Sequential drug delivery by injectable macroporous hydrogels for combined photodynamic-chemotherapy

Yuanyuan Zhong,Zhenghao Zhou,Li Zhang,Dongzhi Yang,Shian Sun,Hao Hong,Yunsu Ma

doi:10.1186/s12951-021-01066-1

Abstract

With hollow mesoporous silica (hMSN) and injectable macroporous hydrogel (Gel) used as the internal and external drug-loading material respectively, a sequential drug delivery system DOX-CA4P@Gel was constructed, in which combretastatin A4 phosphate (CA4P) and doxorubicin (DOX) were both loaded. The anti-angiogenic drug, CA4P was initially released due to the degradation of Gel, followed by the anti-cell proliferative drug, DOX, released from hMSN in tumor microenvironment. Results showed that CA4P was mainly released at the early stage. At 48 h, CA4P release reached 71.08%, while DOX was only 24.39%. At 144 h, CA4P was 78.20%, while DOX release significantly increased to 61.60%, showing an obvious sequential release behavior. Photodynamic properties of porphyrin endow hydrogel (ϕΔ(Gel) = 0.91) with enhanced tumor therapy effect. In vitro and in vivo experiments showed that dual drugs treated groups have better tumor inhibition than solo drug under near infrared laser irradiation, indicating the effectivity of combined photodynamic-chemotherapy.

Highlights

Cancer is still one of the significant threats to human health
The amount of chitosan affected the formation and degradation of hydrogel, results showed in Additional file 1: Table S2 indicated that 73% was optimal for getting fast formation and slowly degradation
With biocompatible dextran oxide, chitosan, porphyrin and Hollow mesoporous silica nanoparticle (hMSN) as the starting materials, a dual drug carrying system DOX-combretastatin A4 phosphate (CA4P)@Gel was constructed, which could be injected in tumor and play therapeutic roles in situ

Summary

Introduction

Cancer is still one of the significant threats to human health. Current cancer therapies, such as chemotherapy [1], phototherapy [2], hyperthermia [3] and radiotherapy [4], are widely applied but they have their own limited properties or unavoidable side effects. Anti-angiogenesis combined with anti-cell proliferation has become a novel tumor therapy strategy, which was referred as “A+ strategy” [11] When both drugs were applied to the tumor site at the right time, they could maximize the therapeutic effect. Kim et al [17] prepared a hydrogel/ microsphere composite, which could sequentially release doxorubicin (DOX) and fluorouracil (Fu) in tumors. We designed and prepared a novel injectable macroporous hydrogel for therapy of 4T1 breast cancer, which could load dual distinct tumor drugs (CA4P and DOX) offering a sequentially delivery profile. The mixture of DOX@ hMSN and NH2-TPP with a mass ratio of 1:5 was dissolved in DMF to acquire system ‘A’, and CA4P was mixed with oxidized dextran at a ratio of 1:1 (in PBS) to prepare system ‘B’. DOX release was calculated by determining unbound DOX in the solution with UV-vis spectrometry [26]

Evaluation of singlet oxygen generation efficiency

Results and discussion

Conclusions