Importance of the field: Vascular delivery of several classes of therapeutic agents may benefit from carriage by red blood cells (RBC), for example, drugs that require delivery into phagocytic cells and those that must act within the vascular lumen. The fact that several protocols of infusion of RBC-encapsulated drugs are now being explored in patients illustrates a high biomedical importance for the field.Areas covered by this review: Two strategies for RBC drug delivery are discussed: encapsulation into isolated RBC ex vivo followed by infusion in compatible recipients and coupling therapeutics to the surface of RBC. Studies of pharmacokinetics and effects in animal models and in human studies of diverse therapeutic enzymes, antibiotics and other drugs encapsulated in RBC are described and critically analyzed. Coupling to RBC surface of compounds regulating immune response and complement, affinity ligands, polyethylene glycol alleviating immune response to donor RBC and fibrinolytic plasminogen activato...

Drug delivery by red blood cells: vascular carriers designed by mother nature

Cell-mediated delivery of nanoparticles: Taking advantage of circulatory cells to target nanoparticles

Drug delivery systems, particularly nanomaterial-based drug delivery systems, possess a tremendous amount of potential to improve the diagnostic and therapeutic effects of drugs. Controlled drug delivery targeted to a specific disease is designed to significantly improve the pharmaceutical effects of drugs and reduce their side effects. Unfortunately, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even with the development of numerous surface markers and targeting modalities. Thus, alternative drug and nanomedicine targeting approaches are desired. Circulating cells, such as erythrocytes, leukocytes, and stem cells, present innate disease sensing and homing properties. Hence, using living cells as drug delivery carriers has gained increasing interest in recent years. This review highlights the recent advances in the design of cell-mediated drug delivery systems and targeting mechanisms. The approaches of drug encapsulation/conjugation to cell c...

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Design Strategies and Applications of Circulating Cell-Mediated Drug Delivery Systems

Autoantibodies against the exocrine pancreas in autoimmune pancreatitis: gene and protein expression profiling and immunoassays identify pancreatic enzymes as a major target of the inflammatory process.

In recent years, the influence of the tumor microenvironment (TME) on cancer progression has been better understood. Macrophages, one of the most important cell types in the TME, exist in different subtypes, each of which has a different function. While classically activated M1 macrophages are involved in inflammatory and malignant processes, activated M2 macrophages are more involved in the wound-healing processes occurring in tumors. Tumor-associated macrophages (TAM) display M2 macrophage characteristics and support tumor growth and metastasis by matrix remodeling, neo-angiogenesis, and suppressing local immunity. Due to their detrimental role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer may prove to be beneficial in the treatment of cancer. Due to the plastic nature of macrophages, their activities may be altered to inhibit tumor growth. In this review, we will discuss the therapeutic options for the modulation and targeting of TAM. Different therapeutic strategies to deplete, inhibit recruitment of, or re-educate TAM will be discussed. Current strategies for the targeting of TAM using nanomedicine are reviewed. Passive targeting using different nanoparticle systems is described. Since TAM display a number of upregulated surface proteins compared to non-TAM, specific targeting using targeting ligands coupled to nanoparticles is discussed in detail.

Nanomedicine Strategies to Target Tumor-Associated Macrophages

Given the important role of macrophages in various disorders, the transient and organ specific suppression of their functions may benefit some patients. Until now, liposome-encapsulated bisphosphonate clodronate has been extensively proposed to this end. In this paper, we demonstrate that erythrocytes loaded with clodronate can also be effective in macrophage depletion. Here, clodronate was encapsulated in erythrocytes through hypotonic dialysis, isotonic resealing and reannealing to final concentrations of 4.1 +/- 0.4 and 10.1 +/- 0.8 micromol/ml of human and murine erythrocytes, respectively. The ability of clodronate-loaded erythrocytes to deplete macrophages was evaluated both in vitro and in vivo. In vitro studies on human macrophages showed that a single administration of engineered erythrocytes was able to reduce cell adherence capacity in a time-dependent manner, reaching 50 +/- 4% reduction, 13 days post treatment. The administration of loaded erythrocytes to cultures of murine peritoneal macrophages was able to reduce macrophage adhesion 67 +/- 3%, 48 h post treatment. In vivo, the ability of clodronate-loaded erythrocytes to deplete macrophages was evaluated both in Swiss and C57BL/6 mice. Swiss mice received 125 microg of clodronate through erythrocytes and 6 days post treatment 69 +/- 7% reduction in the number of adherent peritoneal macrophages and 75 +/- 5% reduction in number of spleen macrophages were observed. C57BL/6 mice received 220 microg clodronate by RBC and 3 and 8 days post treatment 65 +/- 7% reduction in the number of spleen macrophages and the complete depletion of liver macrophages were obtained. In summary, our results indicate that clodronate selectively targeted to the phagocytic cells by a single administration of engineered erythrocytes is able to deplete macrophages, even if not completely. The transient suppression of macrophage functions through clodronate-loaded erythrocytes can be used in many biomedical phenomena and research applications.

