Poly(amidoamine)-Modified Mesoporous Silica Nanoparticles As A Mucoadhesive Drug Delivery System For Intravesical Perfusion

Bladder cancer,with the highest recurrence rate in all malignancy,is a common urologic cancer that arises on the bladder mucosa.Currently,tumor resection followed by intravesical chemotherapy is the primary treatment of bladder cancer,which has limited effectiveness ascribe to short dwell-time of intravesical drugs in bladder.It is very important for prolonging the drug retention time to improve the bioavailability of drugs in the intravesical chemotherapy.Therefore,there is a need to develop mucoadhesive and sustained drug delivery systems to increase drug residence time for intravesical chemotherapy.Poly(amidoamine)(PAMAM)show good adhesion can be explained by electrostatic interactions between positively charged dendrimers and negatively charged mucin.Mesoporous silicon nanoparticles(MSNPs)are natural inorganic materials with excellent biocompatibility,easily surface modification and large specific surface area and surface aperture.They are used as drug carriers,genes and vaccines in the field of biomedicine for drug sustained release and targeted drug release.In this study,a series of PAMAM-modified MSNPs(MSNPs-G0～MSNPs-G3)as mucoadhesive drug delivery systems were prepared by grafting zero-to-three generation PAMAM dendrimers onto the surface of MSNPs.The mucoadhesive properties were assessed via residence time on the porcine bladder wall using fluorescein isothiocyanate-labeled MSNPs(FITC-MSNPs).An anticancer drug,doxorubicin(Dox),was encapsulated in the core of PAMAM-modified MSNPs to form Dox-loaded nanoparticles for intravesical therapy.Drug loading capacity and release profiles were investigated,and the mechanism of drug release was revealed.Finally,the mucoadhesive capacities of Dox-loaded PAMAM-modified MSNPs were investigated for potential bladder cancer therapy.The results are as follows:(1)The results of transmission electron microscopy(TEM)showed that the MSNPs had uniform particle size,and the spherical size was about 55 ± 7 nm.After PAMAM modification,the morphology and particle size remained unchanged.The results of BET showed that MSNPs had larger specific surface area and surface pore,with sizes of 564.0 m3 g-1 and 2.9 nm,respectively.(2)The results of FT-IR and TGA show that the MSNPs surface has been successfully grafted onto PAMAM of different generation.The approximate hydrodynamic diameters of MSNPs-G0 ~ MSNPs-G3 showed that PAMAM modification had no effect on the hydrodynamic diameters of MSNPs.After seven days,the hydrodynamic diameters of MSNPs-G0 and MSNPs-G3 reached 361.7 ± 86.36 nm(PDI 0.48)and 589.1 ± 49.21 nm(PDI 0.70),respectively,while the diameters of MSNPs-G1,MSNPsG2 did not change significantly.This indicates that MSNPs-G1,MSNPs-G2 have good colloid stability.(3)No significant differences in the encapsulation efficiency(%EE)and loading capacity(%LC)were found for PAMAM-modified MSNPs,indicating that the modification of PAMAM onto MSNPs had no effect on the loading capacity of MSNPs.The release of drug-loaded nanoparticles in artificial urine at 37 ℃ indicated that the drug release rate remarkably decreased after PAMAM was added on the nanoparticle surface.(4)The results showed that the hydrodynamic size of MSNPs-G2 after mixing with mucin was higher than that of MSNPs-G0/mucin or MSNPs-G1/mucin,indicating that the mucoadhesivity of PAMAM-modified MSNPs to mucin increased upon an increase in the number of PAMAM amino groups.The results of mucoadhesive properties of PAMAM-modified MSNPs on the bladder wall are consistent with those obtained from mucin-particles studies.The result revealed that the MSNPs-G2 was non-toxic to UMUC-3 cells even at concentrations up to 250 μg m L-1.On the contrary,obvious inhibition of UMUC-3 cells growth was observed when the cells were incubated with free Dox or Dox@MSNPs-G2.(5)The present study demonstrates that mucoadhesive and sustained drug release properties of MSNPs can be controlled by the layer number of PAMAM on the nanoparticle surface.The obtained data demonstrated that MSNPs-G2 showed highest mucoadhesivity to bladder wall as compared with other nanoparticles.Moreover,sustained drug release of Dox@MSNPs-G2 triggered by acidic p H was achieved in artificial urine.All these results indicated the potential of Dox@MSNPs-G2 as mucoadhesive drug delivery systems for intravesical chemotherapy.