Limits...
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.


Effect of imidazole incorporation within CDP upon gene delivery efficiency and intracellular siRNA release. (a) Incorporation of an imidazole derivative within CDP (CDPim) leads to a significant increase in transgene (luciferase) expression levels in transfected HeLa and BHK-21 cells (from [33]). (b) Imidazole incorporation (CDPimid) yields a significant (~4x) increase in the fraction of intracellular siRNA that is released from the polymer and able to migrate through an agarose gel when electrophoresed (from [34]).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3307009&req=5

fig6: Effect of imidazole incorporation within CDP upon gene delivery efficiency and intracellular siRNA release. (a) Incorporation of an imidazole derivative within CDP (CDPim) leads to a significant increase in transgene (luciferase) expression levels in transfected HeLa and BHK-21 cells (from [33]). (b) Imidazole incorporation (CDPimid) yields a significant (~4x) increase in the fraction of intracellular siRNA that is released from the polymer and able to migrate through an agarose gel when electrophoresed (from [34]).

Mentions: The three primary cyclodextrins (CDs)—α, β, and γ—are cyclic oligomers comprised of 6, 7, and 8 glucose moieties, respectively. Functionalization and polymerization efforts were conducted with these cyclodextrin species as part of several studies to assess structure-activity relationships (SARs) of cationic polymers varying in properties such as carbohydrate size, carbohydrate distance from charge centers, and charge center type [28–31]. In general, the cyclodextrins were difunctionalized and reacted with a difunctional comonomer to yield linear, AB-type copolymers (Figure 4). A number of trends emerged from these SAR studies (Table 4) which led to the identification of a preferred structure for the CD-containing polymer (CDP) which was the focus of further development (Figure 5). Designated as “βCDP6,” “CDPim,” or “CAL101” in various publications (hereafter referred to as CAL101), this polymer is made by copolymerization of β-CD diamine and dimethylsuberimidate (which imparts two amidine charge centers separated by six methylene units), and its termini are modified to contain an imidazole derivative. This modification has been shown to facilitate enhanced transgene expression from a plasmid DNA (pDNA) payload and to significantly release intracellular release of siRNA (Figure 6). Nanoparticles made with CAL101 and pDNA yielded significant gene delivery in transfected cultured cells, comparable to that of leading commercially available transfection reagents, with low cytotoxicity. Despite this in vitro potency, these charged colloidal CAL101/nucleic acid nanoparticles rapidly aggregate in physiological medium, rendering them unfit for in vivo application; this phenomenon motivated investigation into incorporation of a stabilizing agent.


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

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

Effect of imidazole incorporation within CDP upon gene delivery efficiency and intracellular siRNA release. (a) Incorporation of an imidazole derivative within CDP (CDPim) leads to a significant increase in transgene (luciferase) expression levels in transfected HeLa and BHK-21 cells (from [33]). (b) Imidazole incorporation (CDPimid) yields a significant (~4x) increase in the fraction of intracellular siRNA that is released from the polymer and able to migrate through an agarose gel when electrophoresed (from [34]).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Effect of imidazole incorporation within CDP upon gene delivery efficiency and intracellular siRNA release. (a) Incorporation of an imidazole derivative within CDP (CDPim) leads to a significant increase in transgene (luciferase) expression levels in transfected HeLa and BHK-21 cells (from [33]). (b) Imidazole incorporation (CDPimid) yields a significant (~4x) increase in the fraction of intracellular siRNA that is released from the polymer and able to migrate through an agarose gel when electrophoresed (from [34]).
Mentions: The three primary cyclodextrins (CDs)—α, β, and γ—are cyclic oligomers comprised of 6, 7, and 8 glucose moieties, respectively. Functionalization and polymerization efforts were conducted with these cyclodextrin species as part of several studies to assess structure-activity relationships (SARs) of cationic polymers varying in properties such as carbohydrate size, carbohydrate distance from charge centers, and charge center type [28–31]. In general, the cyclodextrins were difunctionalized and reacted with a difunctional comonomer to yield linear, AB-type copolymers (Figure 4). A number of trends emerged from these SAR studies (Table 4) which led to the identification of a preferred structure for the CD-containing polymer (CDP) which was the focus of further development (Figure 5). Designated as “βCDP6,” “CDPim,” or “CAL101” in various publications (hereafter referred to as CAL101), this polymer is made by copolymerization of β-CD diamine and dimethylsuberimidate (which imparts two amidine charge centers separated by six methylene units), and its termini are modified to contain an imidazole derivative. This modification has been shown to facilitate enhanced transgene expression from a plasmid DNA (pDNA) payload and to significantly release intracellular release of siRNA (Figure 6). Nanoparticles made with CAL101 and pDNA yielded significant gene delivery in transfected cultured cells, comparable to that of leading commercially available transfection reagents, with low cytotoxicity. Despite this in vitro potency, these charged colloidal CAL101/nucleic acid nanoparticles rapidly aggregate in physiological medium, rendering them unfit for in vivo application; this phenomenon motivated investigation into incorporation of a stabilizing agent.

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.