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Dive into the research topics where P. Peter Ghoroghchian is active.

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Featured researches published by P. Peter Ghoroghchian.


Methods | 2008

Polymersomes: A new multi-functional tool for cancer diagnosis and therapy

Dalia H. Levine; P. Peter Ghoroghchian; Jaclyn Freudenberg; Geng Zhang; Michael J. Therien; Mark I. Greene; Daniel A. Hammer

Nanoparticles are being developed as delivery vehicles for therapeutic pharmaceuticals and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties that make them ideal for these applications. Synthetic control over block copolymer chemistry enables tunable design of polymersome material properties. The polymersome architecture, with its large hydrophilic reservoir and its thick hydrophobic lamellar membrane, provides significant storage capacity for both water soluble and insoluble substances (such as drugs and imaging probes). Further, the brush-like architecture of the polymersome outer shell can potentially increase biocompatibility and blood circulation times. A further recent advance is the development of multi-functional polymersomes that carry pharmaceuticals and imaging agents simultaneously. The ability to conjugate biologically active ligands to the brush surface provides a further means for targeted therapy and imaging. Hence, polymersomes hold enormous potential as nanostructured biomaterials for future in vivo drug delivery and diagnostic imaging applications.


Wiley Interdisciplinary Reviews-nanomedicine and Nanobiotechnology | 2009

In vivo fluorescence imaging: a personal perspective

P. Peter Ghoroghchian; Michael J. Therien; Daniel A. Hammer

In vivo fluorescence imaging with near-infrared (NIR) light holds enormous potential for a wide variety of molecular diagnostic and therapeutic applications. Because of its quantitative sensitivity, inherent biological safety, and relative ease of use (i.e., with respect to cost, time, mobility, and its familiarity to a diverse population of investigators), fluorescence-based imaging techniques are being increasingly utilized in small-animal research. Moreover, there is substantial interest in the translation of novel optical techniques into the clinic, where they will prospectively aid in noninvasive and quantitative screening, disease diagnosis, and post-treatment monitoring of patients. Effective deep-tissue fluorescence imaging requires the application of exogenous NIR-emissive contrast agents. Currently, available probes fall into two major categories: organic and inorganic NIR fluorophores (NIRFs). In the studies reviewed herein, we utilized polymersomes (50 nm to 50 microm diameter polymer vesicles) for the incorporation and delivery of large numbers of highly emissive oligo (porphyrin)-based, organic NIRFs.


Soft Matter | 2006

Quantitative membrane loading of polymer vesicles

P. Peter Ghoroghchian; John J. Lin; Aaron K. Brannan; Paul R. Frail; Frank S. Bates; Michael J. Therien; Daniel A. Hammer

We utilize a series of structurally homologous, multi-porphyrin-based, fluorophores (PBFs) in order to explore the capacity of polymer vesicles (polymersomes) to stably incorporate large hydrophobic molecules, non-covalently within their thick lamellar membranes. Through aqueous hydration of dry, uniform thin-films of amphiphilic polymer and PBF species deposited on Teflon, self-assembled polymersomes are readily generated incorporating the hydrophobic fluorophores in prescribed molar ratios within their membranes. The size-dependent spectral properties of the PBFs allow for ready optical verification ( steady-state absorption and emission spectroscopy) of the extent of vesicle membrane loading and enable delineation of intermembranous molecular interactions. The resultant effects of PBF membrane-loading on polymersome thermodynamic and mechanical stability are further assessed by cryogenic transmission electron microscopy (cryo-TEM) and micropipet aspiration, respectively. We demonstrate that polymersomes can be loaded at up to 10 mol/wt% concentrations, with hydrophobic molecules that possess sizes comparable to those of large pharmaceutical conjugates ( ranging 1.4-5.4 nm in length and = 0.7-5.4 kg mol), without significantly compromising the robust thermodynamic and mechanical stabilities of these synthetic vesicle assemblies. Due to membrane incorporation, hydrophobic encapsulants are effectively prevented from self-aggregation, able to be highly concentrated in aqueous solution, and successfully shielded from deleterious environmental interactions. Together, these studies present a generalized paradigm for the generation of complex multi-functional materials that combine both hydrophilic and hydrophobic agents, in mesoscopic dimensions, through cooperative self-assembly.


Journal of the American Chemical Society | 2008

Ultrafast Excited-State Dynamics of Nanoscale Near-Infrared Emissive Polymersomes

Timothy V. Duncan; P. Peter Ghoroghchian; Igor V. Rubtsov; Daniel A. Hammer; Michael J. Therien

