Publications by authors named "Kevin Carter"

55 Publications

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

ACS Appl Bio Mater 2019 Jan 19;2(1):544-554. Epub 2018 Dec 19.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, United States.

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). Singlet oxygen generation, which was higher for ss-Pheo, enabled photodynamic therapy (PDT). ss-Pheo provided contrast for photoacoustic and fluorescence imaging, and following seamless labeling with Cu, was used for positron emission tomography. ss-Pheo had a long blood circulation and favorable accumulation in an orthotopic murine mammary tumor model. Trimodal tumor imaging was demonstrated, and PDT resulted in delayed tumor growth.
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http://dx.doi.org/10.1021/acsabm.8b00703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919654PMC
January 2019

Membrane Disruption by Very Long Chain Fatty Acids during Necroptosis.

ACS Chem Biol 2019 10 20;14(10):2286-2294. Epub 2019 Sep 20.

Department of Chemistry , University at Buffalo, The State University of New York , Buffalo , New York 14260 , United States.

Necroptosis is a form of regulated cell death which results in loss of plasma membrane integrity, release of intracellular contents, and an associated inflammatory response. We previously found that saturated very long chain fatty acids (VLCFAs), which contain ≥20 carbons, accumulate during necroptosis. Here, we show that genetic knockdown of Fatty Acid (FA) Elongase 7 (ELOVL7) reduces accumulation of specific very long chain FAs during necroptosis, resulting in reduced necroptotic cell death and membrane permeabilization. Conversely, increasing the expression of ELOVL7 increases very long chain fatty acids and membrane permeabilization. , introduction of the VLCFA C24 FA disrupts bilayer integrity in liposomes to a greater extent than a conventional C16 FA. To investigate the microscopic origin of these observations, atomistic Molecular Dynamics (MD) simulations were performed. MD simulations suggest that fatty acids cause clear differences in bilayers based on length and that it is the interdigitation of C24 FA between the individual leaflets that results in disorder in the region and, consequently, membrane disruption. We synthesized clickable VLCFA analogs and observed that many proteins were acylated by VLCFAs during necroptosis. Taken together, these results confirm the active role of VLCFAs during necroptosis and point to multiple potential mechanisms of membrane disruption including direct permeabilization via bilayer disruption and permeabilization by targeting of proteins to cellular membranes by fatty acylation.
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http://dx.doi.org/10.1021/acschembio.9b00616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800604PMC
October 2019

Surfactant-Stripped Micelles for NIR-II Photoacoustic Imaging through 12 cm of Breast Tissue and Whole Human Breasts.

Adv Mater 2019 Oct 15;31(40):e1902279. Epub 2019 Aug 15.

Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.

Surfactant-stripped micelles are formed from a commercially available cyanine fluoroalkylphosphate (CyFaP) salt dye and used for high contrast photoacoustic imaging (PAI) in the second near-infrared window (NIR-II). The co-loading of Coenzyme Q10 into surfactant-stripped CyFaP (ss-CyFaP) micelles improves yield, storage stability, and results in a peak absorption wavelength in the NIR-II window close to the 1064 nm output of Nd-YAG lasers used for PAI. Aqueous ss-CyFaP dispersions exhibit intense NIR-II optical absorption, calculated to be greater than 500 at 1064 nm. ss-CyFaP is detected through 12 cm of chicken breast tissue with PAI. In preclinical animal models, ss-CyFaP is visualized in draining lymph nodes of rats through 3.1 cm of overlaid chicken breast tissue. Following intravenous administration, ss-CyFaP accumulates in neoplastic tissues of mice and rats bearing orthotopic mammary tumors without observation of acute toxic side effects. ss-CyFaP is imaged through whole compressed human breasts in three female volunteers at depths of 2.6-5.1 cm. Taken together, these data show that ss-CyFaP is an accessible contrast agent for deep tissue PAI in the NIR-II window.
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http://dx.doi.org/10.1002/adma.201902279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773519PMC
October 2019

Liposomal formulations of photosensitizers.

