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Molecular ZIP codes in targeted drug delivery.

ABSTRACT: The term "molecular ZIP (or area) codes" refers to an originally hypothetical system of cell adhesion molecules that would control cell trafficking in the body. Subsequent discovery of the integrins, cadherins, and other cell adhesion molecules confirmed this hypothesis. The recognition system encompassing integrins and their ligands came particularly close to fulfilling the original ZIP code hypothesis, as multiple integrins with closely related specificities mediate cell adhesion by binding to an RGD or related sequence in various extracellular matrix proteins. Diseased tissues have their own molecular addresses that, although not necessarily involved in cell trafficking, can be made use of in targeted drug delivery. This article discusses the molecular basis of ZIP codes and the extensive effort under way to harness them for drug delivery purposes.

SUBMITTER: Ruoslahti E

PROVIDER: S-EPMC9282239 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Molecular ZIP codes in targeted drug delivery.

Ruoslahti Erkki E

Proceedings of the National Academy of Sciences of the United States of America 20220630 28

The term "molecular ZIP (or area) codes" refers to an originally hypothetical system of cell adhesion molecules that would control cell trafficking in the body. Subsequent discovery of the integrins, cadherins, and other cell adhesion molecules confirmed this hypothesis. The recognition system encompassing integrins and their ligands came particularly close to fulfilling the original ZIP code hypothesis, as multiple integrins with closely related specificities mediate cell adhesion by binding to ...[more]

PMID: 35771944

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Project description:Nanotechnology-based drug delivery systems (nanoDDSs) have seen recent popularity due to their favorable physical, chemical, and biological properties, and great efforts have been made to target nanoDDSs to specific cellular receptors. CD44/chondroitin sulfate proteoglycan (CSPG) is among the receptors overexpressed in metastatic melanoma, and the sequence to which it binds within the type IV collagen triple-helix has been identified. A triple-helical "peptide-amphiphile" (alpha1(IV)1263-1277 PA), which binds CD44/CSPG, has been constructed and incorporated into liposomes of differing lipid compositions. Liposomes containing distearoyl phosphatidylcholine (DSPC) as the major bilayer component, in combination with distearoyl phosphatidylglycerol (DSPG) and cholesterol, were more stable than analogous liposomes containing dipalmitoyl phosphatidylcholine (DPPC) instead of DSPC. When dilauroyl phosphatidylcholine (DLPC):DSPG:cholesterol liposomes were prepared, monotectic behavior was observed. The presence of the alpha1(IV)1263-1277 PA conferred greater stability to the DPPC liposomal systems and did not affect the stability of the DSPC liposomes. A positive correlation was observed for cellular fluorophore delivery by the alpha1(IV)1263-1277 PA liposomes and CD44/CSPG receptor content in metastatic melanoma and fibroblast cell lines. Conversely, nontargeted liposomes delivered minimal fluorophore to these cells regardless of the CD44/CSPG receptor content. When metastatic melanoma cells and fibroblasts were treated with exogeneous alpha1(IV)1263-1277, prior to incubation with alpha1(IV)1263-1277 PA liposomes, to potentially disrupt receptor/liposome interactions, a dose-dependent decrease in the amount of fluorophore delivered was observed. Overall, our results suggest that PA-targeted liposomes can be constructed and rationally fine-tuned for drug delivery applications based on lipid composition. The selectivity of alpha1(IV)1263-1277 PA liposomes for CD44/CSPG-containing cells represents a targeted-nanoDDS with potential for further development and application.

Dataset Information

Molecular ZIP codes in targeted drug delivery.

Publications

Molecular ZIP codes in targeted drug delivery.

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