Multistage Nanovehicle Delivery System Based on Stepwise Size Reduction and Charge Reversal for Programmed Nuclear Targeting of Systemically Administered Anticancer Drugs

Abstract

The nucleus is the final target of many first‐line chemotherapeutics, but the need to overcome multiple physiological barriers imposes conflicting requirements for size and charge on systemically administered drug delivery systems. Here, an N‐(2‐hydroxypropyl) methacrylamide (HPMA) polymer‐based nanovehicle (PNV) that self‐assembles from anionic HPMA copolymers with charge‐reversal ability and cationic HPMA copolymers with intracellularly detachable subgroups (IDS) is described. The IDS, bearing an anticancer drug and nuclear‐homing cell‐penetrating peptide (R8NLS ligand), is grafted onto the HPMA copolymer via hydrazone linkage. The large, neutrally charged, self‐assembled PNV (≈55 nm) shows good blood persistence and preferential tumor accumulation. After tumoral arrival, the extracellular milieu actuates the disassembly of PNV to linear conjugates (≈10 nm/39 kDa). This first‐stage size reduction exposes R8NLS and allows for deeper tissue penetration and greater cellular internalization. After endocytosis, a second‐stage size reduction occurs when the more acidic endolysosomal pH cleaved the ≈2.4 kDa IDS off the HPMA copolymer backbone and guaranteed the successful nuclear entry via nuclear localization signal assistance. Based on the stepwise size reduction and on‐demand R8NLS exposure, the PNV inhibits growth of HeLa tumors in nude mice by 75%. This work gives important insights into the design of systemic nuclear‐targeted delivery via a multistage size/charge changing way.

A Step‐by‐Step Multiple Stimuli‐Responsive Nanoplatform for Enhancing Combined Chemo‐Photodynamic Therapy

“…[1][2][3][4][5] These nanoparticles are commonly injected intravenously, and during cargo delivery, they encounter various biological barriers in vivo, including blood circulation, tumor tissue penetration, cell internalization, and intracellular trafficking. [7,8] Then the nanoparticles must efficiently enter cells, rapidly escape from endosomes, and release the drug to the cellular compartments in a timely manner. [7,8] Then the nanoparticles must efficiently enter cells, rapidly escape from endosomes, and release the drug to the cellular compartments in a timely manner.…”

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

“…[18][19][20][21][22][23] For example, Yuan et al 24 prepared a charge-switchable nanoparticle (S-NP/DOX) based on zwitterionic polymers. The S-NP/DOX remained negative surface charge in the blood circulation system and switched to positive surface charge in response to the tumor acidity; the tumor-acidity-activated charge conversion could effectively increase the cellular uptake of the carriers and the intracellular concentrations of DOX and, in turn, resulted in enhancing tumor inhibitions.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…Based on the stepwise size reduction and on-demand R8NLS exposure, the polymer-based nanovehicle (PNV) inhibited the growth of HeLa tumors in mice by 75%. [63] Another interesting approach to enhance nuclear delivery is based on the nuclear factor kappa B (NFkB) transcription factor. NFkB is a transcription factor containing both a DNA-binding domain and an NLS domain.…”

“…Both linear poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) as well as poly(amidoamine) (PAMAM) dendrimers modified with hydrazide groups have been used to couple Dox via hydrazone linkers. [32,[55][56][57][58][59][60][61][62][63] HPMA polymers bearing hydrazone linkages have also been explored for the delivery of other anticancer drugs such as paclitaxel and docetaxel. [64] The hydrazone motif has also been used to prepare micelles and nanoparticles that allow pH-dependent release of Figure 1.…”

“…[147] Flierl et al used another approach to overcome the size limitations. In this work, an MTS peptide-peptide nucleic acid (PNA) conjugate was annealed to an oligonucleotide with a complementary PNA sequence and the complex was Linear polymer [177] α,β-Importins Nuclear localization signals (NLSs) [167,168,174,175] CGYGPKKKRKVGG Micelles [18] DRQIKIWFQNRRM-KWKK Nanoparticles [178] PKKRKV Nanoparticles [179] CVKRKKKP Linear polymers [63,79] Cytoplasmic NFkB Linear polymers [180,181] (11 of 26) 1700022 transferred into the cytosol using a PEI carrier. While the carrier allowed endosomal escape, the MTS targeting peptide directed the oligonucleotide to the mitochondria.…”