Biomaterials 2019 10 10;218:119341. Epub 2019 Jul 10.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA. Electronic address:

Photodynamic therapy (PDT) is a clinical ablation modality to treat cancers and other diseases. PDT involves administration of a photosensitizer, followed by irradiation of target tissue with light. As many photosensitizers are small and hydrophobic, solubilization approaches and nanoscale delivery vehicles have been extensively explored. Liposomes and lipid-based formulations have been used for the past 30 years, and in some cases have been developed into well-defined commercial PDT products. This review provides an overview of common liposomal formulation strategies for photosensitizers for PDT and also photothermal therapy. Furthermore, research efforts have examined the impact of co-loading therapeutic cargo along with photosensitizers within liposomes. Additional recent approaches including imaging, overcoming hypoxia, upconversion and activatable liposomal formulations are discussed.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663636PMC
October 2019

Loading and Releasing Ciprofloxacin in Photoactivatable Liposomes.

Biochem Eng J 2019 Jan 11;141:43-48. Epub 2018 Oct 11.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York, 14260, USA.

We demonstrate that ciprofloxacin can be actively loaded into liposomes that contain small amounts of porphyrin-phospholipid (PoP). PoP renders the liposomes photoactivatable, so that the antibiotic is released from the carrier under red light irradiation (665 nm). The use of 2 molar % PoP in the liposomes accommodated active loading of ciprofloxacin. Further inclusion of 2 molar % of an unsaturated phospholipid accelerated light-triggered drug release, with more than 90 % antibiotic release from the liposomes occurring in less than 30 seconds. With or without laser treatment, ciprofloxacin PoP liposomes inhibited the growth of in liquid media, apparently due to uptake of the liposomes by the bacteria. However, when liposomes were first separated from smaller molecules with centrifugal filtration, only the filtrate from laser-treated liposomes was bactericidal, confirming effective release of active antibiotic. These results establish the feasibility of remote loading antibiotics into photoactivatable liposomes, which could lead to opportunities for enhanced localized antibiotic therapy.
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http://dx.doi.org/10.1016/j.bej.2018.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519738PMC
January 2019

Binding of an amphiphilic phthalocyanine to pre-formed liposomes confers light-triggered cargo release.

J Mater Chem B 2018 Nov 22;6(44):7298-7305. Epub 2018 Aug 22.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA.

Liposomes are able to load a range of cargos and have been used for drug delivery applications, including for stimuli-triggered drug release. Here, we describe an approach for imparting near infrared (NIR) light-triggered release to pre-formed liposomes, using a newly-synthesized cationic, amphiphilic phthalocyanine. When simply mixed in aqueous solution with cargo-loaded liposomes, the cationic amphiphilic phthalocyanine, but not a cationic hydrophilic azaphthalocyanine, spontaneously incorporates into the liposome bilayer. This enables subsequent release of loaded cargo (doxorubcin or basic orange) upon irradiation with NIR light. The rate of release could be altered by varying the amount of photosensitizer added to the liposomes. In the absence of NIR light exposure, stable cargo loading of the liposomes was maintained. Introduction.
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http://dx.doi.org/10.1039/C8TB01602JDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456075PMC
November 2018

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

J Control Release 2019 03 23;297:39-47. Epub 2019 Jan 23.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. Electronic address:

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. These were administered intravenously to mice bearing low-passage, patient-derived pancreatic cancer xenografts (PDX). Dox PK was described with a two-compartment model and tumor drug disposition kinetics were modeled with first-order influx and efflux rates. Tumor irradiation with 665 nm laser light (200 J/cm) 1 h after liposome administration increased tumor vascular permeabilization and drug accumulation, which was accounted for in the PK/PD model with increased tumor influx and efflux rates by approximately 12- and 4- fold, respectively. This modeling approach provided an overall 7-fold increase in Dox area under the curve in the tumor, matching experimental data (7.4-fold). A signal transduction model based on nonlinear direct cell killing accounted for observed tumor growth patterns. This PK/PD model adequately describes the CPT anti-PDX tumor response based on enhanced drug delivery at the short drug-light interval used.
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http://dx.doi.org/10.1016/j.jconrel.2019.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399029PMC
March 2019

A multifunctional biodegradable brush polymer-drug conjugate for paclitaxel/gemcitabine co-delivery and tumor imaging.

