Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer

Abstract

The present study was carried out to investigate the potential of cationic functionalization on imatinib nanocrystals to improve the mucoadhesiveness and, thus, delivery to the lesion of cervicovaginal tumors. Amino-group-functionalized imatinib nanocrystals (NC@PDA-NH2) were prepared with near-spheroid shape, nanoscale size distribution, positive zeta potential, and relatively high drug content with the aid of the polydopamine-coating technique. Efficient interaction between NC@PDA-NH2 and mucin was proven by mucin adsorption which was related to the positive zeta-potential value of NC@PDA-NH2 and the change in the size distribution on mixing of NC@PDA-NH2 and mucin. Cellular uptake, growth inhibition, and apoptosis induction in cervicovaginal cancer-related cells demonstrated the superiority of NC@PDA-NH2 over unmodified nanocrystals. For practical intravaginal administration, NC@PDA-NH2 was dispersed in Pluronic F127-based thermosensitive in situ hydrogel, which showed suitable gelation temperature and sustained-release profiles. In comparison with unmodified nanocrystals, NC@PDA-NH2 exhibited extended residence on ex vivo murine vaginal mucosa, prolonged in vivo intravaginal residence, and enhanced inhibition on the growth of murine orthotopic cervicovaginal model tumors indicated by smaller tumor size, longer median survival time, and more intratumor apoptosis with negligible mucosal toxicity. In conclusion, cationic functionalization endowed NC@PDA-NH2 significant mucoadhesiveness and, thus, good potential against cervicovaginal cancer via intravaginal administration.

Polydopamine-Based “Four-in-One” Versatile Nanoplatforms for Targeted Dual Chemo and Photothermal Synergistic Cancer Therapy

“…In particular, PDA has many advantages in applications of nanoscale drug delivery systems. Firstly, PDA films have a dense crosslinked structure that can entirely encapsulate drug nanocarriers, increasing their in vivo stability and avoid premature drug release [31,32,33]. Secondly, the large number of quinone groups on the surface of PDA is able to react easily with amino- and thiol-containing materials, enabling surface modification such as conjugation with PEG and tumor-targeting ligands [31,34,35,36].…”

Injectable hydrogels for anti‐tumour treatment: a review

“…According to reports, the electrostatic interaction of cation‐functionalised chemotherapeutic drugs with negatively charged mucin in mucus and mucosal epithelial cells can significantly prolong the residence time of the drug at the cancer site and improve the anti‐tumour effect by elevating the mucosal permeability [63, 64]. Ci et al [65] prepared polyimide functionalised imatinib nanocrystals (NC@PDA–NH 2 ) using PDA coating technology, and the thermosensitive Pluronic® F127 hydrogel was used as a carrier to slowly release NC@PDA‐NH 2 . It can be seen from the analysis of mucin adsorption that NC@PDA‐NH 2 exhibits an enhanced interaction with mucin compared to that of unmodified nanocrystals and exhibits an extended residence time on the vaginal mucosa of isolated mice.…”

Transmucosal Absorption Enhancers in the Drug Delivery Field

“…While PEs primarily act to improve systemic absorption of poorly permeable actives, which can be achieved by enzyme inhibition, mucoadhesion and direct alteration to barrier integrity, these same functions may assist penetration of actives into tumors. Ci et al [50] assessed the effect of a hydrogel containing cationic nanocrystals of imatinib/TPGS coated with polydopamine, to improve localization and penetration in a model of cervical cancer. The introduction of a cationic coating (polydopamine) inverted the zeta potential of imatinib nanocrystals from −9.27 mV to +27.25 mV and improved binding to mucin.…”