Charge‐Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery

Abstract

DNA‐toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane‐associated but also many intracellular drug‐resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug‐resistance barriers. The cationic polymer poly(L‐lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in‐vivo applications. Herein, PLL is used to demonstrate a pH‐triggered charge‐reversal carrier to solve this problem. PLL's primary amines are amidized as acid‐labile β‐carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid‐labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer‐cell targeted nuclear‐localization polymer–drug conjugate has, thereby, been developed by introducing folic‐acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA‐PLL/amide‐CPT). The conjugate efficiently enters folate‐receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular cleavable disulfide bonds shows much improved cytotoxicity.

In vitro evaluation of anticancer nanomedicines based on doxorubicin and amphiphilic Y-shaped copolymers

“…pH 7.4 (Figure 7), which corresponded to the pHs of late endosomes, tumor tissue, and the circulatory system, respectively. 36 The accelerated DOX release at acidic pH can be attributed to the acid hydrolysis of ester bonds and the improvement of DOX solubility. 37 In addition, it needs to be pointed out that all the nanomedicines displayed a relatively severe burst release in the current work, due to the weak interaction between P(LA-co-GA) and DOX.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…Mixed colocalization with cytoplasm, lysosomes, and nucleus after 12 h incubation confirmed the endolysosomal destabilization and cytoplasmic release. [11,136] Jiang et al used α,β-unsaturated ketone-caged coumarin derivatives to monitor endosomal escape and consequent cytosolic disintegration of polymer nanocarriers. These micellar nanoparticles were obtained by temperature-induced self-assembly of a diblcok copolymer composed of a hydrophilic PEG block and a thermosensitive poly(di(ethylene glycol) monomethyl ether methacrylate) that was modified with an α,β-unsaturated ketone-caged coumarin derivative.…”

“…Upon endocytic internalization and lysosomal accumulation, the acidic pH caused cleavage of acid β-carboxylic acid-amide bond and restoration of the positively charged lysine amine groups. [11] Kataoka and co-workers developed a series of charge-reversal delivery systems that were used to deliver pDNA and small interfering RNA (siRNA). In one example, polyplexes assembled from poly(aspartamide) derivatives bearing 1,2-diaminoethane side chains and pDNA were designed.…”

“…Positive charges [103] Linear polymers [24,[104][105][106][107]113,[116][117][118][119][120][121][122][123][124] Branched polymers [24,106,113,115,116,[125][126][127] Dendrimers [108][109][110][111][112]116] Charge-reversal [103] Linear polymers [11,22,129,132,133,135] Micelles [128,130,131,134,236] Dendrimers [136] Volumetric expansion Nanoparticles [237] Membranedisrupting peptides Endosomes/ lysosomes [102] N-terminal HA2 peptide derivative Linear polymers [21] INF-7 peptide Linear polymers [137,138] GALA PEGylated liposomes …”

“…[9] The decoration of nanoparticles, micelles, and linear polymers with folic acid (FA) has been shown to result in enhanced intracellular accumulation in folate positive cell lines as compared to the receptornegative cells. [9][10][11] The α v β 3 integrin is another receptor that is frequently targeted and exploited to enhance cellular internalization by decorating delivery systems with the arginine-glycine-aspartic acid tripeptide ligand. [12][13][14] A third example of a receptor that is exploited for tumor targeting is the epidermal growth factor receptor (EGFR), which is generally overexpressed and therefore used in the treatment of neck cancer, glioblastoma, and lung adenocarcinoma.…”