Nanoscale Adv 2019 27;1(7):2761-2771. Epub 2019 May 27.

Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.

A multifunctional biodegradable brush polymer-drug conjugate (BPDC) is developed for the co-delivery of hydrophobic paclitaxel (PTX) and hydrophilic gemcitabine (GEM) chemotherapeutics, as well as a tumor imaging agent. A novel ternary copolymer of conventional, acetylenyl-functionalized and allyl-functionalized lactides is prepared to serve as the backbone precursor of BPDC. Acetylenyl groups of the copolymer are then reacted with poly(ethylene glycol) (PEG) side chains and cyanine5.5, a fluorescent probe, azide-alkyne click reactions. Subsequently, the allyl groups of the yielded PEG-grafted brush polymer are used to covalently link PTX and GEM onto the backbone thiol-ene click reactions. The resulting BPDC exhibits an average hydrodynamic diameter of 111 nm. Sustained and simultaneous release of PTX and GEM from the BPDC is observed in phosphate buffered saline, with the release of PTX showing sensitivity in mild acidic conditions. studies using MIA PaCa-2 human pancreatic cancer cells illustrate the cellular uptake and cytotoxicity of the BPDC. , the BPDC possesses long blood circulation, tumor accumulation, and enables optical tumor imaging. Further development and testing is warranted for multifunctional conjugated brush polymer systems that integrate combination chemotherapies and imaging.
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http://dx.doi.org/10.1039/c9na00282kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451085PMC
May 2019

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

Mol Cancer Ther 2019 03 26;18(3):592-601. Epub 2018 Dec 26.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York.

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. interaction with erythrocytes, platelets, and plasma coagulation cascade were generally unremarkable, whereas complement activation was found to be similar to that of commercial Doxil. Blood partitioning suggested that both the Dox and PoP components of LC-Dox-PoP were stably entrapped or incorporated in liposomes. This was further confirmed with pharmacokinetic studies in Fischer rats, which showed the PoP and Dox components of the liposomes both had nearly identical, long circulation half-lives (25-26 hours). In a large orthotopic mammary tumor model in Fischer rats, following intravenous dosing (2 mg/kg Dox), the depth of enhanced Dox delivery in response to 665 nm laser irradiation was over 1 cm. LC-Dox-PoP with laser treatment cured or potently suppressed tumor growth, with greater efficacy observed in tumors 0.8 to 1.2 cm, compared with larger ones. The skin at the treatment site healed within approximately 30 days. Taken together, these data provide insight into nanocharacterization and photo-ablation parameters for a chemophototherapy agent.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0549DOI Listing
March 2019

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

Nat Nanotechnol 2018 12 8;13(12):1174-1181. Epub 2018 Oct 8.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA.

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. SNAP immunization of mice and rabbits is well tolerated with minimal local reactogenicity, and results in orders-of-magnitude higher functional antibody generation compared with other 'mix-and-inject' adjuvants. Serum-stable antigen binding during transit to draining lymph nodes leads to enhanced antigen uptake by phagocytic antigen-presenting cells, with subsequent generation of long-lived, antigen-specific plasma cells. Seamless multiplexing with four additional his-tagged Plasmodium falciparum polypeptides induces strong and balanced antibody production, illustrating the simplicity of developing multistage particulate vaccines with SNAP immunization.
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http://dx.doi.org/10.1038/s41565-018-0271-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286227PMC
December 2018

Zwitterionic Cross-Linked Biodegradable Nanocapsules for Cancer Imaging.

