Craft of Co-encapsulation in Nanomedicine: A Struggle To Achieve Synergy through Reciprocity

Abstract

Achieving synergism, often by combination therapy via codelivery of chemotherapeutic agents, remains the mainstay of treating multidrug-resistance cases in cancer and microbial strains. With a typical core-shell architecture and surface functionalization to ensure facilitated targeting of tissues, nanocarriers are emerging as a promising platform toward gaining such synergism. Co-encapsulation of disparate theranostic agents in nanocarriers-from chemotherapeutic molecules to imaging or photothermal modalities-can not only address the issue of protecting the labile drug payload from a hostile biochemical environment but may also ensure optimized drug release as a mainstay of synergistic effect. However, the fate of co-encapsulated molecules, influenced by temporospatial proximity, remains unpredictable and marred with events with deleterious impact on therapeutic efficacy, including molecular rearrangement, aggregation, and denaturation. Thus, more than just an art of confining multiple therapeutics into a 3D nanoscale space, a co-encapsulated nanocarrier, while aiming for synergism, should strive toward achieving a harmonious cohabitation of the encapsulated molecules that, despite proximity and opportunities for interaction, remain innocuous toward each other and ensure molecular integrity. This account will inspect the current progress in co-encapsulation in nanocarriers and distill out the key points toward accomplishing such synergism through reciprocity.

Figure 1

Scheme showing the various nanocarriers that have been employed in the encapsulation of theranostic agents for facilitated delivery purposes.

Figure 2

(A) Tumor microenvironment is rich in various cells (e.g., cancer cells, cancer-associated fibroblasts, and immune cells); deposits of proteoglycans, hyaluronic acid, collagen, and laminin as an extracellular matrix (ECM); and exhibits augmented angiogenesis. (B) Three salient mechanisms of drug resistance exhibited by the tumor microenvironment: (i) presenting a diffusion barrier against the intratumoral spread of anticancer agents; (ii) curtailing the supply of oxygen and nutrients to the cancer cells that switches on the cellular resistance pathways; and (iii) alleviating the impact of radiotherapy and the immune trapping mechanism where the immune cells, albeit responding to the signaling mechanisms of cancer cells, migrate along the ECM boundary and, thus, fail to permeate the tumor.

Figure 3

Scheme showing the genetic pathways of antibiotic resistance in microorganisms after internalization: degradation by enzymes, enzymatic molecular alteration of the antibiotic rendering them ineffective, and expulsion from the cells with the help of efflux pumps.

Figure 4

Scheme showing a liposomal nanocarrier with co-encapsulated theranostic agents in its core and lipid bilayer. The four quadrants depict the typical structures noted in conventional, therapeutic, stealth, and targeted liposomes along with a range of surface-conjugated ligands.

Figure 5

Isobole showing the various drug interactions in a polymeric nanocarrier with co-encapsulated drugs “A” and “B” expressed as a combination index (CI) and calculated from an equation bearing the half-maximal inhibitor concentrations (IC₅₀) of individual drugs. CI values of <1, 1, and >1 represent synergism, additivity, and antagonism, respectively.

Figure 6

Scheme showing the various stages (1–9) of the HIV lifecycle that the ARVs co-encapsulated in nanocarriers inhibit while aiming to achieve synergism. Abbreviations: CCR5, C–C chemokine receptor type 5; CD4, cluster of differentiation 4; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; and NRTI, nucleoside reverse transcriptase inhibitor.

Figure 7

(A) Scheme showing the conventional surface-functionalized monophasic particle with a more homogeneous structural fabric in comparison to abiphasic Janus particle that elicits demarcation between its two phases, including physicochemical attributes and surface conjugation. (B) Janus particles prepared with varied shapes (e.g., snowman, mushroom, raspberry, ellipsoid, and disc) where the two distinct phases are oriented differently to each other.