Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial).

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

Effects of Liposome-Entrapped Muramyl Tripeptide Phosphatidylethanolamine (L-MTP-PE) on the Tumor Growth and Survival of Mice Bearing Syngeneic Tumor in Combination with a Chemotherapeutic or Immunomodulatory Agent.

Antitumor activities of L-MTP-PE (Liposome entrapped myuramyl tripeptide phosphatidylethanolamine) in the combination treatment with chemo- or immune-therapeutic antitumor agents against various syngeneic tumors were tested.Against Meth A fibrosarcoma solid tumor system, L-MTP-PE showed slight but statistically significant elongation of survival days against 5-FU monotherapy in spite of its non-effect on tumor growth, when combined with 5-FU. Against liver metastasis model of M5076 carcinoma, L-MTP-PE showed a tendency of elongation of survival days by its single drug treatment, however, elongation with statistical significance was observed in the combination treatment with 5-FU in comparison with control group.These data suggest that L-MTP-PE seems to elongate the survival days of the solid tumor bearing mice and the liver metastasis model basically due to its saving effect on chemotherapeutic drug-induced immunosuppression. In the combination with an immunotherapeutic agent in mice, TNF production induced by another biological response modifier OK-432 was potentiated when primed with L-MTP-PE. L-MTP-PE also potentiate the antitumor effect of OK-432 possibly through the enhanced production of TNF-α. Combination of L-MTP-PE and OK-432 is considered to be a candidate for a new treatment model for cancer.

The addition of the immunomodulator mifamurtide to adjuvant chemotherapy for early osteosarcoma: a retrospective analysis.

BACKGROUND: Current treatment recommendations for high grade non-metastatic osteosarcoma include perioperative chemotherapy and surgery. Despite this intensive protocol, approximately 40% of patients will relapse. The addition of the immunomodulator mifamurtide to adjuvant cytotoxic chemotherapy was associated with a significant improvement in 6-year overall survival (OS) in young patients with resectable osteosarcoma, leading to its approval in Europe and other countries. Very limited real-world data are reported on its use. METHODS: We retrospectively evaluated data from osteosarcoma patients who received mifamurtide in the adjuvant setting. Data were obtained from medical records in 2 high-volume bone sarcoma centers. The aim of this study was to collect real-world data on mifamurtide safety and efficacy in Greece. RESULTS: We identified 15 patients with completely resected osteosarcoma who received mifamurtide from September 2015 to January 2020. Median age at diagnosis was 24 years old (16-76). Osteosarcoma arose in the lower extremities (n = 12), in the upper extremities (n = 2) or in the ilium (n = 1). The majority of patients (n = 13) received cisplatin/doxorubicin/methotrexate as perioperative chemotherapy and the remaining patients cisplatin/doxorubicin. After a median follow-up of 46.9 months (range, 32.8-61.1), the median recurrence-free survival was 58.7 months (range, 18.5-98.8) and the median OS 64.1 months (range, 25.6-102.6). Except for fever and chills, the only adverse event probably related to mifamurtide was pericarditis (n = 1). CONCLUSIONS: Mifamurtide was well tolerated in a Greek osteosarcoma population, including patients older than 30 years. The small sample size and the non-comparative design do not allow drawing conclusions on the drug benefit in terms of survival.

Evaluating the antibacterial activity of muramyl dipeptide derivatives, retro-tuftsin derivatives, and anthraquinone oligopeptides against a range of pathogenic bacteria.