Langmuir 2019 02 21;35(5):1440-1449. Epub 2018 Aug 21.

Zwitterionic cross-linked biodegradable nanocapsules (NCs) were synthesized for cancer imaging. A polylactide (PLA)-based diblock copolymer with two blocks carrying acetylenyl and allyl groups respectively was synthesized by ring-opening polymerization (ROP). Azide-alkyne "click" reaction was conducted to conjugate sulfobetaine (SB) zwitterions and fluorescent dye Cy5.5 onto the acetylenyl-functionalized first block of the diblock copolymer. The resulting copolymer with a hydrophilic SB/Cy5.5-functionalized PLA block and a hydrophobic allyl-functionalized PLA block could stabilize miniemulsions because of its amphiphilic diblock structure. UV-induced thiol-ene "click" reaction between a dithiol cross-linker and the hydrophobic allyl-functionalized block of the copolymer at the peripheral region of nanoscopic oil nanodroplets in the miniemulsion generated cross-linked polymer NCs with zwitterionic outer shells. These NCs showed an average hydrodynamic diameter ( D) of 136 nm. They exhibited biodegradability, biocompatibility and high colloidal stability. In vitro study indicated that these NCs could be taken up by MIA PaCa-2 cancer cells. In vivo imaging study showed that, comparing to a small molecule dye, NCs had a longer circulation time, facilitating their accumulation at tumors for cancer imaging. Overall, this work demonstrates the applicability of zwitterionic biodegradable polymer-based materials in cancer diagnosis.
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http://dx.doi.org/10.1021/acs.langmuir.8b01633DOI Listing
February 2019

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

Mol Pharm 2018 09 2;15(9):3682-3689. Epub 2018 Apr 2.

Department of Biomedical Engineering , University at Buffalo, State University of New York , Buffalo , New York 14260 , United States.

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). This dosing approach aims to achieve physiologically relevant Dox and PoP concentrations as well as CPT vascular responses in mice bearing subcutaneous human pancreatic MIA PaCa-2 xenografts. Phototreatment with 2 mg/kg LC-Dox-PoP induced vascular permeabilization, leading to a 12.5-fold increase in Dox tumor influx estimated by a pharmacokinetic model, based on experimental data. Shorter drug-light intervals (0.5-3 h) led to greater tumoral drug deposition and improved treatment outcomes, compared to longer drug-light intervals. At 2 mg/kg Dox, CPT with LC-Dox-PoP liposomes induced tumor regression and growth inhibition, whereas chemotherapy using several other formulations of Dox did not. LC-Dox-PoP liposomes were well tolerated at the 2 mg/kg dose.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00052DOI Listing
September 2018

Multicolor Liposome Mixtures for Selective and Selectable Cargo Release.

Nano Lett 2018 02 2;18(2):1331-1336. Epub 2018 Feb 2.

Department of Biomedical Engineering, University at Buffalo, State University of New York , Buffalo, New York 14260, United States.

Many approaches exist for stimuli-triggered cargo release from nanocarriers, but few can provide for on-demand release of multiple payloads, selectively. Here, we report the synthesis of purpurin-phospholipid (Pur-P), a lipid chromophore that has near-infrared absorbance red-shifted by 30 nm compared to a structurally similar pyropheophorbide-phospholipid (Pyr-P). Liposomes containing small amounts of either Pur-P or Pyr-P exhibited similar physical properties and fluorescence self-quenching. Loaded with distinct cargos, Pur-P and Pyr-P liposomes were mixed into a single colloidal suspension and selectively released cargo depending on irradiation wavelength. Spatiotemporal control of distinct cargo release was achieved by controlling multicolor laser placement. Using basic orange and doxorubicin anthraquinones, multidimensional cytotoxicity gradients were established to gauge efficacy against cancer cells using light-released drug. Wavelength selectivity of cargo release was maintained following intramuscular administration to mice.
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http://dx.doi.org/10.1021/acs.nanolett.7b05025DOI Listing
February 2018

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

ACS Nano 2017 12 5;11(12):12482-12491. Epub 2017 Dec 5.