Formed through cooperative self-assembly of amphiphilic diblock copolymers and electronically conjugated porphyrinic near-infrared (NIR) fluorophores (NIRFs), NIR-emissive polymersomes (50 nm to 50 microm diameter polymer vesicles) define a family of organic-based, soft-matter structures that are ideally suited for deep-tissue optical imaging and sensitive diagnostic applications. Here, we describe magic angle and polarized pump-probe spectroscopic experiments that: (i) probe polymersome structure and NIRF organization and (ii) connect emitter structural properties and NIRF loading with vesicle emissive output at the nanoscale. Within polymersome membrane environments, long polymer chains constrain ethyne-bridged oligo(porphinato)zinc(II) based supermolecular fluorophore (PZn n ) conformeric populations and disperse these PZn n species within the hydrophobic bilayer. Ultrafast excited-state transient absorption and anisotropy dynamical studies of NIR-emissive polymersomes, in which the PZn n fluorophore loading per nanoscale vesicle is varied between 0.1-10 mol %, enable the exploration of concentration-dependent mechanisms for nonradiative excited-state decay. These experiments correlate fluorophore structure with its gross spatial arrangement within specific nanodomains of these nanoparticles and reveal how compartmentalization of fluorophores within reduced effective dispersion volumes impacts bulk photophysical properties. As these factors play key roles in determining the energy transfer dynamics between dispersed fluorophores, this work underscores that strategies that modulate fluorophore and polymer structure to optimize dispersion volume in bilayered nanoscale vesicular environments will further enhance the emissive properties of these sensitive nanoscale probes.


Nanoscale | 2013

Aqueous self-assembly of poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) copolymers: disparate diblock copolymer compositions give rise to nano- and meso-scale bilayered vesicles.

Wei Qi; P. Peter Ghoroghchian; Guizhi Li; Daniel A. Hammer; Michael J. Therien

Nanoparticles formed from diblock copolymers of FDA approved PEO and PCL have generated considerable interest as in vivo drug delivery vehicles. Herein, we report the synthesis of the most extensive family PEO-b-PCL copolymers that vary over the largest range of number-average molecular weights (Mn: 3.6-57k), PEO weight fractions (fPEO: 0.08-0.33), and PEO chain lengths (0.75-5.8k) reported to date. These polymers were synthesized in order to establish the full range of aqueous phase behaviours of these diblock copolymers and to specifically identify formulations that were able to generate bilayered vesicles (polymersomes). Cryogenic transmission electron microscopy (cryo-TEM) was utilized in order to visualize the morphology of these structures upon aqueous self-assembly of dry polymer films. Nanoscale polymersomes were formed from PEO-b-PCL copolymers over a wide range of PEO weight fractions (fPEO: 0.14-0.27) and PEO molecular weights (0.75-3.8k) after extrusion of aqueous suspensions. Comparative morphology diagrams, which describe the nature of self-assembled structures as a function of diblock copolymer molecular weight and PEO weight fraction, show that in contrast to micron-scale polymersomes, which form only from a limited range of PEO-b-PCL diblock copolymer compositions, a multiplicity of PEO-b-PCL diblock copolymer compositions are able to give rise to nanoscale vesicles. These data underscore that PEO-b-PCL compositions that spontaneously form micron-sized polymersomes, as well as those that have previously been reported to form polymersomes via a cosolvent fabrication system, provide only limited insights into the distribution of PEO-b-PCL diblocks that give rise to nanoscale vesicles. The broad range of polymersome-forming PEO-b-PCL compositions described herein suggest the ability to construct extensive families of nanoscale vesicles of varied bilayer thickness, providing the ability to tune the timescales of vesicle degradation and encapsulant release based on the intended in vivo application.


Trends in Biotechnology | 2014

Microparticle, nanoparticle, and stem cell-based oxygen carriers as advanced blood substitutes

Zhimin Tao; P. Peter Ghoroghchian

Here, we discuss recent advances in the development of artificial red blood cell (RBC) substitutes, illustrating lessons learned from initial attempts using perfluorocarbon (PFC) emulsions and acellular hemoglobin-based oxygen carriers (HBOCs). We also highlight novel oxygen-containing microparticles, nanoparticles, and stem cell-derived RBC products, with emphasis on improvements in biocompatibility and oxygen delivery. In addition, we envision future developments for the rational design of advanced blood substitutes that aim to address unmet clinical needs.


Journal of the American Chemical Society | 2017

Maximizing Synergistic Activity When Combining RNAi and Platinum-Based Anticancer Agents

Haihua Xiao; Ruogu Qi; Ting Li; Samuel G. Awuah; Yao Rong Zheng; Wei Wei; Xiang Kang; Haiqin Song; Yongheng Wang; Yingjie Yu; Molly A. Bird; Xiabin Jing; Michael B. Yaffe; Michael J. Birrer; P. Peter Ghoroghchian