Search for new and efficient antibiotic is crucial because of microbial drug resistance and problems with side effects of the administered medication. In this study, we evaluate the in vitro microbiological activity of muramyl dipeptide derivatives, retro-tuftsin derivatives (i.e., tuftsin with reversed amino acid sequences), and combinations of retro-tuftsin derivatives with substituted anthraquinones. The potency of the investigated derivatives towards methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae ESBL (extended-spectrum ß-lactamases) was compared based on the spectroscopically-measured minimal inhibitory concentrations (MIC values). The bacterial growth have also been studied with different concentrations of compounds. Statistical analysis of the results revealed that certain modifications lead to promising activity against S. aureus (anthraquinone analogue - 3c and retro-tuftsin derivative - 2b), while other derivatives exhibit activity against P. aeruginosa (muramyl dipeptide derivative - 1d and retro-tuftsin derivative - 2b). The obtained results of microbiological activity indicate that the structure of the tested compounds may be the basis for further modifications.

Novel chimeric TLR2/NOD2 agonist CL429 exhibited significant radioprotective effects in mice.

Severe ionizing radiation causes the acute lethal damage of haematopoietic system and gastrointestinal tract. Here, we found CL429, the novel chimeric TLR2/NOD2 agonist, exhibited significant radioprotective effects in mice. CL429 increased mice survival, protected mice against the lethal damage of haematopoietic system and gastrointestinal tract. CL429 was more effective than equivalent amounts of monospecific (TLR2 or NOD2) and combination (TLR2 + NOD2) of molecules in preventing radiation-induced death. The radioprotection of CL429 was mainly mediated by activating TLR2 and partially activating NOD2. CL429-induced radioprotection was largely dependent on the activation of TLR2-MyD88-NF-κB signalling pathway. In conclusion, the data suggested that the co-activation of TLR2 and NOD2 could induce significant synergistic radioprotective effects and CL429 might be a potential high-efficiency selective agent.

Further Insights on Structural Modifications of Muramyl Dipeptides to Study the Human NOD2 Stimulating Activity.

A series of muramyl dipeptide (MDP) analogues with structural modifications at the C4 position of MurNAc and on the d-iso-glutamine (isoGln) residue of the peptide part were synthesized. The C4-diversification of MurNAc was conveniently achieved by using CuAAC click strategy to conjugate an azido muramyl dipeptide precursor with structurally diverse alkynes. d-Glutamic acid (Glu), replaced with isoGln, was applied for the structural diversity through esterification or amidation of the carboxylic acid. In total, 26 MDP analogues were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, MDP derivatives with an ester moiety are found to be more potent than reference compound MDP itself or MDP analogues containing an amide moiety. Among the varied lengths of the alkyl chain in ester derivatives, the MDP analogue bearing the d-glutamate dodecyl (C12) ester moiety showed the best NOD2 stimulation potency.

Type 4 hypersensitivity development in a case due to mifamurtide.

BACKGROUND: This report aims to discuss the mechanism of pleural and pericardial effusion related to mifamurtide which is an immunological agent used as adjuvant chemotherapy in osteosarcoma. CASE: Mifamurtide (2 mg/m < sup > 2 < /sup > ) and European and American Osteosarcoma Studies (EURAMOS) protocol were used together intravenously after complete surgical resection. No side effects occurred except for fever after the first dose. However, pleural, pericardial effusion, and splenic nodule formation began 11 months after discontinuation of mifamurtide treatment. Pleural biopsy revealed a type 4 hypersensitivity reaction. We treated the patient with 1,5 mg per day colchicine. Pericardial effusion attacks and nodules in the spleen disappeared. The patient had a mild pleural effusion attack which has not yet repeated. CONCLUSION: Mifamurtide, which activates macrophages, can also activate immunity with a stand by effect and cause a hypersensitivity reaction.

Differential Peptidoglycan Recognition Assay Using Varied Surface Presentations.

