Calcium Phosphate and Calcium Phosphosilicate Mediated Drug Delivery and Imaging - Intracellular Delivery: Fundamentals and Applications - page 728

that calcium phosphate nucleation and growth first occurs within the nanogel and
proceeds outward. Calcium phosphate growth is predicted to stop before the outer
surface of the nanogel is reached; owing to the colloidal stability of the hybrid
particles (Kakizawa 2004 ; Sugawara 2006 ). The outer surface of the hybrid parti-
cles, expected to consist of CHP polymer chains serve as a steric stabilizing agent
(Sugawara 2006 ). Applications for the nanogel hybrid calcium phosphate particles
(measuring approximately 40 nm in diameter) include protein and nucleic acid
delivery as well as bone-repair material (Sugawara 2006 ). Other approaches to
synthesize a hybrid polymer-calcium phosphate nanoparticle include the block
copolymer (Kakizawa 2002 ) and aniomer (Kakizawa 2006 ) self-assembly method
employed by Kakizawa et al . for gene therapy.

3.3 Liposome-Calcium Phosphate Systems

Liposomes have made the most progress as delivery systems for bioagents.
However, liposomes are undergoing further optimization to improve in vivo circu-
lation time and minimize negative effects on normal tissue while efficiently main-
taining a high level of accumulation and sustained drug release to target sites (Hong
1999 ). The advantage of liposomal systems is the potential to encapsulate hydro-
philic molecules in the interior cavity while hydrophobic molecules can be stored
within the phospholipid membrane (Zhang 2009 ).
Synthetic methods for the formation of calcium phosphate-liposome composite
systems include the precipitation of calcium followed by phosphate on the exte-
rior of the liposome forming a CP shell with a liposome/solvent core forming
particles 45-100 nm in diameter (Schmidt 2002 ). Another technique involves the
coprecipitation of supersaturated solutions containing calcium and phosphate on
1,2-dioleoylsn-glycero-3-phosphate (DOPA) liposomes. In this method, carboxy-
ethylphosphoric acid (CEPA) is used as a surface capping agent, preventing addi-
tional precipitation of CP and thus controlling size to around 100-200 nm
(Schmidt 2004 ). The calcium phosphate shell is intended to mitigate the leaky
nature of liposomes by supporting the liposome and protecting its contents from
degradation while in the bloodstream.
Similarly, Chen et al . encapsulated carboxy-seminapthorhodafluor (carboxyS-
NARF-1) in liposomes with a calcium phosphate shell (Chen 2010 ). In this
approach, carboxySNARF-1 was prepared in a phosphate buffered solution which
was used in the synthesis of the L-a-phosphatidylcholine (EPC) liposomes. To
form the calcium phosphate shell on the surface, the carboxySNARF-1 EPC lipo-
somes were added to a calcium chloride solution which initiates the precipitation
of calcium phosphate with the already present phosphate. Again, CEPA was used
as a capping agent to control particle size (Chen 2010 ). The ability to encapsulate
carboxy-SNARF-1 (a pH sensitive dye) has applications in sensing and imaging.
In contrast to the previous systems in which a liposomal core is surrounded
by a calcium phosphate shell, Zhou et al . synthesized nanoparticles consisting of