The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Poly(ethylene glycol) (PEG) is the most used polymer and also the gold standard for stealth polymers in the emerging field of polymer-based drug delivery. The properties that account for the overwhelming use of PEG in biomedical applications are outlined in this Review. The first approved PEGylated products have already been on the market for 20 years. A vast amount of clinical experience has since been gained with this polymer--not only benefits, but possible side effects and complications have also been found. The areas that might need consideration and more intensive and careful examination can be divided into the following categories: hypersensitivity, unexpected changes in pharmacokinetic behavior, toxic side products, and an antagonism arising from the easy degradation of the polymer under mechanical stress as a result of its ether structure and its non-biodegradability, as well as the resulting possible accumulation in the body. These possible side effects will be discussed in this Review and alternative polymers will be evaluated.

Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives

PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented.

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Advances and Challenges of Liposome Assisted Drug Delivery.

Exosomes as drug delivery vehicles for Parkinson's disease therapy.

Sterically stabilized liposomes are considered promising carriers of therapeutic agents because they can facilitate controlled release of the drugs, thereby reducing drug-related toxicity and/or targeted delivery of drugs. Herein, we studied the pharmacokinetics and biodistribution of repeated injections of radiolabeled polyethyleneglycol (PEG) liposomes. Weekly injections of 99m Tc-PEG liposomes dramatically influenced the circulatory half-life in rats. Biodistribution 4 h after the second dose showed a significantly reduced blood content (from 52.6 ± 3.7 to 0.6 ± 0.1% injected dose (ID), P P P

Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes

Polyethyleneglycol (PEG) liposomeshave been shown to be excellent vehicles for scintigraphicimaging of infection and inflammationin variousexperimentalmodels.In this articlewe report on a series of patients with possible infectious and inflammatorydiseasein whom the performanceof @â€œTc-PEG liposomeswas evaluated.The resultsof 99mTcPEG liposome scintigraphyweredirectlycomparedwiththoseof 1111n-immuno globulinG (lgG) scintigraphy.Methods: Thirty-fivepatients(22 men,13women;meanage,51y; range,20â€”76 y), suspectedof having infectiousor inflammatorydisease, received740 MBq @â€˜@â€˜Tc-PEG liposomesintravenously. Imagingwasperformedat 4 and24 h afterinjection.Patientsreceived75 MBq111In-IgG 24 h after administrationof the liposomes.The scintigraphicresults were comparedand verified by culture, biopsy,surgery,and follow-upof at least6 mo. Results: Of the 16 proveninfections and inflammalions,15 were detectedby @Tc-PEG liposome scintigraphy:soft-tissueinfection(n = 3), septicarthritis(n = 3), autoimmunepolyarthritis(n = 2), infectedhipprosthesis(n = 1), infected osteosynthesis (n = 1), spondylodiscitis (n = 1), infected aorticprosthesis(n = I), colitis(n = 1),abdominalabscess(n = 1), and pneumonia (n = 1). @Tc-PEGliposome and â€˜11In-lgG scintigraphybothmissed1 caseof endocarditis.In addition,an 111In-lgG scan of a patient with mild soft-tissueinfectionwas false-negative.Concordantly false-positivescanswererecorded from 2 patients,both with uninfectedpseudarthrosisand focal signsof sterileinflammation.Duringliposomaladministration,1 patientexperiencedflushingand chesttightness,which rapidly disappearedafter loweringthe infusionrate. No other adverse eventswere observed.Conclusion: This clinicalevaluationof @Tc-PEG liposomesshowsthat focal infectionand inflamma lion can be adequatelyimagedwiththis newagent.The perfor manceof @â€œTc-PEG liposomesis at leastas effectiveas that of 111In-IgG. Withthe simpleand safepreparationandthe physical and logisticadvantagesof a @â€œTc label, @â€˜@â€˜Tc-PEG liposomes couldbeanattractiveagentforinfectionor inflammation imaging.

