Surfactant-Stripped Pheophytin Micelles for Multimodal Tumor Imaging and Photodynamic Therapy.

Porphyrin-based nanomaterials can inherently integrate multiple contrast imaging functionalities with phototherapeutic capabilities. We dispersed pheophytin (Pheo) into Pluronic F127 and carried out low-temperature surfactant-stripping to remove the bulk surfactant. Surfactant-stripped Pheo (ss-Pheo) micelles exhibited a similar size, but higher near-infrared fluorescence, compared to two other nanomaterials also with high porphyrin density (surfactant-stripped chlorophyll micelles and porphysomes).

Highly-Soluble Cyanine J-aggregates Entrapped by Liposomes for Optical Imaging around 930 nm.

Near infrared (NIR) dyes are useful for optical imaging. Liposomes have been used extensively for delivery of diverse cargos, including hydrophilic cargos which are passively loaded in the aqueous core. However, most currently available NIR dyes are only slightly soluble in water, making passive entrapment in liposomes challenging for achieving high optical contrast.

Pharmacokinetics and pharmacodynamics of liposomal chemophototherapy with short drug-light intervals.

Chemophototherapy (CPT) merges photodynamic therapy with chemotherapy and can substantially enhance drug delivery. Using a singular liposomal formulation for CPT, we describe a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to investigate observed antitumor effects. Long-circulating, sterically-stabilized liposomes loaded with doxorubicin (Dox) stably incorporate small amounts of a porphyrin-phospholipid (PoP) photosensitizer in the bilayer.

Blood Interactions, Pharmacokinetics, and Depth-Dependent Ablation of Rat Mammary Tumors with Photoactivatable, Liposomal Doxorubicin.

Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with antitumor synergy between chemo- and photocomponents. Long-circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays.

A malaria vaccine adjuvant based on recombinant antigen binding to liposomes.

Pfs25 is a malaria transmission-blocking vaccine antigen candidate, but its apparently limited immunogenicity in humans has hindered clinical development. Here, we show that recombinant, polyhistidine-tagged (his-tagged) Pfs25 can be mixed at the time of immunization with pre-formed liposomes containing cobalt porphyrin-phospholipid, resulting in spontaneous nanoliposome antigen particleization (SNAP). Antigens are stably presented in uniformly orientated display via his-tag insertion in the cobalt porphyrin-phospholipid bilayer, without covalent modification or disruption of antigen conformation.

Ingestible roasted barley for contrast-enhanced photoacoustic imaging in animal and human subjects.

Photoacoustic computed tomography (PACT) is an emerging imaging modality. While many contrast agents have been developed for PACT, these typically cannot immediately be used in humans due to the lengthy regulatory process. We screened two hundred types of ingestible foodstuff samples for photoacoustic contrast with 1064 nm pulse laser excitation, and identified roasted barley as a promising candidate.

Short Drug-Light Intervals Improve Liposomal Chemophototherapy in Mice Bearing MIA PaCa-2 Xenografts.

Chemophototherapy (CPT) is an emerging tumor treatment that combines phototherapy and chemotherapy. Long-circulating (LC) liposomes can stably incorporate 2 mol % porphyrin-phospholipid (PoP) in the bilayer and load doxorubicin (Dox) to generate LC-Dox-PoP liposomes, for single-agent CPT. Following intravenous administration to mice, LC-Dox-PoP liposomes (2 mg/kg Dox) circulated with similar blood concentration ranges produced by a typical human clinical dose of DOXIL (50 mg/m Dox).

Intrabilayer Cu Labeling of Photoactivatable, Doxorubicin-Loaded Stealth Liposomes.

Doxorubicin (Dox)-loaded stealth liposomes (similar to those in clinical use) can incorporate small amounts of porphyrin-phospholipid (PoP) to enable chemophototherapy (CPT). PoP is also an intrinsic and intrabilayer Cu chelator, although how radiolabeling impacts drug delivery has not yet been assessed. Here, we show that Cu can radiolabel the stable bilayer of preformed Dox-loaded PoP liposomes with inclusion of 1% ethanol without inducing drug leakage.

Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes.

Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation.

Multifunctional Liposomes for Image-Guided Intratumoral Chemo-Phototherapy.

Intratumoral (IT) drug injections reduce systemic toxicity, but delivered volumes and distribution can be inconsistent. To improve IT delivery paradigms, porphyrin-phospholipid (PoP) liposomes are passively loaded with three hydrophilic cargos: sulforhodamine B, a fluorophore; gadolinium-gadopentetic acid, a magnetic resonance (MR) agent; and oxaliplatin, a colorectal cancer chemotherapeutic. Liposome composition is optimized so that cargo is retained in serum and storage, but is released in less than 1 min with exposure to near infrared light.

Surfactant-stripped naphthalocyanines for multimodal tumor theranostics with upconversion guidance cream.

Surfactant-stripped, nanoformulated naphthalocyanines (nanonaps) can be formed with Pluronic F127 and low temperature membrane processing, resulting in dispersed frozen micelles with extreme contrast in the near infrared region. Here, we demonstrate that nanonaps can be used for multifunctional cancer theranostics. This includes lymphatic mapping and whole tumor photoacoustic imaging following intradermal or intravenous injection in rodents.

Implantable Tin Porphyrin-PEG Hydrogels with pH-Responsive Fluorescence.