Bacterial peptidoglycan (PG) is recognized by the human innate immune system to generate an appropriate response. To gain an appreciation of how this essential polymer is sensed, a surface plasmon resonance (SPR) assay using varied PG surface presentation was developed. PG derivatives were synthesized and immobilized on the surface at different positions on the molecule to assess effects of ligand orientation on the binding affinities of NOD-like receptors (NLRs). NLRP1 and NOD2 are cytosolic innate immune proteins known to generate an immune response to PG. Both possess conserved leucine rich repeat domains (LRR) as proposed sites of molecular recognition, though limited biochemical evidence exists regarding the mechanisms of PG recognition. Here direct biochemical evidence for the association of PG fragments to NOD2 and NLRP1 with nanomolar affinity is shown. The orientations in which the fragments were presented on the SPR surface influenced the strength of PG recognition by both NLRs. This assay displays fundamental differences in binding preferences for PG by innate immune receptors and reveals unique recognition mechanisms between the LRRs. Each receptor uses specific ligand structural features to achieve optimal binding, which will be critical information to manipulate these responses and combat diseases.

Muramyl Tripeptide Plus Chemotherapy Reduces Metastasis in Non-Metastatic Osteosarcoma: A Single-Center Experience.

BACKGROUND: The immunomodulator mifamurtide plus a chemotherapy regimen has been shown to significantly improve the outcome in non-metastatic osteosarcoma patients. We report the results of the addition of mifamurtide to chemotherapy in newly diagnosed patients with osteosarcoma. METHODS: A total of 36 children with osteosarcoma without detectable metastasis were treated between November 2010 and April 2018 at the Ankara University Department of Pediatric Oncology. Mifamurtide was added to the chemotherapy regimen in 17 patients while the remaining 19 did not receive mifamurtide. The probabilities of metastasis and overall survival were compared between the groups. RESULTS: The 43-month survival rate was 87.5% and 89.9% in the patients who received and did not receive mifamurtide, respectively (p=0.65). Common side effects of mifamurtide were chills and fever. The addition of mifamurtide in the high-risk group with ≤95% necrosis tended to decrease the probability of distant metastasis (36.4% vs. 58.3%) (p=0.39). The time to metastasis in the group with positive surgical margins (4 months in one patient in the non-mifamurtide group, 7 and 20 months in the mifamurtide group) was also longer in the mifamurtide group. During the 43-month follow up period, median time to metastasis was longer in the mifamurtide group (20 vs. 5 months). In addition, mifamurtide plus chemotherapy decreased the risk of metastasis in the cases with primary site relapse. CONCLUSIONS: The addition of mifamurtide to chemotherapy might improve event-free survival by decreasing the probability of distant metastasis in bad histologic responders, and also by increasing the time to distant metastasis in the surgical margin positive group. Additional clinical studies are necessary to determine the long-term effects of mifamurtide on metastatic disease.
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The Brief Analysis of Peptide-combined Nanoparticle: Nanomedicine's Unique Value.

Therapeutic peptides (TPs) are biological macromolecules which can act as neurotransmitters, hormones, ion channel ligands and growth factors. Undoubtedly, TPs are crucial in modern medicine. But low bio-stability and some special adverse reactions reduce their places to the application. With the development of nanotechnology, nanoparticles (NPs) in pharmaceutical science gained much attention. They can encapsulate the TPs into their membrane or shell. Therefore, they can protect the TPs against degradation and then increase the bioavailability, which was thought to be the biggest advantage of them. Additionally, targeting was also studied to improve the effect of TPs. However, there were some drawbacks of nano TPs like low loading efficiency and difficulty to manufacture. Nowadays, lots of studies focused on improving effect of TPs by preparing nanoparticles. In this review, we presented a brief analysis of peptide-combined nanoparticles. Their advantages and disadvantages were listed in terms of mechanism. And several examples of applications were summarized.

Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma.