RNAi approaches have been widely combined with platinum-based anticancer agents to elucidate cellular responses and to target gene products that mediate acquired resistance. Recent work has demonstrated that platination of siRNA prior to transfection may negatively influence RNAi efficiency based on the position and sequence of its guanosine nucleosides. Here, we used detailed spectroscopic characterization to demonstrate rapid formation of Pt-guanosine adducts within 30 min after coincubation of oxaliplatin [OxaPt(II)] or cisplatin [CisPt(II)] with either guanosine monophosphate or B-cell lymphoma 2 (BCL-2) siRNA. After 3 h of exposure to these platinum(II) agents, >50% of BCL-2 siRNA transcripts were platinated and unable to effectively suppress mRNA levels. Platinum(IV) analogues [OxaPt(IV) or CisPt(IV)] did not form Pt-siRNA adducts but did display decreased in vitro uptake and reduced potency. To overcome these challenges, we utilized biodegradable methoxyl-poly(ethylene glycol)-block-poly(ε-caprolactone)-block-poly(l-lysine) (mPEG-b-PCL-b-PLL) to generate self-assembled micelles that covalently conjugated OxaPt(IV) and/or electrostatically complexed siRNA. We then compared multiple strategies by which to combine BCL-2 siRNA with either OxaPt(II) or OxaPt(IV). Overall, we determined that the concentrations of siRNA (nM) and platinum(II)-based anticancer agents (μM) that are typically used for in vitro experiments led to rapid Pt-siRNA adduct formation and ineffective RNAi. Coincorporation of BCL-2 siRNA and platinum(IV) analogues in a single micelle enabled maximal suppression of BCL-2 mRNA levels (to <10% of baseline), augmented the intracellular levels of platinum (by ∼4×) and the numbers of resultant Pt-DNA adducts (by >5×), increased the cellular fractions that underwent apoptosis (by ∼4×), and enhanced the in vitro antiproliferative activity of the corresponding platinum(II) agent (by 10-100×, depending on the cancer cell line). When combining RNAi and platinum-based anticancer agents, this generalizable strategy may be adopted to maximize synergy during screening or for therapeutic delivery.


The New England Journal of Medicine | 2012

At a Loss

Joseph F. Merola; P. Peter Ghoroghchian; Martin A. Samuels; Bruce D. Levy; Joseph Loscalzo

A 31-year-old woman was admitted to the hospital after being unable to eat or drink for 1 week. She had had nausea, vomiting, and abdominal discomfort, as well as episodes of crampy epigastric pain with vomiting and intermittent chills and sweats, for 8 months.


European Journal of Cancer | 2016

Statins and survival outcomes in patients with metastatic renal cell carcinoma

Rana R. McKay; Xun Lin; Laurence Albiges; Andre Poisl Fay; Marina D. Kaymakcalan; Suzanne S Mickey; P. Peter Ghoroghchian; Rupal S. Bhatt; Samuel D. Kaffenberger; Ronit Simantov; Toni K. Choueiri; Daniel Y.C. Heng

BACKGROUND A growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era. PATIENTS AND METHODS We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. RESULTS We identified 4736 patients treated with sunitinib (n=1059), sorafenib (n=772), axitinib (n=896), temsirolimus (n=457), temsirolimus+interferon (IFN)-α (n=208), bevacizumab+temsirolimus (n=393), bevacizumab+IFN-α (n=391) or IFN-α (n=560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659-0.972, p=0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584-0.961, p=0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445-0.972, p=0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703-2.275, p=0.410). Adverse events were similar between users and non-users. CONCLUSIONS We demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.


Nature Communications | 2017

Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer

Ruogu Qi; Yongheng Wang; Peter M. Bruno; Haihua Xiao; Yingjie Yu; Ting Li; Sam Lauffer; Wei Wei; Qixian Chen; Xiang Kang; Haiqin Song; Xi Yang; Xing Huang; Alexandre Detappe; Ursula A. Matulonis; David Pepin; Michael T. Hemann; Michael J. Birrer; P. Peter Ghoroghchian

Advanced-stage epithelial ovarian cancers are amongst the most difficult to treat tumors and have proven to be refractory to most cytotoxic, molecularly targeted, or immunotherapeutic approaches. Here, we report that nanoparticle-drug conjugates (NDCs) of monomethyl auristatin E (MMAE) significantly increase loading on a per-vehicle basis as compared to antibody-drug conjugates (ADCs). Their intraperitoneal administration enabled triggered release of the active MMAE toxin to inhibit tumor growth and to extend animal survival to >90 days in a cell-line xenograft model of disseminated ovarian cancer. In a patient-derived xenograft model of advanced-stage and platinum-resistant ovarian cancer, an MMAE-based NDC doubled the duration of tumor growth inhibition as compared to cisplatin. NDCs of highly potent toxins thus introduce a translatable platform that may be exploited to maximize the safety and efficacy of cytotoxic chemotherapies, combining the best features of ADCs with those of nanoparticle-based therapeutics.Improving the safety and efficacy of chemotherapeutics will help to enhance their effects. Here, the authors show that intraperitoneal delivery of nanoparticle conjugates of a potent toxin prolongs tumor inhibition and survival as compared to cisplatin in advanced-stage and platinum-resistant ovarian cancer mouse models.

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Daniel A. Hammer

Applied Science Private University

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Guizhi Li

University of Pennsylvania

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Paul R. Frail

University of Pennsylvania

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Yingjie Yu

Massachusetts Institute of Technology

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Haiqin Song

Massachusetts Institute of Technology

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Zhimin Tao

Massachusetts Institute of Technology

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