Macrophage depletion induced by clodronate-loaded erythrocytes.

Tenofovir (9-(R)-2-(phosphonomethoxypropyl)adenine (PMPA)) and zidovudine (azidothy- midine (AZT)) are potent anti-HIV agents that have shown a strong synergy in in vitro studies. In this paper we have investigated both the potentiality of this synergy in vivo and the possibility to administer AZT and PMPA simultaneously as a single drug AZTpPMPA. The pharmacokinetic studies reported here have shown that AZTpPMPA administered intraperitoneally in mice performs as a prodrug, providing a slow delivery of AZT and PMPA in circulation. C57BL/6 mice infected with the retroviral complex LP-BM5 were used to evaluate the efficacy of AZTpPMPA in inhibiting disease progression. Furthermore, the effectiveness of the heterodinucleotide was compared with that of AZT and PMPA, administered as single drugs, or as a combination (AZT plus PMPA). The results obtained showed that AZTpPMPA is able to reduce lymphoadenopathy (88%), splenomegaly (64%), lymph node BM5 proviral DNA content (49%) and hypergamma- globulinaemia (40%). However, upon AZT plus PMPA administration, similar (splenomegaly and lymphoadenopathy reduction) or better results (64% hypergammaglobulinaemia reduction and 75% lymph node BM5 proviral DNA content inhibition) were obtained. Furthermore, these results overlapped those obtained upon PMPA administration. Thus, no synergy between PMPA and AZT was observed in murine AIDS and administration of AZT does not improve the antiviral results obtained by PMPA administration.

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Inhibition of murine AIDS by a heterodinucleotide of azidothymidine and 9-(R)-2-(phosphonomethoxypropyl)adenine

Summary. In order to increase the understanding of blood cytopenias in HIV infection we have investigated the bone marrow in murine AIDS. C57BL/6 mice infected with the LP-BM5 retrovirus show a decrease in cellularity, numerous haemophagocytic histiocytes, a reduction of all erythroid precursor cells, an increase in eosinophil number and an increase in lymphocytes. Immunostaining with an anti-Pr60gag antibody shows that the majority of bone marrow cells express the viral protein. Thus, the bone marrow in MAIDS has many similarities with the bone marrow from patients with advanced AIDS and may prove useful as a model for therapy aimed at treating blood cytopenias.

The bone marrow in murine AIDS.

ABSTRACT Blood cytopenia is a common feature in HIV infection, occurring in up to 70% of patients with AIDS. Since at present it is not clear to what extent this is intrinsic to HIV infection or due to opportunistic infections and antiretroviral agents we have investigated the long-term effects of conventional and new antiviral drugs on the bone marrow of normal and immunodeficient mice. The results show that azidothymidine (AZT), dideoxycytidine (DDC) and dideoxycytidine 5′-triphosphate (DDCTP) alone or in combination are all effective in inhibiting the expression of the retroviral protein Pr60 gag in bone marrow cells. However, DDCTP was the most effective in preventing bone marrow cytopenia. Combined treatments of AZT plus DDCTP result in a reduction in erythroid precursors compared to that resulting from DDCTP administration, while DDC plus DDCTP results in a differential cell count similar to that found in uninfected mice. Thus, the bone marrow in murine AIDS may prove useful as a model for therapy of retroviral infections and for treating blood cytopenias.

Andrea Carnevali

Papers

Macrophage depletion induced by clodronate-loaded erythrocytes.

Inhibition of murine AIDS by a heterodinucleotide of azidothymidine and 9-(R)-2-(phosphonomethoxypropyl)adenine

The bone marrow in murine AIDS.

Effect of antiviral treatments on the bone marrow in murine aids