Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles

Li, Feng; Snow-Davis, Candace; Du, Chengan; Bondarev, Mikhail L.; Saulsbury, Marilyn D.; Heyliger, Simone O.

doi:10.3791/54338

Cited by 11 publications

(23 citation statements)

References 23 publications

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“…This conjugation approach can enhance the affinity of drugs with carriers and reduce drug leakage. 56,79–82 The phospholipid bilayer of liposomes, the lipophilic core of micelles, and the internal oil phase of emulsions are a few examples of components that serve as LDC reservoirs. For example, a fatty acid derivative of diminazene diaceturate was loaded into solid lipid nanoparticles with high efficiency.…”

Section: Advantages Of Lipid–drug Conjugatesmentioning

confidence: 99%

“…For example, an acid-sensitive doxorubicin–palmitate conjugate was loaded into DSPE-PEG micelles. 56 Due to the increased lipophilicity of the prodrug, loading of prodrug in micelle was highly efficient. This formulation demonstrated excellent drug loading stability, due to enhanced interaction between drug and micelle hydrophobic core.…”

Section: Delivery Systems For Lipid–drug Conjugatementioning

confidence: 99%

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Lipid–Drug Conjugate for Enhancing Drug Delivery

2017

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Lipid–drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. The conjugation of lipids to drug molecules increases lipophilicity and also changes other properties of drugs. The conjugates demonstrate several advantages including improved oral bioavailability, improved targeting to the lymphatic system, enhanced tumor targeting, and reduced toxicity. Based on the chemical nature of drugs and lipids, various conjugation strategies and chemical linkers can be utilized to synthesize LDCs. Linkers and/or conjugation methods determine how drugs are released from LDCs and are critical for the optimal performance of LDCs. In this review, different lipids used for preparing LDCs and various conjugation strategies are summarized. Although LDCs can be administered without a delivery carrier, most of them are loaded into appropriate delivery systems. The lipid moiety in the conjugates can significantly enhance drug loading into hydrophobic components of delivery carriers and thus generate formulations with high drug loading and superior stability. Different delivery carriers such as emulsions, liposomes, micelles, lipid nanoparticles, and polymer nanoparticles are also discussed in this review.

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Section: Advantages Of Lipid–drug Conjugatesmentioning

confidence: 99%

Section: Delivery Systems For Lipid–drug Conjugatementioning

confidence: 99%

Lipid–Drug Conjugate for Enhancing Drug Delivery

2017

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“… 36 , 37 C14 and C16 fatty acyls are used in conjugation with antidrugs as a lipid-antidrug prodrug. 38 , 39 The current findings suggest that there is a threshold level of hydrophobicity for N-acyl-CM4 and a certain helical content. When it exceeds the threshold level, it drives the N-acyl-CM4 to cross the membrane into the intracellular space.…”

Section: Discussionmentioning

confidence: 53%

Effect of Hydrophobicity on the Anticancer Activity of Fatty-Acyl-Conjugated CM4 in Breast Cancer Cells

et al. 2020

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Antimicrobial peptides (AMPs) are important anticancer resources, and exploring AMP conjugates as highly effective and selective anticancer agents would represent new progress in cancer treatment. In this study, we synthesized C4–C16 fatty-acyl-conjugated AMP CM4 and investigated its physiochemical properties and cytotoxicity activity in breast cancer cells. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and reversed-phase high-performance liquid chromatography (RP-HPLC) showed that long-chain fatty acyl (≥C12) conjugation prevented N-acyl-CM4 from trypsin hydrolysis. RP-HPLC and circular dichroism (CD) spectra showed that the hydrophobicity and helical content of N-acyl-CM4 increased with the acyl length. The acyl chain length was positively related to the cytotoxicity of C8–C16 conjugates, and C12–C16 fatty acyl conjugates exhibited significant cytotoxicity against MX-1, MCF-7, and MDA-MB-231 cells, with IC 50 values <8 μM. Flow cytometry and confocal laser scanning microscopy results showed that N-acylated conjugation significantly increased the membrane affinity in breast cancer cells, and C12–C16 acyl conjugates were capable of translocating to the intracellular space, thereby targeting mitochondria and inducing apoptosis. N-acyl-CM4 showed low cytotoxicity against normal mammalian cells and erythrocytes, especially ≤C12 fatty acyl conjugates, exhibiting selective cytotoxicity to breast cancer cells. The current work indicated that increasing hydrophobicity by attaching long fatty acyl (≥C12) to AMPs may be an effective method to improve the anticancer activity, together with selectivity and resistance to trypsin hydrolysis. This finding provides a good strategy to develop AMPs as effective anticancer agents in the future.

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“…The particle size and polydispersity index (PDI) were determined with Malvern Nano ZS based on the dynamic light scattering [11]. The MONs were diluted with water before measurement.…”

Section: Particle Size and Zeta Potentialmentioning

confidence: 99%

Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer

Chang

Jiang

et al. 2020

Applied Materials Today

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Disulfiram (DSF) is currently tested in several clinical trials for cancer treatment in combination with copper (Cu) ions. Usually, DSF and Cu are administered in two separate formulations. In the body, DSF and Cu ions form diethyldithiocarbamate copper complex [Cu(DDC) 2 ] which has potent antitumor activities. However, the "two formulation" approach often achieved low Cu(DDC) 2 concentration at tumor regions and resulted in compromised anticancer efficacy. Therefore, preformed Cu(DDC) 2 complex administered in a single formulation will have better anticancer efficacy. However, the poor aqueous solubility of Cu(DDC) 2 is a significant challenge for its clinical use. In this work, a biomimetic nanoparticle formulation of Cu(DDC) 2 was produced with a novel SMILE (Stabilized Metal Ion Ligand complex) method developed in our laboratory to address the drug delivery challenges. The Metal-organic Nanoparticle (MON) is composed of Cu(DDC) 2 metal-organic complex core and surface decorated bovine serum albumin (BSA). Importantly, we designed a 3D-printed microfluidic device to further improve the fabrication of BSA/Cu(DDC) 2 MONs. This method could precisely control the MON preparation process and also has great potential for large scale production of Cu(DDC) 2 MON formulations. We also used a computational modeling approach to simulate the MON formation process in the microfluidic device. The optimized BSA/Cu(DDC) 2 MONs demonstrated good physicochemical properties. The MONs also showed potent antitumor activities in the breast cancer cell monolayers as well as the 3D-cultured tumor spheroids. The BSA/Cu(DDC) 2 MONs also effectively inhibited the growth of tumors in an orthotopic 4T1 breast tumor model. This current study provided a novel method to prepare a biomimetic MON formulation for DSF/Cu cancer therapy.

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Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles

Cited by 11 publications

References 23 publications

Lipid–Drug Conjugate for Enhancing Drug Delivery

Lipid–Drug Conjugate for Enhancing Drug Delivery

Effect of Hydrophobicity on the Anticancer Activity of Fatty-Acyl-Conjugated CM4 in Breast Cancer Cells

Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer

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