Tetracarboxy porphyrins can be polymerized with polyethylene glycol (PEG) diamines to generate hydrogels with intense, near-infrared, and transdermal fluorescence following subcutaneous implantation. Here, we show that the high density porphyrins of the preformed polymer can be chelated with tin via simple incubation. Tin porphyrin hydrogels exhibited increasing emission intensities, ratios, and lifetimes from pH 1 to 10.

Deep tissue photoacoustic computed tomography with a fast and compact laser system.

Photoacoustic computed tomography (PACT) holds great promise for biomedical imaging, but wide-spread implementation is impeded by the bulkiness of flash-lamp-pumped laser systems, which typically weigh between 50 - 200 kg, require continuous water cooling, and operate at a low repetition rate. Here, we demonstrate that compact lasers based on emerging diode technologies are well-suited for preclinical and clinical PACT. The diode-pumped laser used in this study had a miniature footprint (13 × 14 × 7 cm), weighed only 1.

Sphingomyelin Liposomes Containing Porphyrin-phospholipid for Irinotecan Chemophototherapy.

Porphyrin-phospholipid (PoP) liposomes can entrap anti-cancer agents and release them in response to near infrared (NIR) light. Doxorubicin, when remotely loaded via an ammonium sulfate gradient at a high drug-to-lipid ratio, formed elongated crystals that altered liposome morphology and could not be loaded into liposomes with higher PoP content. On the other hand, irinotecan could also be remotely loaded but did not form large crystals and did not induce liposome elongation.

Surfactant-Stripped Frozen Pheophytin Micelles for Multimodal Gut Imaging.

Edible, surfactant-stripped, frozen micelles are formed from pheophytin (demetallated chlorophyll), a pigment that is naturally consumed in human diets. Pheophytin nanoparticles pass completely and safely through the gastrointestinal tract and enable trimodal gut contrast imaging via photoacoustic, fluorescence, and positron emission tomography techniques.

Axial PEGylation of Tin Octabutoxy Naphthalocyanine Extends Blood Circulation for Photoacoustic Vascular Imaging.

Attachment of polyethylene glycol (PEG) can prolong blood circulation of biological molecules, a useful trait for a vascular imaging agent. Here, we present a route for modifying octabutoxy naphthalocyanine (ONc) with PEG, via axial conjugation following ONc chelation with Sn(IV) chloride (Sn-ONc). Tin chelation caused ONc absorbance to shift from 860 to 930 nm.

Therapeutic surfactant-stripped frozen micelles.

Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like 'top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and 'bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient.

Rapid Light-Triggered Drug Release in Liposomes Containing Small Amounts of Unsaturated and Porphyrin-Phospholipids.

Prompt membrane permeabilization is a requisite for liposomes designed for local stimuli-induced intravascular release of therapeutic payloads. Incorporation of a small amount (i.e.

A Phosphorus Phthalocyanine Formulation with Intense Absorbance at 1000 nm for Deep Optical Imaging.

Although photoacoustic computed tomography (PACT) operates with high spatial resolution in biological tissues deeper than other optical modalities, light scattering is a limiting factor. The use of longer near infrared wavelengths reduces scattering. Recently, the rational design of a stable phosphorus phthalocyanine (P-Pc) with a long wavelength absorption band beyond 1000 nm has been reported.

Slit-enabled linear-array photoacoustic tomography with near isotropic spatial resolution in three dimensions.

Due to its unique capability of visualizing optical absorption in deep tissues, photoacoustic tomography is increasingly used in biomedical imaging. Among various types of transducer arrays, the linear array is perhaps the most widely used in photoacoustic tomography because it is commercially available and readily allows ultrasound imaging. However, the three-dimensional imaging capability of a linear array is limited due to its poor elevational resolution.

Metal Chelation Modulates Phototherapeutic Properties of Mitoxantrone-Loaded Porphyrin-Phospholipid Liposomes.

Liposomes incorporating porphyrin-phospholipid (PoP) can be formulated to release entrapped contents in response to near-infrared (NIR) laser irradiation. Here, we examine effects of chelating copper or zinc into the PoP. Cu(II) and Zn(II) PoP liposomes, containing 10 molar % HPPH-lipid, exhibited unique photophysical properties and released entrapped cargo in response to NIR light.

Porphyrin-phospholipid liposomes with tunable leakiness.

Drug bioavailability is a key consideration for drug delivery systems. When loaded with doxorubicin, liposomes containing 5 molar % porphyrin-phospholipid (HPPH liposomes) exhibited in vitro and in vivo serum stability that could be fine-tuned by varying the drug-to-lipid ratio. A higher drug loading ratio destabilized the liposomes, in contrast to standard liposomes which displayed an opposite and less pronounced trend.

A porphyrin-PEG polymer with rapid renal clearance.

Tetracarboxylic porphyrins and polyethylene glycol (PEG) diamines were crosslinked in conditions that gave rise to a water-soluble porphyrin polyamide. Using PEG linkers 2 kDa or larger prevented fluorescence self-quenching. This networked porphyrin mesh was retained during dialysis with membranes with a 100 kDa pore size, yet passed through the membrane when centrifugal filtration was applied.

Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release.

Stealth liposomes can be used to extend the blood circulation time of encapsulated therapeutics. Inclusion of 2 molar % porphyrin-phospholipid (PoP) imparted optimal near infrared (NIR) light-triggered release of doxorubicin (Dox) from conventional sterically stabilized stealth liposomes. The type and amount of PoP affected drug loading, serum stability and drug release induced by NIR light.