INTRODUCTION: The controversial results on the mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising drug. The European Commission has granted a marketing authorisation to mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation. METHODS AND ANALYSIS: Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2 and ≤50 years with newly diagnosed high-risk localised or metastatic osteosarcoma. The main objective is to evaluate the impact on event-free survival (EFS) of mifamurtide on intention-to-treat population. The secondary objectives are to evaluate the impact of mifamurtide on overall survival, to evaluate the feasibility and toxicity of the planned treatment, to correlate biology/immunology with the mifamurtide efficacy/toxicity. With a total of 126 enrolled patients and 51 events, the power is 80% if mifamurtide is associated with an 18% improvement of the 3-year EFS (52%vs70%, equivalent to an HR=0.55), with a one-sided logrank test alpha=10%. As relevant historical data are available (aggregate treatment effect from the INT-0133 trial and individual data from the control group of the Sarcome-09/OS2006 trial), a Bayesian analysis is also planned. ETHICS AND DISSEMINATION: This study was approved by the 'Comité de Protection des Personnes Ile de France I' (12/06/2018), complies with the Declaration of Helsinki and French laws and regulations, and follows the International Conference on Harmonisation E6 Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, as well as biological ancillary studies will be presented at appropriate international congresses and published in international peer-review journals. TRIAL REGISTRATION NUMBER: EudraCT 2017-001165-24, NCT03643133.

NOD2 agonist murabutide alleviates radiation-induced injury through DNA damage response pathway mediated by ATR.

Injury-induced by ionizing radiation (IR) severely reduces the quality of life of victims. The development of radiation protectors is regarded as one of the most resultful strategies to alleviate damages caused by IR exposure. In the present study, we investigated the radioprotective effects of the agonist of nucleotide-binding-oligomerization-domain-containing proteins 2 called murabutide (MBD) and clarified the potential mechanisms. Our results showed that the pretreatment with MBD effectively protected cultured cells and mice against IR-induced toxicity and the pretreatment with MBD in vitro and in vitro also inhibited apoptosis caused by IR exposure. The downregulation of γ-H2AX and the upregulation of ATR signaling pathways by MBD treatment indicated that the radioprotective effects of MBD were due to the stimulation of DNA damage response (DDR) pathway to repair DNA double-strand breaks caused by IR exposure. As the radioprotective effects of MBD were diminished by the ATR selective inhibitor rather than the ATM inhibitor, ATR pathway was confirmed to be a more crucial checkpoint pathway in mediating the stimulation of DDR pathway by MBD. Taken together, our data provide a novel and effective protector to relieve the injury induced by IR exposure.

Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study.

BACKGROUND: Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial's analysis through a prior distribution. METHODS: Motivated by a RCT intended to evaluate the impact on event-free survival of mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. RESULTS: The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. CONCLUSION: In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.

Synthesis and Application of Methyl N,O-Hydroxylamine Muramyl Peptides.

The innate immune system's interaction with bacterial cells plays a pivotal role in a variety of human diseases. Carbohydrate units derived from a component of bacterial cell wall, peptidoglycan (PG), are known to stimulate an immune response. Nonetheless, access to modified late-stage peptidoglycan intermediates is limited due to their synthetic complexity. A method to rapidly functionalize PG fragments is needed to better understand the natural host-PG interactions. Here methyl N,O-hydroxylamine linkers are incorporated onto a synthetic PG derivative, muramyl dipeptide (MDP). The modification of MDP maintained the ability to stimulate a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) immune response dependent on the expression of nucleotide-binding oligomerization domain-containing protein 2 (Nod2). Intrigued by this modification's maintenance of biological activity, several applications were explored. Methyl N,O-hydroxylamine MDP was amendable to N-hydroxylsuccinimide (NHS) chemistry for bioconjugation to fluorophores as well as a self-assembled monolayer for Nod2 surface plasmon resonance analysis. Finally, linker incorporation was applicable to larger PG fragments, both enzymatically generated from Escherichia coli or chemically synthesized. This methodology provides rapid access to PG probes in one step and allows for the installation of a variety of chemical handles to advance the molecular understanding of PG and the innate immune system.

Squalane-based emulsion vaccine delivery system: composition with murabutide activate Th1 response.

