Therapeutic oxygen delivery by perfluorocarbon-based colloids

https://doi.org/10.1016/j.cis.2021.102407Get rights and content

Highlights

  • Fluorocarbon nanoemulsions effectively deliver oxygen to tissues, relieve hypoxia.

  • Fluorocarbon-stabilized microbubbles provide an alternate oxygen delivery option.

  • Phase-shift emulsions combine enhanced circulation half-life and tumor penetration.

  • Proper choice of fluorocarbon, shell components, dispersion technology is critical.

  • PFC colloids improve diagnostic imaging, deliver therapeutic energy, drugs, genes.

Abstract

After the protocol-related indecisive clinical trial of Oxygent, a perfluorooctylbromide/phospholipid nanoemulsion, in cardiac surgery, that often unduly assigned the observed untoward effects to the product, the development of perfluorocarbon (PFC)-based O2 nanoemulsions (“blood substitutes”) has come to a low. Yet, significant further demonstrations of PFC O2-delivery efficacy have continuously been reported, such as relief of hypoxia after myocardial infarction or stroke; protection of vital organs during surgery; potentiation of O2-dependent cancer therapies, including radio-, photodynamic-, chemo- and immunotherapies; regeneration of damaged nerve, bone or cartilage; preservation of organ grafts destined for transplantation; and control of gas supply in tissue engineering and biotechnological productions. PFC colloids capable of augmenting O2 delivery include primarily injectable PFC nanoemulsions, microbubbles and phase-shift nanoemulsions. Careful selection of PFC and other colloid components is critical. The basics of O2 delivery by PFC nanoemulsions will be briefly reminded. Improved knowledge of O2 delivery mechanisms has been acquired. Advanced, size-adjustable O2-delivering nanoemulsions have been designed that have extended room-temperature shelf-stability. Alternate O2 delivery options are being investigated that rely on injectable PFC-stabilized microbubbles or phase-shift PFC nanoemulsions. The latter combine prolonged circulation in the vasculature, capacity for penetrating tumor tissues, and acute responsiveness to ultrasound and other external stimuli. Progress in microbubble and phase-shift emulsion engineering, control of phase-shift activation (vaporization), understanding and control of bubble/ultrasound/tissue interactions is discussed. Control of the phase-shift event and of microbubble size require utmost attention. Further PFC-based colloidal systems, including polymeric micelles, PFC-loaded organic or inorganic nanoparticles and scaffolds, have been devised that also carry substantial amounts of O2. Local, on-demand O2 delivery can be triggered by external stimuli, including focused ultrasound irradiation or tumor microenvironment. PFC colloid functionalization and targeting can help adjust their properties for specific indications, augment their efficacy, improve safety profiles, and expand the range of their indications. Many new medical and biotechnological applications involving fluorinated colloids are being assessed, including in the clinic. Further uses of PFC-based colloidal nanotherapeutics will be briefly mentioned that concern contrast diagnostic imaging, including molecular imaging and immune cell tracking; controlled delivery of therapeutic energy, as for noninvasive surgical ablation and sonothrombolysis; and delivery of drugs and genes, including across the blood-brain barrier. Even when the fluorinated colloids investigated are designed for other purposes than O2 supply, they will inevitably also carry and deliver a certain amount of O2, and may thus be considered for O2 delivery or co-delivery applications. Conversely, O2-carrying PFC nanoemulsions possess by nature a unique aptitude for 19F MR imaging, and hence, cell tracking, while PFC-stabilized microbubbles are ideal resonators for ultrasound contrast imaging and can undergo precise manipulation and on-demand destruction by ultrasound waves, thereby opening multiple theranostic opportunities.

Introduction

Once the flagship of medically-dedicated perfluorocarbon (PFC) research, and catching most of the limelight, oxygen-carrying PFC nanoemulsions, the so-called “blood substitutes”, have so far not met expectations. No satisfactory injectable O2-delivering product has yet reached the marketplace. By contrast, another primary endeavor in medically-oriented PFC research, that is, the development of contrast-enhancing agents for diagnostic imaging, has been more successful. Several products have been licensed for use as contrast agents for ultrasound (US) imaging, as well as for ophthalmology and for in vivo cell tracking. The search for O2-delivering therapeutics has, however, not been forsaken. Further colloidal PFC products, including nanoemulsions (NEs), microbubbles (MBs) and phase-shift nanoemulsions (P-SNEs) (Scheme 1), are undergoing clinical investigations for O2 delivery, in particular for O2-dependent cancer radiotherapy, chemotherapy and photodynamic therapy. Concurrently, further PFC-based products are undergoing clinical trials for molecular imaging diagnosis of liver, breast, ovarian, prostate and colon cancers; guidance for surgical procedures; enhancement of immunotherapy; ablation of uterine fibroids; treatment of allergic asthma; treatment of smoke inhalation injury; delivery of drugs to the brain, as for management of brain tumors and neurodegenerative diseases, and assessment of treatment efficacy.

