Liposomes are good candidates as drug carriers and have been widely investigated in drug delivery systems [31, 32]. Basically, liposomes are self-assembled vesicles composed of a lipid bilayer, which forms a closed shell surrounding an internal aqueous phase. The major advantages of liposomal carriers for drug delivery are that they are biodegradable and nontoxic [31, 32]. Moreover, size, charge, and surface functionalization of liposomes are easily controllable and such systems are suitable for carrying both hydrophobic and hydrophilic drug molecules [31, 32]. Owing to these favorable characteristics, liposomes were the first nanoplatforms to make the transition from conceptual stage to clinical application, and are now an established technology platform with considerable clinical acceptance [7, 31, 32].

Paoli et al. reported the synthesis of liposomal formulations with particle size in the range 80–113 nm [33]. The liposomes were preconjugated with suitable fluorophores (calcein or AF-750) and radiolabeled with ¹⁸F or ⁶⁴Cu for dual-modality PET/optical imaging. A model hydrophilic drug was encapsulated in the liposomal system and administered in mice bearing bilateral Met-1 tumors, to assess the relative stability and circulation kinetics of the drug-loaded liposomes, while maintaining temperature sensitivity. Using in vivo PET imaging and ex vivo fluorescent imaging of tumors, the authors could demonstrate that the accumulation of the drug was increased by up to 177-fold by liposomal encapsulation.

In a recent study, Lee et al. reported the synthesis of a chelator compound, 4-DEAP-ATSC, which serves as the ⁶⁴Cu loading and entrapment agent in liposomal formulations [34]. The authors demonstrated that the ⁶⁴Cu-DEAP-ATSC complex could be loaded into PEGylated liposomal doxorubicin (PLD) and HER2-targeted PLD (MM-302) with >90 % efficiency and that ⁶⁴Cu-loaded liposomal formulations were stable in human plasma up to 24 h. In vivo PET imaging studies in BT474-M3 (HER2-overexpressing breast carcinoma) xenografts after administration of ⁶⁴Cu-MM-302 showed heterogeneous distribution within tumors. The biodistribution profiles were quantitatively consistent with tissue-based analysis, and radioactivity uptake in the tumor (4.8 ± 0.7 %ID/g at 24 h postinjection) correlated with liposomal drug deposition. The promising results obtained in this study suggest that clinical translation of this strategy might aid in the identification of cancer patients who are most suited for undergoing liposomal therapy.

Micelles are colloidal particles with a size usually within a range of 5–100 nm, and are currently under investigation for targeted delivery of hydrophobic anticancer drugs [35]. When tagged with suitable positron emitting radioisotopes, these systems can be used for image-guided drug delivery. Among the various micellar structures, the polymeric micelles are the most extensively used for drug delivery applications [35, 36]. The polymeric micelles generally consist of a unique core—shell structure. The inner core is the hydrophobic part of the block copolymer, which encapsulates the hydrophobic drug. The outer shell or corona of the hydrophilic block of the copolymer is often composed of PEG, and it protects the drug from the aqueous environment and also imparts particle stability and excellent dispersibility in an aqueous solution. Because of these characteristics, polymeric micelles have several advantages as drug carriers such as enhancing the aqueous solubility of hydrophobic drugs, prolonging the circulation time of the drug in the blood, improving the in vivo stability of the drug, providing both passive and active tumor targeting abilities, and reducing nonspecific uptake by the RES [35, 36].

In the first use of micellar systems for PET image-guided drug delivery in tumor-bearing mice, Xiao et al. reported the synthesis of multifunctional unimolecular micelles made of a hyperbranched amphiphilic block copolymer [37]. The hyperbranched block copolymer of the micellar system was conjugated with cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides (cRGD , for integrins α _v β ₃ targeting) and macrocyclic chelators [1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA)], for ⁶⁴Cu-labeling. An anticancer drug , doxorubicin (DOX ), was also covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arm to enable targeted drug delivery and pH-controlled drug release. In vitro studies showed that cRGD-conjugated unimolecular micelles exhibited a much higher cellular uptake in human glioblastoma (U87MG) cells due to integrin α _v β ₃-mediated endocytosis compared to nontargeted unimolecular micelles, thereby leading to a significantly higher cytotoxicity. In vivo PET imaging and biodistribution studies in U87MG (human glioblastoma) xenografts revealed that targeted unimolecular micelles (conjugated with cRGD peptide) exhibited a much higher level of tumor accumulation (~5 %ID/g) than nontargeted unimolecular micelles (~2.5 % ID/g) at 4 h postinjection (Fig. 2a). Administration of a blocking dose of cRGD peptide (10 mg/kg of mouse body weight) followed by administration of radiolabeled unimolecular micelle conjugated with cRGD peptide reduced the tumor uptake significantly (~2 % ID/g), which confirmed integrin α _v β ₃ specificity of the targeted micelle in vivo (Fig. 2a). These results were further confirmed by ex vivo optical imaging using the fluorescence signal of DOX (Fig. 2b).

