Porphyrins are organic heterocyclic macrocycles with photophysical properties well-suited for clinical phototherapy and cancer imaging. However, their wider application in the clinical management of disease is barred by poor aqueous solubility, bioavailability, tumour accumulation and skin phototoxicity. These limitations instigated the development of supramolecular platforms that improved porphyrin pharmacokinetics and tumour-homing. The supramolecular formulation of porphyrins also facilitates single agent-mediated deeper tissue photoactivation, extended imaging and theranostic multimodality, and synergistic application of multiple therapies. Supramolecular porphyrin structures can overcome additional limitations of porphyrin-mediated photodynamic therapy (PDT), including low depths of tissue penetration that restrict PDT to superficial lesions, inability to treat hypoxic tumours, and incomplete tumour damage. In this review, we discuss the photophysical properties of porphyrins, and overview the clinically-relevant advantages and challenges arising from their incorporation within supramolecular platforms. Specifically, fundamentals underlying the ability of these platforms to ameliorate passive and active porphyrin delivery to tumours, achieve deeper tissue PDT via red-shifted porphyrin Q-bands, energy transfer and sonodynamic effects, and enable new porphyrin-mediated theranostics and synergistic therapeutic capabilities will be explained and exemplified with seminal and cutting-edge in vivo studies.

Sonodynamic therapy (SDT) is a promising therapeutic platform for minimally invasive cancer treatment in which acoustically susceptible drug agents, sonosensitizers, are activated by deep-tissue-penetrating low frequency ultrasound. Despite growing research in recent years, the field has yet to clearly elucidate broadly applicable mechanisms by which acoustic cavitation triggers sonosensitizer therapeutic activity, creating difficulties in achieving substantial and translatable therapeutic efficacy. In this review, we will critically analyze the proposed mechanisms underlying SDT and overview how nanomedicines can complement and extend these mechanisms to deliver more efficacious SDT. In doing so, we aim to highlight potential avenues toward viable implementation of SDT as a cancer therapy.

Lipoprotein mimetic nanostructures, which consist of an amphiphilic lipid shell, a hydrophobic core, and an apolipoprotein mimetic peptide, serve as a versatile platform for the design of drug delivery vehicles as well as the investigation of supramolecular assemblies. Porphyrin incorporation into biomimetic lipoproteins allows one to take advantage of the inherent multimodal photophysical properties of porphyrins, yielding various fluorescence, photoacoustic, and photodynamic agents. To facilitate their incorporation into a lipoprotein structure, porphyrins have been conjugated through a variety of strategies. However, the effects of the conjugate structure on the associated nanoparticle’s phototherapeutic properties warrants further investigation. Herein, we systematically investigated the effects of two widely utilized porphyrin conjugates, oleylamide and lipid, on biophotonic properties of their resultant porphyrin-lipoprotein nanoparticles in vitro and in vivo. Specifically, we demonstrated that incorporation of the porphyrin moiety as an oleylamide conjugate leads to a highly stable J-aggregate with strong photoacoustic contrast, while incorporation as an ampiphilic lipid moiety into the lipid shell yields an effective fluorescent and photodynamic agent. The current study proposes a rational design strategy for next-generation lipoprotein-based phototheranostic agents, for which nanoassembly-driven biophotonic and therapeutic properties can be tailored through the specific selection of porphyrin conjugate structures.

Porphyrin aggregates have attractive photophysical properties for phototherapy and optical imaging, including quenched photosensitization, efficient photothermal conversion, and unique absorption spectra. Although hydrophobic porphyrin photosensitizers have long been encapsulated into liposomes for drug delivery, little is known about the membrane properties of liposomes with large amphiphilic porphyrin compositions. In this paper, a porphyrin-lipid conjugate was incorporated into liposomes formed of saturated or unsaturated lipids to study the membrane composition-dependent formation of highly ordered porphyrin J-aggregates and disordered aggregates. Porphyrin-lipid readily phase-separates in saturated membranes, forming J-aggregates that are destabilized during the ripple phase below the main thermal transition. Porphyrin-lipid J-aggregates are photostable with a photothermal efficiency of 54 ± 6%, comparable to gold. Even at high porphyrin-lipid compositions, porphyrin J-aggregates coexist with a minority population of disordered aggregates, which are photodynamically active despite being fluorescently quenched. For photothermal applications, liposome formulations that encourage porphyrin-lipid phase separation should be explored for maximum J-aggregation.

Limited tumor nanoparticle accumulation remains one of the main challenges in cancer nanomedicine. Here, we demonstrate that subtherapeutic photodynamic priming (PDP) enhances the accumulation of nanoparticles in subcutaneous murine prostate tumors ∼3−5-times without inducing cell death, vascular destruction, or tumor growth delay. We also found that PDP resulted in an ∼2-times decrease in tumor collagen content as well as a significant reduction of extracellular matrix density in the subendothelial zone. Enhanced nanoparticle accumulation combined with the reduced extravascular barriers improved therapeutic efficacy in the absence of off-target toxicity, wherein 5 mg/kg of Doxil with PDP was equally effective in delaying tumor growth as 15 mg/kg of Doxil. Overall, this study demonstrates the potential of PDP to enhance tumor nanomedicine accumulation and alleviate tumor desmoplasia without causing cell death or vascular destruction, highlighting the utility of PDP as a minimally invasive priming strategy that can improve therapeutic outcomes in desmoplastic tumors.

Size-controlled discoidal and cholesteryl oleated-loaded spherical, intrinsically multimodal porphyrin-lipid nanoparticles targeted glioblastoma via apoE3 and LDLR.

Scavenger receptor class B type I (SR-BI) plays an important role in trafficking cholesteryl esters between the core of high density lipoprotein and the liver. Interestingly, this integral membrane protein receptor is also implicated in the metabolism of cholesterol by cancer cells, whereby overexpression of SR-BI has been observed in a number of tumors and cancer cell lines, including breast and prostate cancers. Consequently, SR-BI has recently gained attention as a cancer biomarker and exciting target for the direct cytosolic delivery of therapeutic agents. This brief review highlights these key developments in SR-BI-targeted cancer therapies and imaging probes. Special attention is given to the exploration of high density lipoprotein nanomimetic platforms that take advantage of upregulated SR-BI expression to facilitate targeted drug-delivery and cancer diagnostics, and promising future directions in the development of these agents.

Ultrasound (US) is one of the most commonly used clinical imaging techniques. However, the use of US and US-based intravenous agents extends far beyond imaging. In particular, there has been a surge in the fabrication of multimodality US contrast agents and theranostic US agents for cancer imaging and therapy. The unique interaction of US waves with microscale and nanoscale agents has attracted much attention in the development of contrast agents and drug-delivery vehicles. The dimensions of the agent not only dictate how it behaves in vivo, but also how it interacts with US for imaging and drug delivery. Furthermore, these agents are also unique due to their ability to convert from the nanoscale to the microscale and vice versa, having imaging and therapeutic utility in both dimensions. Here, we review multimodality and multifunctional US-based agents, according to their size, and also highlight recent developments in size conversion US agents. WIREs Nanomed Nanobiotechnol 2016, 8:796-813. doi: 10.1002/wnan.1398 For further resources related to this article, please visit the WIREs website.