Background Like most protein macromolecular drugs, the half-life of rhIFNɑ-2b is short, with a low drug utilization rate, and the preparation and release conditions significantly affect its stability. Methods A nanoporous ion-responsive targeted drug delivery system (PIRTDDS) was designed to improve drug availability of rhIFNα-2b and target it to the lung passively with sustained release. Chitosan rhIFNα-2b carboxymethyl nanoporous microspheres (CS-rhIFNα-2b-CCPM) were prepared by the column method. Here, an electrostatic self-assembly technique was undertaken to improve and sustain rhIFNα-2b release rate. Results The size distribution of the microspheres was 5~15 μm, and the microspheres contained nanopores 300~400 nm in diameter. The in vitro release results showed that rhIFNα-2b and CCPM were mainly bound by ionic bonds. After self-assembling, the release mechanism was transformed into being membrane diffusion. The accumulative release amount for 24 hrs was 83.89%. Results from circular dichrogram and SDS-PAGE electrophoresis showed that there was no significant change in the secondary structure and purity of rhIFNα-2b. Results from inhibition rate experiments for A549 cell proliferation showed that the antitumor activity of CS-rhIFNα-2b-CCPM for 24 hrs retained 91.98% of the stock solution, which proved that the drug-loaded nanoporous microspheres maintained good drug activity. In vivo pharmacokinetic experimental results showed that the drugs in CS-rhIFNα-2b-CCPM can still be detected in vivo after 24 hrs, equivalent to the stock solution at 6 hrs, which indicated that CS-rhIFNα-2b-CCPM had a certain sustained-release effect in vivo. The results of in vivo tissue distribution showed that CS-rhIFNα-2b-CCPM was mainly concentrated in the lungs of mice (1.85 times the stock solution). The pharmacodynamics results showed that CS-rhIFNα-2b-CCPM had an obvious antitumor effect, and the tumor inhibition efficiency was 29.2%. Conclusion The results suggested a novel sustained-release formulation with higher drug availability and better lung targeting from CS-rhIFNα-2b-CCPM compared to the reference (the stock solution of rhIFNα-2b), and, thus, should be further studied.

Background: Protein drugs have disadvantages, such as short half-lives, unstable biological activities, and low utilization efficiency. Objective: In this paper, a porous ion-responsive targeted drug delivery system was designed, combining biodegradable carriers with ion exchange technology to overcome problems for protein drug delivery systems. Method: Carboxymethyl chitosan porous microspheres (CCPM) were prepared using an emulsification-chemical crosslinking method. Chitosan-bovine serum albumin-carboxymethyl chitosan porous microspheres (CBCCPM) were prepared using a dynamic ion exchange method and static self-assembly technology. Results: CCPM were round in appearance mostly with a particle size distribution of 5-15 μm, which facilitates passive targeting to the lungs. CCPM had a total ion exchange capacity of 9.97 ± 0.07 mmol/g and showed a strong ability to attract and contain positively charged drugs. A potentiometric titration curve was used to identify the dissociation behavior of exchangeable groups on the microspheres; the optimal pH for ion exchange of microspheres was ≥ 4.3. CCPM had ion responsiveness, in vitro degradation ability, thermal stability and biocompatibility. In vitro release results confirmed that BSA and CCPM were mainly bound together by ionic bonds and the drug release mechanism of the self-assembled microspheres changed from particle diffusion to membrane diffusion under pH 7.4 PBS solution containing 0.02% Tween 80. Circular dichroism and sodium dodecyl-sulfate polyacrylamide gel electrophoresis results showed no significant change in the secondary structure and purity of BSA after binding to CCPM. The cumulative in vitro release rate of microspheres after 24 hours was 86.78%. Conclusion: In this paper, CBCCPM, a porous ion-responsive targeted drug delivery system, was designed.

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The authors are regretful for submitting and approving the publication of incorrect Figure 4 in this article. Below is the corrected version along with the revised caption. The electronic version of the article has already been corrected.