https://jnm.snmjournals.org/content/jnumed/41/4/622.full.pdf

99mTc-PEG Liposomes for the Scintigraphic Detection of Infection and Inflammation: Clinical Evaluation

In this study a new 99m Tc labeling method for polyethyleneglycol (PEG)-coated liposomes is described. The in vitro and in vivo characteristics were compared with the conventional 99m Tc-HMPAO-labeled PEG-coated liposomes. Methods: PEG-coated liposomes were labeled with 99m Tc by the hydrazino nicotinyl (HYNIC) derivative of distearoylphosphatidyl-ethanolamine (DSPE) and compared with PEG-coated liposomes labeled with 99m Tc-HMPAO. In vitro stability tests were performed. Biodistribution and imaging characteristics of both liposomal preparations were determined in rats with Staphylococcus aureus infection in the left calf muscle. Results: Per liposome, 230 hydrazine groups were incorporated. The labeling efficiency of the 99m Tc-HYNIC liposomes was greater than 95%, so no postlabeling purification was required, in contrast to the 99m Tc-HMPAO liposomes. The 99m Tc-HYNIC liposomes showed greater in vitro stability than the conventional 99m Tc-HMPAO liposomes. Abscess uptake of the 99m Tc-HYNIC liposomes was significantly greater (1.74 ± 0.38%ID/g versus 1.26 ± 0.29%ID/g, 24 h postinjection, P < 0.03). Furthermore, kidney uptake of the 99m Tc-HYNIC liposomes was one third of the uptake of the 99m Tc-HMPAO liposomes (0.79 ± 0.07%ID/g versus 2.47 ± 0.35%ID/g, 24 h postinjection, P < 0.0001). Conclusion: This new 99m Tc-HYNIC-based labeling method for liposomes is rapid, efficient and easy to perform. Most importantly, the 99m Tc-labeled liposomes have an improved stability and in vivo characteristics. The new labeling method is a major step forward toward a radiopharmaceutical for infection imaging that can be prepared in a one-step procedure within 15 min at room temperature and thus can be applied in every routine clinical practice.

https://jnm.snmjournals.org/content/jnumed/40/1/192.full.pdf

A Novel Method to Label Liposomes with 99mTc by the Hydrazino Nicotinyl Derivative

Liposomes for scintigraphic detection of infection and inflammation.

In the present study, the potential role of 99mTc-PEG-liposome to determine the extent and severity of active disease of Crohn's colitis was investigated. Patients suspected of having an exacerbation of Crohn's disease underwent a 99mTc-PEG-liposome scan (740 MBq, imaging at 4 and 24 h p.i.). A barium enema or endoscopy was performed as the standard verification procedure. Disease activity indices (Clinical Disease Activity Index and Van Hees Activity Index) were calculated. In seven patients positive images of colon segments affected by Crohn's colitis were obtained using 99mTc-PEG-liposomes. Only a moderate relation between 99mTc-liposome scan grading and verification procedures was found (Spearman rank r = 0.22). In accordance with previous studies, no significant correlation was found between the clinical disease activity indices and the verification procedures. This study was prematurely terminated because of unacceptable side-effects in 3 out of 9 patients, which occured almost immediately after starting the infusion. The complaints consisted of dyspnea and facial erythema. The symptoms were self-limiting when the infusion was stopped. In conclusion, the extent of Crohn's colitis can be established non-invasively with 99mTc-PEG-liposome scintigraphy. However, in view of the encountered side-effects, the PEG-liposomal preparation may have to be modified.

E.T.M. Dams

Papers

Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes

99mTc-PEG Liposomes for the Scintigraphic Detection of Infection and Inflammation: Clinical Evaluation

A Novel Method to Label Liposomes with 99mTc by the Hydrazino Nicotinyl Derivative

Liposomes for scintigraphic detection of infection and inflammation.

Tc-99m-PEG-Liposomes for the evaluation of colitis in Crohn's disease.