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Cyclodextrin-containing polymers: versatile platforms of drug delivery materials.

Heidel JD, Schluep T - J Drug Deliv (2012)

Bottom Line: As is discussed in this paper, CDPs can incorporate therapeutic payloads into nanoparticles via covalent attachment of prodrug/drug molecules to the polymer (the basis of the Cyclosert platform) or by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads (the basis of the RONDEL platform).For each of these two approaches, we review the relevant molecular architecture and its rationale, discuss the physicochemical and biological properties of these nanoparticles, and detail the progress of leading drug candidates for each that have achieved clinical evaluation.Finally, we look ahead to potential future directions of investigation and product candidates based upon this technology.

View Article: PubMed Central - PubMed

Affiliation: Calando Pharmaceuticals, Inc., 225 South Lake Avenue, Suite 300, Pasadena, CA 91101, USA.

ABSTRACT
Nanoparticles are being widely explored as potential therapeutics for numerous applications in medicine and have been shown to significantly improve the circulation, biodistribution, efficacy, and safety profiles of multiple classes of drugs. One leading class of nanoparticles involves the use of linear, cyclodextrin-containing polymers (CDPs). As is discussed in this paper, CDPs can incorporate therapeutic payloads into nanoparticles via covalent attachment of prodrug/drug molecules to the polymer (the basis of the Cyclosert platform) or by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads (the basis of the RONDEL platform). For each of these two approaches, we review the relevant molecular architecture and its rationale, discuss the physicochemical and biological properties of these nanoparticles, and detail the progress of leading drug candidates for each that have achieved clinical evaluation. Finally, we look ahead to potential future directions of investigation and product candidates based upon this technology.

No MeSH data available.


Formation of inclusion complexes between adamantane (AD) and β-cyclodextrin allows straightforward, noncovalent incorporation of stabilizing (via PEG-AD conjugates) and/or targeting (via ligand-PEG-AD conjugates) components to a polymer-nucleic acid nanoparticles (polyplex) (Figure from [21]).
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fig7: Formation of inclusion complexes between adamantane (AD) and β-cyclodextrin allows straightforward, noncovalent incorporation of stabilizing (via PEG-AD conjugates) and/or targeting (via ligand-PEG-AD conjugates) components to a polymer-nucleic acid nanoparticles (polyplex) (Figure from [21]).

Mentions: While PEGylation of cationic polymer-based nanoparticles to extend circulation times and prevent aggregation was widely performed, it typically required covalent attachment of PEG at the same polymer functional sites required for nucleic acid binding. This tradeoff is undesirable, and it was overcome in this case due to exploitation of the β-CD moiety within CAL101 (Figure 7). Forming strong noncovalent inclusion complexes with β-CD (association constant of ~ 104-105 M−1), adamantane (AD) was conjugated to one terminus of a linear PEG (AD-PEG) and added to CAL101 either before (pre-PEGylation) or after (post-PEGylation) CAL101 had been combined with the nucleic acid of interest. In this manner, simple physical mixing of these components was sufficient to achieve sufficient interaction and incorporation of AD-PEG into the nanoparticles. A minimum PEG length of 5 kDa was shown to be required to prevent salt-induced aggregation of these nanoparticles [21], and thermodynamic analysis suggests that length-dependent interactions among PEG chains on the surface of nanoparticles contribute significantly to the effective stabilization [36]. This AD-PEG5000 conjugate was the focus of future development work for this RONDEL delivery platform as well as clinical translation of the CALAA-01 therapeutic candidate.


Cyclodextrin-containing polymers: versatile platforms of drug delivery materials.

Heidel JD, Schluep T - J Drug Deliv (2012)

Formation of inclusion complexes between adamantane (AD) and β-cyclodextrin allows straightforward, noncovalent incorporation of stabilizing (via PEG-AD conjugates) and/or targeting (via ligand-PEG-AD conjugates) components to a polymer-nucleic acid nanoparticles (polyplex) (Figure from [21]).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3307009&req=5

fig7: Formation of inclusion complexes between adamantane (AD) and β-cyclodextrin allows straightforward, noncovalent incorporation of stabilizing (via PEG-AD conjugates) and/or targeting (via ligand-PEG-AD conjugates) components to a polymer-nucleic acid nanoparticles (polyplex) (Figure from [21]).
Mentions: While PEGylation of cationic polymer-based nanoparticles to extend circulation times and prevent aggregation was widely performed, it typically required covalent attachment of PEG at the same polymer functional sites required for nucleic acid binding. This tradeoff is undesirable, and it was overcome in this case due to exploitation of the β-CD moiety within CAL101 (Figure 7). Forming strong noncovalent inclusion complexes with β-CD (association constant of ~ 104-105 M−1), adamantane (AD) was conjugated to one terminus of a linear PEG (AD-PEG) and added to CAL101 either before (pre-PEGylation) or after (post-PEGylation) CAL101 had been combined with the nucleic acid of interest. In this manner, simple physical mixing of these components was sufficient to achieve sufficient interaction and incorporation of AD-PEG into the nanoparticles. A minimum PEG length of 5 kDa was shown to be required to prevent salt-induced aggregation of these nanoparticles [21], and thermodynamic analysis suggests that length-dependent interactions among PEG chains on the surface of nanoparticles contribute significantly to the effective stabilization [36]. This AD-PEG5000 conjugate was the focus of future development work for this RONDEL delivery platform as well as clinical translation of the CALAA-01 therapeutic candidate.

Bottom Line: As is discussed in this paper, CDPs can incorporate therapeutic payloads into nanoparticles via covalent attachment of prodrug/drug molecules to the polymer (the basis of the Cyclosert platform) or by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads (the basis of the RONDEL platform).For each of these two approaches, we review the relevant molecular architecture and its rationale, discuss the physicochemical and biological properties of these nanoparticles, and detail the progress of leading drug candidates for each that have achieved clinical evaluation.Finally, we look ahead to potential future directions of investigation and product candidates based upon this technology.

View Article: PubMed Central - PubMed

Affiliation: Calando Pharmaceuticals, Inc., 225 South Lake Avenue, Suite 300, Pasadena, CA 91101, USA.

ABSTRACT
Nanoparticles are being widely explored as potential therapeutics for numerous applications in medicine and have been shown to significantly improve the circulation, biodistribution, efficacy, and safety profiles of multiple classes of drugs. One leading class of nanoparticles involves the use of linear, cyclodextrin-containing polymers (CDPs). As is discussed in this paper, CDPs can incorporate therapeutic payloads into nanoparticles via covalent attachment of prodrug/drug molecules to the polymer (the basis of the Cyclosert platform) or by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads (the basis of the RONDEL platform). For each of these two approaches, we review the relevant molecular architecture and its rationale, discuss the physicochemical and biological properties of these nanoparticles, and detail the progress of leading drug candidates for each that have achieved clinical evaluation. Finally, we look ahead to potential future directions of investigation and product candidates based upon this technology.

No MeSH data available.