Emulsions play an important role in present-day subunit vaccine delivery. Squalane-based emulsion was formulated using surfactants viz., Pluronic F68, Span 85 along with Murabutide (MB) as immunepotentiator. Particle size and zetapotential of the final optimized emulsion was found to be 134 nm and -13 mV, respectively. The in vitro cellular uptake studies performed using fluorescein isothiocyanate (FITC)-labeled ovalbumin (OVA) clearly revealed the rapid uptake of antigen in the presence of emulsion. The in vivo subcutaneous studies involving measurement of OVA-specific IgG antibody titers, Th1/Th2 cytokines were performed and a marked up regulation in IL-2, IL-12 and IFN-γ cytokines indicate Th1 immune response. Results supported that the squalane-based delivery system enhanced the uptake of the antigen by immune cells and elicited humoral as well as cell-mediated immune response in mice. These results indicate the promising application of the new squalane based oil-in-water (O/W) emulsion as capable vaccine delivery system useful for vaccine development.

[Muramyldipeptide - based compounds in current medicine: focus on glucosaminylmuramyl dipeptide].

The role of immune mechanisms in the pathogenesis of almost all human diseases shown in recent decades, increase in antibiotic resistance and secondary immunodeficiency, aging of the population and widespread use of immunosuppressive drugs and procedures suggest a wider use of immunomodulators in current clinical practice, but the use of most of them limits the lack of knowledge. The most promising compounds for the development as immunomodulating agents and adjuvants for a wide range of vaccines are low molecular weight fragments of peptidoglycan - muramylpeptides. The article describes the mechanisms of action of muramylpeptides, their biological effects and properties of medicines developed on their basis. Special emphasis is placed to glucosaminylmuramyl dipeptide registered in the Russian Federation under the trade name Likopid, which is currently the best - studied drug in its group. The results of Likopid studies when used as a prophylactic and therapeutic agent for infections of various localization in adults and children, for oncological diseases and complications of chemotherapy and radiation therapy, psoriasis, atopic and other diseases are presented. It is emphasized that in diseases associated with human papillomavirus and plaque psoriasis, according to current criteria of evidence - based medicine, Likopid should be classified as drug with level A efficacy (high efficiency in 80-100% of patients). High safety of Likopid in adults and children, including newborns, is noted.

[Glucosaminylmuramyl dipeptide in treatment of respiratory tract diseases]. / Gliukozaminilmuramildipeptid v terapii infektsionnykh zabolevanii respiratornogo trakta.

INTRODUCTION: Immunomodulators are used as part of a comprehensive therapy of respiratory tract diseases. The systematization of the accumulated data on the use of glucosaminylmuramyldipeptide (GMDP) has great scientific and practical interest. PURPOSE: To study the data on the effectiveness and safety of GMDP in the treatment of infectious diseases of the respiratory tract. MATERIAL AND METHODS: Literature search was carried out in Scientific Electronic Library (elibrary.ru), Google Scholar, ScienceDirect, Cochrane library, Pubmed/MEDLINE and search engines. The level of evidence reliability and methodological quality of researches were assessed. RESULTS: 17 full-text publications were selected based on the results of 13 prospective clinical trials with acceptable methodological quality (including one blind placebo-controlled trial). The effectiveness of GMDP in acute respiratory viral infections, influenza, recurrent respiratory tract infections, rhinosinusitis and chronic tonsillitis was demonstrated. DISCUSSION: An important advantage is that a significant part of the studies was performed with the participation of the child population. Since the use of GMDP in multiple therapy significantly reduces antibiotic consumption (often unjustified). It seems reasonable to estimate the pharmacoeconomic costs of managing adult patients with respiratory tract diseases. Further research can improve understanding of the role of GMDP in the treatment of various medical conditions. CONCLUSION: The use of GMDP in the treatment of respiratory tract diseases makes it possible to faster achieve a clinical effect, reduce the number of relapses, lengthen the relapse-free period, as well as to potentiate the effect of antibacterial therapy (if necessary), reducing the need for antibiotics.

The Efficiency and Toxicity of Mifamurtide in Childhood Osteosarcoma.