Department of Biomedical Engineering, University at Buffalo, State University of New York , Buffalo, New York 14260, United States.

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. Dox-PoP liposomes labeled with intrabilayer copper behaved nearly identically to unlabeled ones in vitro and in vivo with respect to physical parameters, pharmacokinetics, and CPT efficacy. Positron emission tomography and near-infrared fluorescence imaging visualized orthotopic mammary tumors in mice with passive liposome accumulation following administration. A single CPT treatment with 665 nm light (200 J/cm) strongly inhibited primary tumor growth. Liposomes accumulated in lung metastases, based on NIR imaging. These results establish the feasibility of CPT interventions guided by intrinsic multimodal imaging of Dox-loaded stealth PoP liposomes.
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http://dx.doi.org/10.1021/acsnano.7b06578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004286PMC
December 2017

A dual-channel endoscope for quantitative imaging, monitoring, and triggering of doxorubicin release from liposomes in living mice.

Sci Rep 2017 Nov 14;7(1):15578. Epub 2017 Nov 14.

Department of Biomedical, Industrial & Human Factors Engineering, Wright State University, Dayton, OH, USA.

Doxorubicin (Dox) is approved for use in liposomal form for the treatment of ovarian cancer. We previously developed a long-circulating Dox formulation in liposomes containing small amounts of porphyrin-phospholipid, which enables on-demand drug release with near-infrared irradiation. In this study, we present and evaluate a dual-modal, dual-channel light endoscope that allows quantitative reflectance and fluorescence imaging for monitoring of local Dox concentrations in target areas. The endoscope consists of two flexible imaging fibers; one to transmit diagnostic and therapeutic light to the target, and the other to detect fluorescent and reflected light. Thus, the endoscope serves for imaging, for light delivery to trigger drug release, and for monitoring drug concentration kinetics during drug release. We characterized the performance of this endoscope in tissue phantoms and in an in vivo model of ovarian cancer. This study demonstrates the feasibility of non-invasive, quantitative mapping of Dox distribution in vivo via endoscopic imaging.
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http://dx.doi.org/10.1038/s41598-017-15790-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686102PMC
November 2017

Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes.

Mol Cancer Ther 2017 11 20;16(11):2452-2461. Epub 2017 Jul 20.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York.

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. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. , cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669815PMC
November 2017

Multifunctional Liposomes for Image-Guided Intratumoral Chemo-Phototherapy.

Adv Healthc Mater 2017 Aug 15;6(16). Epub 2017 May 15.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA.

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. Light-triggered release occurs with PoP-induced photooxidation of unsaturated lipids and all cargos release concurrently. In subcutaneous murine colorectal tumors, drainage of released cargo is delayed when laser treatment occurs 24 h after IT injection, at doses orders of magnitude lower than systemic ones. Delayed light-triggering results in substantial tumor shrinkage relative to controls a week following treatment, although regrowth occurs subsequently. MR imaging reveals that over this time frame, pools of liposomes within the tumor migrate to adjacent regions, possibly leading to altered spatial distribution during triggered drug release. Although further characterization of cargo loading and release is required, this proof-of-principle study suggests that multimodal theranostic IT delivery approaches hold potential to both guide injections and interpret outcomes, in particular when combined with chemo-phototherapy.
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http://dx.doi.org/10.1002/adhm.201700253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568974PMC
August 2017

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

Nanoscale 2017 Mar;9(10):3391-3398

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA. and Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.