The same group of authors further extended the work by conjugation of anti-CD105 monoclonal antibody (TRC105) with the unimolecular micelles (instead of cRGD peptide as done in the previous study) [38]. TRC105-conjugated unimolecular micelles showed a higher CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with nontargeted unimolecular micelles. Similar to the previous study, in vivo PET imaging and biodistribution studies in 4T1 murine breast tumor-bearing mice showed that a tumor accumulation of ~6 % ID/g of targeted micelles (i.e., conjugated with TRC105) was higher than that of nontargeted micelles (~3 % ID/g) at 5 h postinjection. In a recent study, the same group of authors reported the development of a new type of unimolecular micelle formed by brush-shaped amphiphilic block copolymers [39]. As in the previous study, the unimolecular micelle was conjugated with TRC105, loaded with DOX and radiolabeled with ⁶⁴Cu for PET image-guided drug delivery in 4T1 tumor-bearing mice and similar results were obtained. The encouraging results obtained in all these studies clearly indicate that unimolecular micelles are promising form of nanomedicine for targeted cancer theranostics .

Over the last few years, there is growing interest toward the use of endogenous organic nanostructures, such as ferritins, melanin, etc. as drug delivery platforms due to their native biocompatibility and biodegradability [26, 40, 41]. In this direction, it is desirable to develop endogenous systems that intrinsically possess both contrast and drug delivery properties. Recently, Zhang et al. reported the synthesis of melanin nanoparticles as an efficient endogenous system for multimodality image-guided drug delivery [26]. Melanin is a biopolymer with good biocompatibility and biodegradability, intrinsic photoacoustic properties, and binding ability to various types of chemotherapeutic drugs [41]. The synthesized nanoparticles were PEGylated, loaded with an anticancer drug (Sorafenib ), radiolabeled with a ⁶⁴Cu adopting chelator-free approach, and then used for dual modality PET and photoacoustic image-guided drug delivery. In vivo PET imaging and biodistribution studies after intravenous administration of the nanoplatforms in hepatocellular carcinoma (HepG2) tumor-bearing mice revealed rapid tumor uptake by passive targeting (5.5 ± 0.3 % ID/g at 4 h postinjection) with a good tumor to background contrast. The results of PET imaging were further corroborated by photoacoustic imaging. Furthermore, the authors could successfully demonstrate the antitumor effects of drug-loaded melanin nanoparticles by studying the inhibition of tumor growth in vivo. The promising results obtained in this study prove that melanin nanoparticles are an efficient biosystem for multimodality image-guided drug delivery and hold potential for clinical translation in the foreseeable future.

Among the various metallic nanoparticles reported to date, gold nanostructures possess unique characteristics that enable their use as contrast agents, therapeutic entities, and frameworks to attach functional molecules, therapeutic cargo, or targeting ligands [42, 43]. Owing to their ease of synthesis, easy surface functionalization, and nontoxicity, gold nanostructures have emerged as powerful nanoplatforms for cancer theranostics [42]. The development of a multifunctional gold nanorod-based nanoplatform for PET image-guided drug delivery was reported by Xiao et al. [44]. The bare gold nanorods had a length and diameter of approximately 45 and 10 nm, respectively. The gold nanorods were PEGylated and an anticancer drug (DOX ) and tumor targeting agent (cRGD ) were conjugated to it. A chelator, NOTA, was attached onto the distal ends of the PEG arms for ⁶⁴Cu labeling. Based on flow cytometry analysis, cRGD-conjugated gold nanorods loaded with DOX exhibited a higher uptake and cytotoxicity in U87MG cells compared to nontargeted gold nanorods in vitro. However, in vivo PET imaging and biodistribution studies showed that targeted and nontargeted gold nanorods had a similar distribution pattern, in particular in respect to tumor uptake (~5 % ID/g). Despite this limitation, this study demonstrated the potential of gold nanorods as an efficient nanoplatform for cancer theranostics .