The
currently available systemic chemotherapy for treating breast
cancer often results in serious systemic side effects and compromises
patient compliance. The distinct anatomical features of human breasts
(e.g., embryological origin of breast skin, highly developed internal
lymphatic and venous circulation, and the presence of mammary fat
layers) help in preferential accumulation of drugs into breasts after
topical application on breast region. This unique feature is termed
as localized transdermal delivery which could be utilized for effectively
delivering anticancer agents to treat breast cancer and reducing the
systemic side effects by limiting their presence in blood. However,
the clinical effectiveness of this drug delivery approach is highly
limited by barrier properties of skin reducing the permeation of anticancer
drugs. In the present work, we have developed high permeation vesicles
(HPVs) using phospholipids and synergistic combination of permeation
enhancers (SCOPE) to improve the skin permeation of drugs. Docetaxel
(DTX) was used as a model drug for hypothesis testing. The optimized
SCOPE mixture composed of sodium oleate/sodium lauryl ether sulfate/propylene
glycol in 64:16:20% w/w ratio. DTX HPVs were prepared using phospholipid:
SCOPE, 8:2% w/w ratio. DTX HPVs exhibited as a uniform deformable
vesicles with size range 124.2 ± 7.6 nm, significantly improved
skin permeation profile, and sustained drug release until 48 h. Superior
vesicle deformability, better vesicle membrane fluidization, and SCOPE
mediated enhancement in skin fluidization were the prime factors behind
enhancement of DTX permeation. The improved cellular uptake, reduced
IC50 values, and higher apoptotic index of DTX HPVs in
MCF-7 and MDA-MB-231 cells ensured the therapeutic effectiveness of
HPV based therapy. Also, HPVs were found to be predominantly internalized
inside cells through clathrin and caveolae-dependent endocytic pathways.
Bioimaging analysis in mice confirmed the tumor penetration potential
and effective accumulation of HPVs inside tumors after topical application.
In vivo studies were carried out in comparison with marketed intravenous
DTX injection (Taxotere) to compare the effectiveness of topical chemotherapy.
The topical application of DTX HPV gel in tumor bearing mice resulted
in nearly 4-fold tumor volume reduction which was equivalent to intravenous
Taxotere therapy. Toxicity analysis of DTX HPV gel in comparison with
intravenous Taxotere dosing showcased remarkably lower levels of toxicity
biomarkers (aspartate transaminase (AST), alanine transaminase (ALT),
blood urea nitrogen (BUN), and creatinine), indicating improved safety
of topical chemotherapy. Overall results warranted the effectiveness
of topical DTX chemotherapy to reduce tumor burden with substantially
reduced risk of systemic toxicities in breast cancer.