A Transformable Amphiphilic and Block Polymer−Dendron Conjugate for Enhanced Tumor Penetration and Retention with Cellular Homeostasis Perturbation via Membrane Flow

Abstract

An approach for stealthy-to-sticky transition of nanomedicines has been demonstrated to augment the therapeutic efficacy: the nanomedicines are nonsticky (or "stealthy") during circulation in the bloodstream, but become sticky at tumor sites for effective interaction with cell membranes during capillary extravasation and cellular internalization. [2] For example, the pH-triggered charge reversal of tumor microenvironment-responsive nanomedicines has been reported to facilitate extravasation and penetration of anticancer agents into tumor tissues. [3] However, pH-triggered charge reversal cannot be realized in luminal or perivascular compartments due to their neutral pH environments. The mildly acidic regions in tumor tissues are often 100-200 µm away from the tumor vascular network, which prevents effective extravasation and penetration of anticancer agents via this approach. [3c,4] Additionally, the published work has been focused on the tumor penetration while the retention of delivered therapeutic agents at the tumor site is overlooked, which is another major bottleneck in tumor therapy.Enzymes that are abundantly expressed at the tumor invasion margin or in the angiogenesis area may serve as better alternative triggers for the stealthy-to-sticky transformation. Efficient penetration and retention of therapeutic agents in tumor tissuescan be realized through rational design of drug delivery systems. Herein, a polymer−dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), is presented, which allows a cathepsin-B-triggered stealthy-to-sticky structural transformation. The compositions and ratios are optimized through dissipative particle dynamics simulations. GFLG-DP displays tumor-specific transformation and the consequently released dendron-Ppa is found to effectively accumulate on the tumor cell membrane. The interaction between the dendron-Ppa and the tumor cell membrane results in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in the solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with the endoplasmic reticulum disrupts cell homeostasis, making tumor cells more vulnerable and susceptible to photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems.

Concentration Control of Chemosensitizing, Cell Protectiveness, and Cytotoxic Properties of Pluronics

“…Previously, we have shown that the volume of the PPO block determines the extent of perturbation exerted by Pluronic insertion into the lipid bilayer . Gu et al showed the great potential for the embedding of a bulk hydrophobic amphiphile in the lipid portion of the cell membrane to cause a cascade of apoptosis-like intracellular events leading to cell death . We suggested that PPO blocks of Pluronics also trigger a set of intracellular reactions that finally disable MDR …”

“…7 Gu et al showed the great potential for the embedding of a bulk hydrophobic amphiphile in the lipid portion of the cell membrane to cause a cascade of apoptosislike intracellular events leading to cell death. 35 We suggested that PPO blocks of Pluronics also trigger a set of intracellular reactions that finally disable MDR. 4 PEG−Glycocalyx Interaction Enhances Cell Viability.…”

Combined Self-Assembled Hendeca-Arginine Nanocarriers for Effective Targeted Gene Delivery to Bladder Cancer

“…The third permeation barrier is composed of densely packed BCa cell aggregates and a dense extracellular matrix. 5 , 23 , 24 The method by which intravesically administered drugs reach distant BCa cells solely depends on the direct penetration of drugs across the third permeation barrier in a layer-by-layer manner. 3 Multicellular spheroids (MCSs) have been proposed as an in vitro 3D-cultured tumor model to evaluate the tumor penetration of drugs.…”

New insights into ruthenium(ii) metallodendrimers as anticancer drug nanocarriers: from synthesis to preclinic behaviour

“…7,[22][23][24] Also, among the recently investigated complexes displaying promising results as anticancer drugs, the ruthenium(II)-cyclopentadienyl complex [Ru(Z 5 -C 5 H 5 )(PPh 3 ) 2 Cl] (RuCp) tested in vitro by our group in a set of cancer cell lines showed promising activity. 15 Nanomaterials such as dendrimers 25,26 and derivatives [27][28][29][30] present desirable and attractive characteristics for application in the biomedical field. Dendrimers are monodispersed globular macromolecules that can be easily functionalized, and thus can act as a drug carrier and/or target chemical groups.…”

“…Nanomaterials such as dendrimers 25,26 and derivatives 27–30 present desirable and attractive characteristics for application in the biomedical field. Dendrimers are monodispersed globular macromolecules that can be easily functionalized, and thus can act as a drug carrier and/or target chemical groups.…”