The aim of the present study was to evaluate the efficiency and side effects of mifamurtide in childhood osteosarcoma (OS). In total, 477 doses of 2 mg/m intravenous (IV) mifamurtide, along with paracetamol as a premedication, were given to 15 patients with primary nonmetastatic OS after complete surgical resection and to 3 patients with progressive OS. The most common side effects encountered in the patients were chills and fever (17/18). These reactions were observed in 4 patients during the administration of each dose, in a single patient during the last administration, and in the remaining 12 patients during the first or initial 2 administrations. Headache, myalgia, and arthralgia were observed in 2 patients during each infusion. Headache was observed in 1 patient with additional hearing loss during the first 2 infusions. One patient had back pain occuring within the first infusion. Of the 15 patients with primary nonmetastatic OS and treated with the addition of mifamurtide to chemotherapy, 13 showed a complete remission, and 2 patients were still under treatment with a complete remission. Of 3 patients with progressive disease, 2 died while the disease progressed further in the third case over a 51-month period. The 3-year overall survival and event-free survival distributions were 87.5% (mean follow-up time, 46.12; 95% confidence interval, 37.79-52.45 mo) and 75.6% (mean follow-up time, 31.30; 95% confidence interval, 26.54-36.06 mo), respectively. We consider that mifamurtide therapy is a safe and well-tolerated agent in childhood OS.

Pharmacokinetics of lipid-drug conjugates loaded into liposomes.

Drugs that are neither lipophilic nor suitable for encapsulation via remote loading procedures are generally characterized by low entrapment efficiencies and poor retention in liposomes. One approach to circumvent this problem consists in covalently linking a lipid to the drug molecule in order to permit its insertion into the vesicle membrane. The nature of the conjugated lipid and linker, as well as the composition of the liposomal bilayer were found to have a profound impact on the pharmacokinetic properties and biodistribution of the encapsulated drugs as well as on their biological activity. This contribution reviews the past and recent developments on liposomal lipid-drug conjugates, and discusses important issues related to their stability and in vivo performance. It also provides an overview of the data that were generated during the clinical assessment of these formulations. The marketing authorization of the immunomodulating compound mifamurtide in several countries as well as the promising results obtained with the lipid prodrug of mitomycin C suggest that carefully designed liposomal formulations of lipid-drug conjugates is a valid strategy to improve a drug's pharmacokinetic profile and with that its therapeutic index and/or efficacy.

Tunable degradation of acetalated dextran microparticles enables controlled vaccine adjuvant and antigen delivery to modulate adaptive immune responses.

Subunit vaccines are often poorly immunogenic, and adjuvants and/or delivery vehicles, such as polymeric microparticles (MPs), can be used to enhance immune responses. MPs can also be used to understand cell activation kinetics and the significant impact antigen and adjuvant release has on adaptive immune responses. By controlling antigen and adjuvant release, we can determine if it is important to have precise temporal control over release of these elements to optimize the peak and duration of protective immunity and improve vaccine safety profiles. In order to study the effect of tunable adjuvant or antigen delivery on generation of adaptive immunity, we used acetalated dextran (Ace-DEX) MPs. Ace-DEX MPs were used because their tunable degradation can be controlled based on polymer cyclic acetal coverage (CAC). Ace-DEX MPs of varying degradation profiles were used to deliver murabutide or ovalbumin (OVA) as a model adjuvant or antigen, respectively. When murabutide was encapsulated within Ace-DEX MPs to test for controlled adjuvant delivery, fast-degrading MPs exhibited higher humoral and cellular responses in vivo at earlier time points, while slow-degrading MPs resulted in stronger responses at later time points. When OVA was encapsulated within Ace-DEX MPs to test for controlled antigen delivery, fast-degrading MPs induced greater antibody and cytokine production throughout the length of the experiment. This differential response suggests the need for distinct, flexible control over adjuvant or antigen delivery and its impact on immune response modulation.