Dual acid-responsive supramolecular nanoparticles as new anticancer drug delivery systems

Abstract

Considering the specific pH gradients of tumour microenvironments, a dual acid-responsive drug delivery system, which can respond to the tumor extracellular and intercellular pH stimuli, has been fabricated via simple host-guest recognition. Firstly, we synthesise 2,4,6-trimethoxybenzaldehyde modified dextran (Dex-TMBA) and mPEG-imine-β-cyclodextrin (PIC), respectively. And then, through the host-guest recognition between the cyclodextrin (CD) of PIC and the benzene ring of Dex-TMBA, a kind of dual acid-responsive supramolecular drug delivery system can be fabricated. Under neutral pH conditions, anticancer drugs can be loaded by forming supramolecular nanoparticles via the host-guest recognition. While, at tumor extracellular pH (∼6.8), the acid-labile benzoic-imine of PIC cleaves and the nanoparticles are amino positively charged to facilitate cell internalization. Subsequently, due to the hydrolysis of acetal bonds in Dex-TMBA under significantly increased acidity in subcellular compartments such as the endosomes (∼5.3), the loaded doxorubicin releases from the endocytosed drug delivery. This dual acid-responsive nanoparticles can efficiently load and release drugs, acting as drug delivery systems for enhancing anticancer efficiency.

Benzoic‐Imine‐Based Physiological‐pH‐Responsive Materials for Biomedical Applications

“…In another system, nanoaggregates of mPEGÀimine/b-cyclodextrin was synthesized and showede nhanced cell internalization through the switchable positive surfacec harge. [78] Ac omplexo fs iRNA with PEGÀPLLÀ CA was also found to significantly suppress the tumor by decreasingt he mRNAe xpression level on am ousem odel that was grafted with prostate carcinoma, whilst no toxicity and an undesirable immunological responsewere observed. [79] Triggering the active targeting property by using benzoicimine-bonded PEGylation was reportedb yQ uan et al [80] The RGD peptide was mounted onto the hydrophilic shell of polymeric micelles and furthers hielded by the PEG moiety at neutral pH value.…”

“…Further dissociation of the micelles at pH≈5.0 facilitated drug release and the diffusion of DOX into the nucleus. In another system, nanoaggregates of mPEG−imine/β‐cyclodextrin was synthesized and showed enhanced cell internalization through the switchable positive surface charge . A complex of siRNA with PEG−PLL−CA was also found to significantly suppress the tumor by decreasing the mRNA expression level on a mouse model that was grafted with prostate carcinoma, whilst no toxicity and an undesirable immunological response were observed…”

Multifunctional Polymer Nanocarrier for Efficient Targeted Cellular and Subcellular Anticancer Drug Delivery

“…The final synthetic step was coupling of the functional PEO to the amphiphilic diblock copolymer H 2 N-PLA-PDMAEMA-TPP + through the formation of pH-sensitive aromatic imine group (Scheme c). The benzoic imine bond, hydrolyzable at slightly acidic pH (∼6.8) while stable at neutral and basic conditions, was recently investigated and successfully introduced into several drug delivery systems. − The presence of such a link, cleavable at slightly acidic conditions, in the junction point between the PEO and the PLA blocks of current multifunctional triblock copolymer is intended to ensure both the “stealth” properties during nanocarrier’s circulation in the bloodstream and the detachment of the PEO block in the vicinity of tumor site where the extracellular pH is approximately 6.8, thus enhancing cell internalization. The reaction between the primary amine and aldehyde end groups of the two functional polymers was performed in dry DMF under mild conditions.…”

Method for the Instant In-Flight Manufacture of Black Phosphorus to Assemble Core@Shell Nanocomposites for Targeted Photoimmunotherapy

“…Cyanine 5.5 (Cy5.5)-labeled PD-L1 was included in the nanocomposites instead of PD-L1 to measure the amount of released peptide as fluorescence intensity. Upon a decrease in pH from 7.4 to 6.5, the fluorescence intensity increased significantly, likely due to cleavage of imine bonds at pH 6.5−6.8 through the protonation of PLL in H. 40,41 This response may be suitable to release PD-L1 in the tumor extracellular environment, which has typically neutral to slightly acidic pH (6.5−7.0). 42 Intracellular uptake of BP@DHCA nanocomposites into HCT-116 (human colon cancer) and B-16 (murine tumor) cells was evaluated by fluorescence-activated cell sorting (FACS) and confocal microscopy.…”