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. Without further modification, pre-formed nanonaps were used for positron emission tomography and passively accumulated in subcutaneous murine tumors. Because the nanonaps used absorb light beyond the visible range, a topical upconversion skin cream was developed for anti-tumor photothermal therapy with laser placement that can be guided by the naked eye.
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http://dx.doi.org/10.1039/c6nr09321cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435468PMC
March 2017

Chemophototherapy: An Emerging Treatment Option for Solid Tumors.

Adv Sci (Weinh) 2017 Jan 24;4(1):1600106. Epub 2016 May 24.

Department of Biomedical Engineering University at Buffalo State University of New York Buffalo NY 14260.

Near infrared (NIR) light penetrates human tissues with limited depth, thereby providing a method to safely deliver non-ionizing radiation to well-defined target tissue volumes. Light-based therapies including photodynamic therapy (PDT) and laser-induced thermal therapy have been validated clinically for curative and palliative treatment of solid tumors. However, these monotherapies can suffer from incomplete tumor killing and have not displaced existing ablative modalities. The combination of phototherapy and chemotherapy (chemophototherapy, CPT), when carefully planned, has been shown to be an effective tumor treatment option preclinically and clinically. Chemotherapy can enhance the efficacy of PDT by targeting surviving cancer cells or by inhibiting regrowth of damaged tumor blood vessels. Alternatively, PDT-mediated vascular permeabilization has been shown to enhance the deposition of nanoparticulate drugs into tumors for enhanced accumulation and efficacy. Integrated nanoparticles have been reported that combine photosensitizers and drugs into a single agent. More recently, light-activated nanoparticles have been developed that release their payload in response to light irradiation to achieve improved drug bioavailability with superior efficacy. CPT can potently eradicate tumors with precise spatial control, and further clinical testing is warranted.
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http://dx.doi.org/10.1002/advs.201600106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5238751PMC
January 2017

Sphingomyelin Liposomes Containing Porphyrin-phospholipid for Irinotecan Chemophototherapy.

Theranostics 2016 1;6(13):2329-2336. Epub 2016 Oct 1.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260.

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. The loading, stability, and NIR light-triggered release of irinotecan in PoP liposomes was altered by the types of lipids used and the presence of PEGylation. Sphingomyelin, which has been explored previously for liposomal irinotecan, was found to produce liposomes with relatively improved serum stability and rapid NIR light-triggered drug release. PoP liposomes composed from sphingomyelin, cholesterol and 2 molar percent PoP rapidly released irinotecan in vivo in response to NIR irradiation as monitored by intravital microscopy and also induced effective tumor eradication in mice bearing MIA Paca-2 subcutaneous tumor xenografts.
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http://dx.doi.org/10.7150/thno.15701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118598PMC
October 2017

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

Small 2016 Jun 28;12(22):3039-47. Epub 2016 Apr 28.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA.

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., 5 molar percent) of an unsaturated phospholipid, such as dioleoylphosphatidylcholine (DOPC), accelerates near infrared (NIR) light-triggered doxorubicin release in porphyrin-phospholipid (PoP) liposomes by an order of magnitude. In physiological conditions in vitro, the loaded drug can be released in a minute under NIR irradiation, while liposomes maintain serum stability otherwise. This enables rapid laser-induced drug release using remarkably low amounts of PoP (i.e., 0.3 molar percent). Light-triggered drug release occurs concomitantly with DOPC and cholesterol oxidation, as detected by mass spectrometry. In the presence of an oxygen scavenger or an antioxidant, light-triggered drug release is inhibited, suggesting that the mechanism is related to singlet oxygen mediated oxidization of unsaturated lipids. Despite the irreversible modification of lipid composition, DOPC-containing PoP liposome permeabilization is transient. Human pancreatic xenograft growth in mice is significantly delayed with a single chemophototherapy treatment following intravenous administration of 6 mg kg(-1) doxorubicin, loaded in liposomes containing small amounts of DOPC and PoP.
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http://dx.doi.org/10.1002/smll.201503966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899298PMC
June 2016