# Biodegradable Contrast Agents for Photoacoustic Imaging
## 5 Polymeric Materials as Biodegradable PA Agents
### Biodegradable Polymers as PA Agents  
Conventional biodegradable synthetic polymers have been extensively applied as contrast agents for PAI, as mentioned above. As a representative example, poly(lactic-_co_-glycolic acid) (PLGA) can be used for biodegradable agents. The polymer is typically obtained from cyclic monomers of lactic acid and glycolic acid through statistical copolymerization or block copolymerization (Figure 8A). Because of the ester linkages in the backbone, PLGA is subject to hydrolysis under aqueous conditions. Furthermore, the composition ratio between lactic acid and glycolic acid determines the rate of hydrolysis. The higher the content of glycolide repeating units, the faster the polymer hydrolyzes. In contrast, the incorporation of lactic units tends to retard the degradation. [PERSON] et al. used PLGA to fabricate a biodegradable nanoparticle agent through the double emulsion method [PERSON] et al. (2017). Herein, PLGA positioned in a polymer shell and imparted biodegradability as well as sufficient mechanical properties to the nanoparticles. Therefore, the resulting hierarchical PLGA-based agent  
Figure 7: PA signaling of cellulose nanoparticles (CNPs). (**A**) Spectral imaging of CNPs, showing a maximum absorbance peak at 700 nm, which was used for all subsequent imaging experiments (red solid curve). The background PA spectrum of normal tissue is also shown for reference (black dots). The inset shows a PA image of a subcutaneously implanted bolus of CNPs at 0.5 mg\(\cdot\)mL\({}^{-1}\) (”Pos.”) and a matrigel only implant (”Neg.”). The solid circle highlights a normal region used to create the tissue-only spectrum. The scale bar in the inset is 3 mm. (**B**) Normalized PA data for CNPs and a “flat” graphite absorber, illustrating the change in laser power as a function of wavelength. (**C**) Representative PA images of a phantom scanned with a tomographic imaging system. Ci–Civ are CNPs. Ci: 0.70 nM, Ci: 0.35 nM; Ciiii: 0.15 nM; Civ: 0.07 nM. Cv is 0.70 nM GNRs. Scale bar in C is 4 mm. PA data for CNPs and GNRs collected using the tomographic scanner for both CNPs and GNRs with 700 nm incident radiation using either molar (**D**) or mass units (**E**). Error bars in C are plotted in red and represent the standard deviation of 3 replicate samples and are \(<\)10% RSD. Reprinted with permission from ([PERSON] et al., 2014). Copyright Elsevier, 2014.  
was multimodal: (i) the agent was able to generate PA signals when stimulated by a laser pulse owing to AuNPs incorporated in the core, (ii) further incorporation of a dye in the core enabled fluorescent imaging and (iii) the agent showed potential for delivering paclitaxel, a cancer therapeutic drug, as demonstrated by in vitro experiments. Thus, therapists--a combined concept of remedial therapy and diagnostic imaging--was achieved.  
In another example, a synthetic block copolymer that contains Pt(II) complexes was used [78]. In this work, an organic-inorganic hybrid contrast agent was designed using functional polymers. First, the polymerization of equimolar amounts of 4-aminomethyl piperidine (AMPD) and equimolar \(N\),\(N^{\prime}\)-bis(acryloyl)cystamine (BAC) via a Michael addition reaction afforded the poly(AMBD-BAC) backbone. The disulfide bond in BAC provided redox-responsive behavior and was cleaved when exposed to glutathione (GSH). Postpolymerization modification introduced poly(ethylene glycol) moieties into the backbone, which facilitated drug delivery and reduced nonspecific adsorption during circulation in physiological environments. Furthermore, diethylenetriaminepentaacetic acid (DTPA) and Cisplatin were added sequentially to form Pt(II) complexes that generated PA signals (Figure 8B). The functional polymers were developed into nanoparticles under aqueous conditions and the resulting particles allowed in vivo imaging of rat cerebral vasculature, taking advantage of the PA signal. Cytotoxicity tests further confirmed that the polymeric material was biocompatible.