Starting with a critical assessment of a problematic Phase III trial of Oxygent (Alliance Pharmaceutical Corp., San Diego, CA), an O2-carrying PFC NE product, in cardiac surgery, this short review will present PFC-based colloids that are, or may be, used for O2 delivery. It will insist on the critical question of PFC selection and NE design and fabrication, highlight recent advances in the field and progress in our understanding of PFC behavior at fluid interfaces. After a brief reminder of the basics of PFC NE-based O2 transport and delivery, it will expose further demonstration of their capacity to deliver O2 to tissues in various circumstances. We will then discuss alternative O2-delivery options that rely on the administration of PFC-stabilized injectable MBs or on MBs generated in vivo by vaporization of P-SNEs, as well as on other colloids and scaffolds that involve PFCs or other highly fluorinated components. We will also allude to other emerging PFC-based procedures and indications that are being investigated for diagnostic, therapeutic and theranostic purposes, embracing contrast imaging, cell tracking, controlled delivery of energy and of therapeutics, including across the blood-brain barrier. Even when developed for other purposes, these products possess a definite O2 carrying capacity and the knowledge acquired in their investigation could benefit to O2 carrier development. Finally, the Prospects section will highlight some critical issues, desirable developments, and offer some opinions about the development of PFC-based O2 delivery products. The paper's organization is further detailed in the Table of Content.

Citations are leaning towards recent reviews from which numerous earlier papers can be retrieved. The italicized prefix F- conventionally signifies perfluoro. F-colloids will refer to colloids comprising highly fluorinated components. Recourse to acronyms will be minimized. Commercial PFC-based product names are in italics.

Section snippets

An inconclusive clinical trial

PFC-based oxygen carriers have suffered a serious drawback when Alliance Pharmaceutical Corp. closed its operations subsequent to a failed clinical study. The development of the most advanced PFC nanoemulsion of that time, Oxygent AF0144, a phospholipid-shelled 60% w/v F-octylbromide (C8F17Br 3) emulsion comprizing a small fraction of F-decylbromide (C10F21Br 4, 2%) for stabilization against Ostwald ripening [1,2], was interrupted in 2001 when a Phase III study in coronary artery bypass graft

The perfluorocarbon colloids at work

Intravascular administration of PFCs requires their dispersion as injectable aqueous formulations. The colloids used in nanomedicines for O2 delivery (3 The perfluorocarbon colloids at work, 4 Oxygen delivery by PFC nanoemulsions, 5 The O, 6 O) and other purposes (Section 7) consist primarily of NEs, MBs, and P-SNEs (Scheme 1). The latter involve liquid NE droplets that can be converted in vivo into gas MBs upon activation (vaporization) by heat, sound or light. Further colloids intended for

Oxygen delivery by PFC nanoemulsions

The early objective of developing PFC-based O2-delivering “blood substitutes” has not been forsaken. Further evidence of O2 delivery efficacy by means of PFC NEs has been secured. New, highly stable size-controlled NEs have been developed. The alternative option of using MBs or P-SNE-derived MBs for O2 delivery is being actively investigated. Additional indications for O2-delivering therapeutics have emerged. Potentiation of the foremost O2-dependent cancer treatment strategies, including

The O2 microbubble delivery option—a change in paradigm

An alternate option for O2 delivery relies on the direct administration of PFC-stabilized O2 micro- or nanobubbles rather than emulsion droplets. This represents a definite change in paradigm since in the former case the PFC does no longer act as a solvent for physical dissolution of O2, but as a gaseous stabilizer of an O2 microbubble. Such MBs can also be generated through vaporization of NE droplets. US exposure can prompt on-demand O2 delivery from MBs located at the disease site.

O2 delivery by further PFC-based colloids

A few recent studies that investigate O2 transport by fluorinated colloids other than PFC NEs, MBs or P-SNEs, in which O2 delivery is either a deliberate part of a theranostic strategy, or that pursue other goals, but inevitably also provide an O2 reservoir, are illustrated here. Examples of F-alkylated or F-arylated components of fluorinated polymeric micelles formed for this purpose are provided in Table 7. 1O2 production and PDT efficacy of micelles made of PEGylated copolymers bearing

Perfluorocarbon colloids can also deliver other gases, contrast, energy, drugs, genes, and have a clear vocation for theranostics

The recent years have witnessed an outburst of prospective PFC-based nanomedicines for an increasing number of indications other than O2 delivery. Objectives include increasingly sophisticated diagnostic imaging modalities, focused delivery of energy in various forms, controlled as and when required delivery of therapeutics, … and even control of urinary stress. Even when the primary goal is different, the F-colloids put to work predictably do carry, and can release a certain amount of O2.

Prospects

The past decade has witnessed an amazing surge of the number of new PFC-based O2-carrying colloids and medical indications investigated. Our knowledge of PFC colloid preparation, stabilization, physics and in vivo behavior has considerably progressed. Substantial O2 delivery efficacy data further support the capacity of PFC nanoemulsions to help relieve tissue hypoxia, potentiate O2-dependent cancer treatment, regenerate damaged tissues, preserve isolated organs, etc. In view of these data, we

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We acknowledge the European INTERREG V Program (Nanotransmed) for financial support.

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