Cell deformation and acquired drug resistance: elucidating the major influence of drug-nanocarrier delivery systems

Abstract

Chemo-cycles of doxorubicin-nanocarriers are reported to be highly indicative of cell deformations and are a progressive indicator of acquired drug resistance.

A graphene-sandwiched DNA nano-system: regulation of intercalated doxorubicin for cellular localization

“…DOX also interferes and disrupts the nuclear membrane leading to loss of nucleus integrity which leads to shrinkage of the nuclear area (observed for NSA of DOX at 24 h) leading towards cell death. 40 We have shown earlier 14,18 that DOX is liberated from (non-DNA-conjugated) nanosystems upon their lysosomal processing; consequently, a greater cellular accumulation of DOX-nanosystems would be responsible for releasing a greater amount of DOX intracellularly (DOX-dumping) which would dramatically improve the nuclear uptake of the drug as compared to free DOX as well as the G-DOX.…”

“…We have previously reported G-DOX and G-Cys-Fe 3 O 4 -DOX (without DNA) to demonstrate a marked increase in nuclear accumulation within 4 h of nanosystem incubation in HeLa cells. 14 Here, incorporation of nucleic acid into the NP design was correlated to lysosomal retention of the DNA-bound DOX. Taken together, the current work and our previously published results yield interesting insights into the localization control of the nanosystems and the roles of individual biomaterial components in cellular internalization and pharmacological efficiency such as the controlled release of DOX from its nanoconjugate systems, improved nanosystem biocompatibility and increased cytotoxicity.…”

“…7,15 Nanocarriers may enhance the drug delivery efficacy by inuencing the internalization mechanisms such as receptor mediated endocytosis and may further also modify the cell morphology index and potentiate acquired resistance in repetitive chemocycles. 14,16,17 Previously we have shown the nuclear DOX-enriching efficiency of modular NPs with or without cell-targeting moieties. 14,18,19 DOX is a potent chemotherapy drug which inhibits topoisomerase-II resulting in cell death.…”

“…11,12 We have addressed interactions between GO-based biomaterials and cancer cells in the past, 13 and also demonstrated that cellular deformations induced by similar multicomponent systems and post chemotherapeutic cycles in vitro implicate activation of acquired drug resistance mechanisms in cells. 14 In addition, such nanosystemarchitectures may have optimal interactions with serum proteins and inuence the protein binding affinities and nally may improve the PK. 7,15 Nanocarriers may enhance the drug delivery efficacy by inuencing the internalization mechanisms such as receptor mediated endocytosis and may further also modify the cell morphology index and potentiate acquired resistance in repetitive chemocycles.…”

“…We have recently reported that such synergetic effects are notable when the nanocarriers deliver chemotherapy drugs, inducing cellular morphological changes which may translate into plausible kinetic perturbations in uptake of anticancer drugs leading to acquired resistance specially in repeated chemotherapy cycles for DOX. 14 Thus, the objectives of this work were to: (1) enhance the drug delivery ability using GO and complementary Fe 3 O 4 multicomponent differentiating architectures, to synthesize G-DNA-DOX-Fe 3 O 4 and Fe 3 O 4 -DNA-DOX and (2) achieve controlled cellular localization using the uniqueness of DNA's traits, including intercalation capacity for DOX, (3) evaluate nanosystems for their plasma protein binding ability, (4) study cellular kinetics, cell distribution and disposition at the nucleus, lysosomal region and the cytoplasm using HeLa cells, (5) assess the morphological changes induced in HeLa cells in terms of the nuclear surface area (NSA), cell surface area (CSA), cell roundness and nuclear to cytoplasmic (N/C) ratio, and (6) to compare nanosystem efficacy with the free form of DOX.…”