Loading of Drugs to Poly Alkyl Cyanoacrylate Nanoparticles

The drugs were loaded to PACA nanoparticles, either by incorporation during the polymerization process or by absorption onto the surface of the preformed particles. The former case can lead to the covalent coupling of the drug to the polymer,26 or to the formation of a solid solution or solid dispersion of the drug in the polymer network. The addition of the drug to empty nanoparticles may lead to covalent coupling27 of the drug; alternatively, the drug may be bound by sorption. The sorption can also lead either to the diffusion of the drug into the polymer network and the formation of a solid solution,28 or to surface adsorption of the drug.29 In the majority of cases, the type of drug loading will determine the carrier capacity. The carrier capacity is defined as the percentage of drug associated with a given amount of nanoparticles for a given initial concentration of drug without considering the characteristics of the adsorption isotherm.30,31 Several drugs such as betaxolol

32 33 34

chlorhydrate, hematoporphyrin, and primaquine were adsorbed onto the preformed PACA nanoparticles, whereas drugs such as doxorubicin35 and actinomycin D were incorporated into the nanoparticles during the polymerization process. The incorporation of rose bengal into the poly (butyl-2-cyanoacrylate) nanoparticles during the polymerization led to much greater carrier capacity than did the simple adsorption method.29 The rose bengal incorporated into nanoparticles during polymerization is expected to be either dissolved, dispersed in, or adsorbed on the polymer matrix and remaining to be adsorbed on the particle surface. In contrast, after the adsorption process, the drug solely occupies the external surface of the nanoparticles, including minor pores and pits. Adsorption of hematoporphyrin onto PIBCA nanoparticles resulted in poor carrier capacity of the nanoparticles, because the drug was adsorbed mainly at the surface of the nano-particles.33 A similar report by Beck et al.28 describes the preparation of PBCA nanoparticles loaded with mitoxantrone using both the incorporation and adsorption methods. The proportion of mitoxantrone bound to the particles was analyzed to be about 15% of the initial drug concentration with the incorporation method and about 8% with the adsorption method.

The type of drug binding onto the nanoparticles may result in different release mechanisms and rates.36 Whether the drug is present in the form of a solid solution or a solid dispersion, its release characteristics mainly depend on the degradation rate of the polymer.30 Drug desorption (tested in phosphate buffered medium pH 5.9) resulted essentially from a shift in the equilibrium conditions between free and adsorbed drug following the dilution of the nanoparticle suspension, modification of the pH conditions, or enzymatic hydrolysis by the added esterases. The release of hematopor-phyrin was very rapid at physiological temperature and pH, and hence would not be useful for in vivo applications.33 Finally, the surface charge of the particles and binding type between the drug and nanoparticles are the important parameters that determine the rate of desorption of the drug in the nanoparticles.32 Recently, Poupaert and Couvreur37 developed a computational derived structural model of doxorubicin interacting with oligomeric PACA in nanoparticles. The oligomeric PACAs are highly lipophilic entities and scavenge the amphiphilic doxorubicin during the polymerization process by extraction of protonated species from the aqueous environment to an increasingly lipophilic phase embodied by the growing PACAs. Interesting, hydrogen bonds were established between the N and H function of doxorubicin and the cyano groups of alkylcya-noacrylate. Therefore, the cohesion in this assembly comes from a blend of dipole-charge interaction, H-bonds, and hydrophobic forces. Upon hydrolytic erosion of the nanoparticles involving mainly the hydrolysis of ester groups to carboxylate, the assembly of doxorubicin-PACA tends to loosen the cohesion as the hydrophobic forces decline due to water intrusion and the increasing contribution of repulsive forces between anionic carboxylates. This creates, for example, a high local gradient of doxorubicin at the cell membrane surface, permitting MDR efflux to be overwhelmed. Very recently, heparin-PIBCA copolymer nanoparticles were developed as a carrier for hemoglobin,38 which was indicated for treatment in thrombosis oxygen-deprived pathologies. In water, these copolymers spontaneously form nanoparticles with a ciliated surface of heparin. The heparin bound to the nanoparticle preserved its antithrombotic activity. The bound hemoglobin also maintained its capacity to bind ligands.

The integration of drugs with polymerization additives was observed in the case of 5-fluor-ouracil (5-FU)-loaded PBCA nanoparticles.39 5-FU in acidic solution (pH 2-3) may interfere in the initiation process through its amino groups via the formation of zwitterions. The proposed zwitter-ionic mechanism of initiation was supported by the molecular weight profiles of the polymer, as determined by gel permeation chromatography, and the covalent linkage of the cytostatic to the main polymer chain. 1H NMR analyses demonstrated that a significant fraction of 5-FU was covalently bonded to the PBCA chains through its amino groups, preferentially through one of the two nitrogen atoms.

Stella et al.40 developed a new concept to target the folate-binding protein by designing poly (ethylene glycol) (PEG)-coated biodegradable nanoparticles coupled to folic acid. This system is the soluble form of the folate receptor that is over expressed on the surface of many tumoral cells.

The copolymer poly[aminopoly(ethylene glycol)cyanoacrylate-co-hexadecyl cyanoacrylate] [poly(H2NPEGCA-co-HDCA)] was synthesized, and their nanoparticles were prepared using the nanoprecipitation technique. The nanoparticles were then conjugated to the activated folic acid via PEG terminal amino groups and purified from unreacted products. The specific interaction between the conjugate folate-nanoparticles and the folate-binding protein was confirmed by surface plasmon resonance. This interaction did not occur with the nonconjugated nanoparticles used as a control.

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