical liposome membrane (3–4 nm) comprised of phospholipids (1-stearoyl-2-oleoyl-sn-Glycero-3-Phosopho-choline—SOPC). (C) Chemical structures of NIR fluorophores PZn₂–PZn₅. [This image was reproduced from Ghoroghchian et al. [9] with permission from Copyright (2005) National Academy of Sciences, USA.]

Fig. 2

General application of polymersome architecture in therapeutics. Schematic representation of polymersome assembly illustrating three possible applications, namely optical imaging, drug delivery, and targeted-therapy.

Fig. 3

Kinetics of doxorubicin loaded polymersomes. (A) Cumulative in situ release of doxorubicin, loaded within 200 nm diameter PEO(2 K)-b-PCL(12 K)-based polymersomes, under various physiological conditions (pH 5.5 and 7.4; T = 37 °C) as measured fluorometrically over 14 days. N = 4 samples at each data point; individual data points for each sample varied by less than 10% of the value displayed at each time interval. (B) Release rates of DOX (V_dox) from 200 nm diameter PEO(2 K)-b-PCL(12 K)-based polymersomes vs. time. Dotted and solid lines represent exponential fits obtained by regression analysis (R² = 0.99 for each curve), and the displayed equations correspond to the respective release regimes (α, β, β′). (C) Schematic illustrating differing regimes of DOX release via (α) intrinsic drug permeation through intact vesicle membranes vs. (β and β′) release predominantly by PCL matrix degradation. [This image was reproduced from Ghoroghchian et al. [10] with permission from Copyright (2006) American Chemical Society.]

Fig. 4

Anti-tumor effects of doxorubicin loaded polymersome in mice. Mice were inoculated with tumor cells on day 0, were administered drug (free dox, dox loaded polymersome, or DOXIL) or PBS on day 7, and sacrificed on day 16. Images of tumor bearing mice administered PBS (A) and DOX polymersomes at the culmination of the study, day 16. (B); (C–E) Average tumor Volume vs. Time, Tumor volumes of the 5 mice per group averaged. Error bars are reported as standard error.

Fig. 5

Tumor imaging by NIR-emmisive polymersome. Fluorescence images obtained using eXplore Optix instrument of the same mouse taken prior to administration of NIR-emissive polymersomes, and at 4, 8, and 12 h post tail-vein injection. (A) Prone position, (B) supine position (λ_ex = 785 nm, λ_em = 830–900 nm). The arrows in the prone and supine positions suggest location of organs. In the supine position, the arrow suggests the fluorescence emanating from the lower portion of the mouse body is from the tumor; it may also be emanating from the gut of the mouse due to break down of food.