Image-guided nanosystems for targeted delivery in cancer therapy

Abstract

Current challenges in early detection, limitations of conventional treatment options, and the constant evolution of cancer cells with metastatic and multi-drug resistant phenotypes require novel strategies to effectively combat this deadly disease. Nanomedical technologies are evolving at a rapid pace and are poised to play a vital role in diagnostic and therapeutic interventions - the so-called "theranostics" - with potential to advance personalized medicine. In this regard, nanoparticulate delivery systems can be designed with tumor seeking characteristics by utilizing the inherent abnormalities and leaky vasculature of solid tumors or custom engineered with targeting ligands for more specific tumor drug targeting. In this review we discuss some of the recent advances made in the development of multifunctional polymeric nanosystems with an emphasis on image-guided drug and gene delivery. Multifunctional nanosystems incorporate variety of payloads (anticancer drugs and genes), imaging agents (optical probes, radio-ligands, and contrast agents), and targeting ligands (antibodies and peptides) for multi-pronged cancer intervention with potential to report therapeutic outcomes. Through advances in combinatorial polymer synthesis and high-throughput testing methods, rapid progress in novel optical/radiolabeling strategies, and the technological breakthroughs in instrumentation, such as hybrid molecular and functional imaging systems, there is tremendous future potential in clinical utility of theranostic nanosystems.

Fig. (1)

Novel radiolabeled scFv antibodies for targeted imaging of tumors. The figure shows in vivo tumor targeting and imaging of ^99mTc-labeled M40 single chain fragment antibody (scFv) in mouse bearing both sarcomatoid (VAMT-1) and epithelioid (M28) mesothelioma. (A) Single photon emission computed tomography/X-ray computed tomography (SPECT/CT) fused coronal image of ^99mTc-M40 imaged 3 hours after injection. (B) 3D fused SPECT/CT coronal image. (C) blocking control study (the target-mediated uptake is confirmed by ≈ 70 % reduction in tumor activity following administration of 10-fold excess of unlabeled scFv). (D) Positron emission tomography/X-ray computed tomography (PET/CT) fused coronal image of 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) imaged 1 hour after injection (for comparison). The figure shows the ability of the novel M40 scFv to target both sarcomatoid (VAMT-1) and epithelioid (M-28) mesothelioma tumors effectively in mouse models demonstrating the utility of such agents in imaging/detection of all subtypes of mesotheliomas. Adapted with permission from Ref. [29]. Copyright AACR (2011).

Fig. (2)

Passive and active tumor drug targeting. The scheme shows the passive and active targeting mechanisms of multifunctional image guided nanoparticles and the difference in the vasculature of normal and tumor tissues. Drugs and small molecules diffuse freely in and out of the normal and tumor blood vessels due to their small size and thus the effective drug concentration in the tumor drops rapidly with time. On the opposite, macromolecular drugs and nanoparticles can passively target tumors due to the leaky vasculature, but they cannot diffuse back into blood stream due to their large size (EPR effect). Targeting molecules such as antibodies or peptides present on the nanoparticles can selectively bind to cell surface receptors/antigens overexpressed by tumor cells and can be taken up by receptor-mediated endocytosys (active targeting). The image guiding molecules and contrast agents conjugated/encapsulated in the nanoparticles can be useful for targeted imaging and (non-invasive) visualization of nanoparticle accumulation/localization, as well as for mechanistic understanding of events and efficacy of drug treatment simultaneously.

Fig. (3)

Radiolabeled immunoliposomes for targeted imaging of tumors. SPECT/CT fused images (coronal view, and transverse view) of ¹¹¹In- labeled targeted immunoliposomes taken after 24 h after injection in mouse bearing both sarcomatoid (VAMT-1) and epithelioid (M28) mesothelioma. The uptake of the radiolabeled immunoliposome in both epithelioid (M28) and sarcomatoid (VAMT-1) subtypes of mesothelioma tumors at 24 h is clearly seen. Adapted with permission from Ref. [101]. Copyright Elsevier (2011).

Fig. (4)

Multifunctional nanosytems for theranostics. Schematic representation of the formation of: (A) multifunctional self-assembled targeted nanoparticle, and (B) multifunctional targeted radio-immunoliposome from the corresponding building blocks. The multifunctional nanoparticles and liposomes can be engineered by self-assembly of polymers/lipids containing various functionalities such as amphiphilic block copolymers, to facilitate formation of stable nanoparticles loaded with drugs, genes, and imaging agents; antibody and radiolabeled polymer blocks for targeting and imaging; as well as, PEG chains for enabling long circulation half-life in vivo.

Fig. (5)

Image-guided gene silencing using polymeric nanoparticles. (A) Schematic representation of siRNA-loaded in hydrophobically-modified GC and PEI nanoparticle (siRNA-GC-PEI NP). (B) In vivo NIR fluorescence imaging of SCC7 tumor-bearing mice 1 h post-injection of Cy5.5-siRNA-GC-PEI NP. (C) In vivo knockdown of targeted proteins by siRNA (left image) and siRNA-GC-PEI NP (right image) after i.v. injection in B16F10-RFP tumor-bearing mice. The mice were observed by dual modality imaging using light microscopy and by NIR fluorescence imaging system. Adapted with permission from Ref. [152]. Copyright Elsevier (2010).